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Review

Re-Sensitizing Cancer Stem Cells to Conventional Chemotherapy Agents

by
Mariyam Kim
,
Laura Bakyt
,
Azamat Akhmetkaliyev
,
Dana Toktarkhanova
and
Denis Bulanin
*
Department of Biomedical Sciences, Nazarbayev University School of Medicine, Astana 010000, Kazakhstan
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2023, 24(3), 2122; https://doi.org/10.3390/ijms24032122
Submission received: 30 November 2022 / Revised: 26 December 2022 / Accepted: 4 January 2023 / Published: 20 January 2023
(This article belongs to the Special Issue Combating Drug Resistance in Cancer—from Novel Biomarkers to Enhanced Therapeutic Efficacy)
Versions Notes

Abstract

:
Cancer stem cells are found in many cancer types. They comprise a distinct subpopulation of cells within the tumor that exhibit properties of stem cells. They express a number of cell surface markers, such as CD133, CD44, ALDH, and EpCAM, as well as embryonic transcription factors Oct4, Nanog, and SOX2. CSCs are more resistant to conventional chemotherapy and can potentially drive tumor relapse. Therefore, it is essential to understand the molecular mechanisms that drive chemoresistance and to target them with specific therapy effectively. Highly conserved developmental signaling pathways such as Wnt, Hedgehog, and Notch are commonly reported to play a role in CSCs chemoresistance development. Studies show that particular pathway inhibitors combined with conventional therapy may re-establish sensitivity to the conventional therapy. Another significant contributor of chemoresistance is a specific tumor microenvironment. Surrounding stroma in the form of cancer-associated fibroblasts, macrophages, endothelial cells, and extracellular matrix components produce cytokines and other factors, thus creating a favorable environment and decreasing the cytotoxic effects of chemotherapy. Anti-stromal agents may potentially help to overcome these effects. Epigenetic changes and autophagy were also among the commonly reported mechanisms of chemoresistance. This review provides an overview of signaling pathway components involved in the development of chemoresistance of CSCs and gathers evidence from experimental studies in which CSCs can be re-sensitized to conventional chemotherapy agents across different cancer types.

1. Introduction

Despite significant progress in cancer therapy with conventional anti-cancer chemotherapy agents, a substantial portion of patients experiences disease progression, metastasis, and relapse [1]. For decades, tumor formation and propagation mechanisms were explained by the stochastic clonal expansion model, proposed in 1976 by Dr. Nowell, according to which cells accumulate mutations with time and the one with the most aggressive phenotype drives tumor formation [2]. Hence, any of the tumor cells may potentially transform into malignant ones. Evidence suggests that this model may be accurate for several cancers. However, it is still far from being ideal. A growing body of evidence suggests a more plausible hierarchical model in which different populations of cells exist within a tumor with variable potency of tumorigenesis [3]. The most potent fraction exhibits stem cell-like properties of self-renewal and differentiation capacity called cancer stem cells (CSCs) [4]. These cells are theoretically able to regenerate the parental tumor. The hierarchical theory was first proposed after identifying leukemia-initiating cells (LICs) in acute myeloid leukemia. LICs represented only a small fraction of cells (0.2–100/106 leukemic blasts) but were able to re-establish tumors in immunodeficient mice [4]. This work started the interest in exploring the presence of CSCs in other hematological and solid malignancies. In 2001, brain CSCs were identified, followed by breast, melanoma, and many other cancers [2]. To date, CSCs are still being determined.
Distinct cell surface markers are used as a surrogate to identify cells with functional properties of CSCs. CD133 or prominin-1, a transmembrane glycoprotein, is used to select highly chemo- and radioresistant glioma cells subset [3]. Expression of CD133 was also a negative predictor of the outcome for patients. Interestingly, overexpression of CD133 turned hepatocellular carcinoma cells, prostate cancer cells, and melanoma cells into CSCs.
Breast CSCs highly express CD44 and are commonly highly resistant to radiotherapy, likely due to enhanced free radical scavenging mechanisms [5]. The same marker was proposed for head and neck CSCs identification; however, its use is more controversial. Recent evidence suggests that a combination of CD44 and CD133 in colorectal cancer is associated with a sevenfold increase in tumorigenicity compared to CD133 alone (1.45 times). Gastric cancer cells expressing CD44 showed enhanced self-renewal capacity and, interestingly, could give rise to a subpopulation of CD44-cells [5]. Aldehyde dehydrogenase appears to be more uniformly expressed by different CSCs. The Mammalian ALDHs family consists of 18 isotypes. It was initially proposed to be highly expressed in hematopoietic stem cells but later was identified in breast CSCs, head and neck squamous cell carcinoma, gliomas, etc. [5,6,7]. ALDH overexpression was shown to be linked to poor outcomes [8].
EpCAM is another surface marker and a glycoprotein expressed on healthy epithelial cells. It gained recognition for identifying CSCs of breast, colon, hepatocellular and pancreatic cancers [8]. As CSCs closely resemble normal stem cells, it is not surprising that embryonic transcription factors such as Oct4, Nanog, and SOX2 may be re-activated and considered internal markers of CSCs [9]. Oct4+ cells exhibit more stem cell-like properties, such as enhanced self-renewal, tumorigenicity, and chemotherapy resistance. It was used to identify CSCs in breast, non-small cell lung cancer, gastrointestinal cancers, and hepatocellular cancer [10]. Nanog is generally required to support pluripotency and is downregulated in differentiated cells. Evidence suggests that Nanog expression correlates directly with the activity of cancer stem cells in non-small cell lung cancer, functioning like a switch between CSCs and differentiated cancer cells [11]. Sox2 is essential for early embryonic development and supports stem cells’ undifferentiated state. In cancer stem cell research, it is considered a marker of stemness. Sox2 was proposed to be used to identify bladder cancer stem cells as well as non-small cell lung carcinomas [12].
Numerous studies claim that CSCs play a critical role in cancer propagation, recurrence, and chemotherapy resistance [6,7]. Cancer stem cells are inherently more resistant to chemotherapy than their differentiated counterparts. Traditional chemotherapy targets the bulk of differentiated cancer cells, effectively reducing the tumor mass but selecting highly resistant CSCs that can regenerate the tumor. These cells then drive tumor relapse and are essential constraints to a disease-free state. Studies show that radiation therapy triggers the upregulation of embryonic transcription factors such as Sox2, Nanog, and Oct4 in breast cancer cells and induces a stem cell-like state [6,7]. Consistent with this observation, another study reported similar findings in hepatocellular carcinoma cells [13]. Understanding mechanisms driving chemoresistance is crucial for effectively targeting CSCs and sensitization to existing chemotherapy. This review will provide an overview of commonly reported mechanisms possessed by cancer stem cells that are implicated in chemotherapy resistance and discuss current target-specific therapies.
In addition, this article aims to provide an information about mechanisms and specific components of the signaling pathways to be involved in the development of chemoresistance of CSC. Moreover, it summarizes existing experimental studies demonstrating how pathway inhibitors may be used to re-sensitize CSCs to conventional chemotherapy by targeting particular pathway and cell environment components.

2. Notch Signaling Pathway

As an evolutionarily conserved route, the Notch signaling pathway plays a crucial role in the regulation of communication between neighboring cells during different stages of embryogenesis, differentiation, and apoptosis [14]. Notch signaling operates through the interaction of four Notch receptors (1–4) with two distinct families of ligands, Jagged (1–2) and Delta-like ligands (1, 3–4). Notch receptor, a heterodimer, contains extracellular, transmembrane, and intracellular domains. Upon binding the ligand, the receptor undergoes a conformational change with subsequent activation of the two-step proteolytic cleavage. Disintegrin, metalloproteinase (ADAM), and γ-secretase mediate the first and second cleavage, respectively. The latter releases an active intracellular domain, which translocates to the nucleus and regulates target gene expression [15]. Well-studied targets of the Notch pathway, Hes-1 and Hey-1, play an essential role in cell fate decisions to commit to certain cell types. Its functions were shown to be implicated in different aspects of cancer biology: promotion of angiogenesis, metastasis, evasion of the immune system, and promoting and maintaining the stemness of CSCs in certain cancers including but not limited to esophageal, skin squamous cell carcinomas, colorectal, lung, certain B- and T-cell leukemias, and breast cancer [16].
Vinson et al., reported that compared to the general pool of cancer cells, CSCs of colorectal cancer showed an increase of Notch signaling for up to 10–30 times with upregulation of HES1, Notch-1, and Jagged-1 expression [17]. Therefore, it was proposed to promote self-renewal through interaction with p27 and migration through involvement in epithelial-to-mesenchymal transition (EMT) via negative regulation of E-cadherin and β-catenin expression [18]. Moreover, Notch directly regulates c-Myc and cyclin D expression, which are known to be cell-cycle regulators [19]. Consistent with these findings, studies targeting HES-2 with shRNA resulted in a loss of stem cell-like properties and further differentiation of CSCs. This may indicate that Notch negatively regulates differentiation in breast cancer cells, resulting in the maintenance of stem cell state contributing to tumor formation [19].
Recent evidence suggests that the Notch pathway contributes to chemoresistance as well. Exposure of breast cancer cell lines to doxorubicin, docetaxel, and therapy with selective estrogen receptor modulators (SERMs) resulted in selecting a chemoresistant population of cells with increased expression of Notch 1 and Notch 4 [20]. Similarly, targeting Notch 1 with Psoralidin, these cells exhibited suppressed growth and increased apoptosis in animal models [20]. These findings are consistent with the work of Below and colleagues, who suggest that ovarian CSCs resistance is driven by Notch [21]. Inhibition of this pathway resulted in the sensitization of cancer cells to cisplatin and suppressed stemness. It was also demonstrated that the upregulation of Hes1 is responsible for stem cell-like properties of ovarian CSCs and subsequently enhanced chemotherapy resistance [22]. Additionally, targeted inhibition of the Notch pathway restored the sensitivity of lung CSCs to Gefitinib [23]. All of these findings suggest that inhibition of the Notch pathway may help to sensitize CSCs and increase the efficacy of classical anti-cancer therapy. Additional details of the Notch signaling pathway components in chemoresistance of CSCs is shown below in Table 1.
Table
Table 1. Summary of evidence for the role of Notch signaling in chemoresistance of cancer stem cells.
Table 1. Summary of evidence for the role of Notch signaling in chemoresistance of cancer stem cells.
Cancer TypeInhibitorExperimental EvidenceReferences
Colorectal cancerDAPT, a gamma-secretase inhibitorThe decreased growth of 5-FU and oxaliplatin-resistant cells in vivo and in vitro[24]
DLD-1 and DAPT, compound E Sensitized and significantly enhanced taxane-induced mitotic arrest and apoptosis both in vitro and in vivo[25]
GSI-34, a gamma-secretase inhibitorSignificantly sensitized the cells to oxaliplatin- and 5-fluorouracil through apoptosis [26]
DLL4 inhibitorEnhanced oxaliplatin action and decreased activity of prosurvival pathways. Combination with irinotecan treatment reduced the frequency of CSCs[27]
MedulloblastomaGamma-secretase inhibitor-18Induced apoptosis in vitro in nestin-positive medulloblastoma cells with stem cell-like properties [28]
Ovarian cancerGSI, siRNA Dramatically increased platinum-based therapy sensitivity both in vivo and in vitro[29]
shRNA knockdownResulted in the sensitization of ovarian cancer cells exhibiting stem cell markers to carboplatin in vitro[30]
InsulinomaDAPTReversed resistance to 5-FU in vitro tumor proliferation in vivo was significantly decreased when the drugs were used in combination compared to their use as single agents[31]
Breast cancerGSIEnhanced doxorubicin antitumor activity in vitro and in vivo[32]
PsoralidinThis resulted in growth inhibition and induction of apoptosis in breast CSCs resistant to doxorubicin[22]
Notch1 monoclonal antibodiesSensitized triple-negative breast CSCs to docetaxel [33]
Esophageal cancersiRNAReduced levels of 5-FU resistance in vivo[34]
Prostate cancer GSIEnhanced the antitumor effect of docetaxel in prostate cancer stem-like cells[35]
siRNA, compound E, GSIDepleted chemoresistant prostate cancer-initiating cells in vitro and in vivo[36]

3. The Wnt Pathway

The Wnt signaling pathway is another important signaling pathway that plays a role in embryonic development, maintenance of tissue homeostasis, self-renewal, as well as differentiation [37]. There are three main WNT pathways: the canonical, involving β-catenin, T cell-specific transcription factor (TCF), and lymphoid enhancer-binding factor (LEF), non-canonical—β-catenin independent, and non-canonical responsible for intracellular calcium regulation [38]. In humans, the Wnt family comprises 19 secretory lipid-modified glycoproteins, which interact with around ten isoforms of Frizzled receptors and different co-receptors, mainly low-density receptor-related protein 5/6 [38]. Interaction with ligands in the canonical pathway determines the stability of the critical player β-catenin [39]. In the absence of a ligand, β-catenin is phosphorylated and further undergoes degradation by the proteasome. However, upon ligand binding, β-catenin escapes destruction and accumulates in the cytoplasm. This allows subsequent β-catenin translocation to the nucleus and activation of transcription complex consisting of T-cell specific transcription factor and enhancer-binding factor (TCF-LEF). As a result, genes involved in cell fate determination and proliferation are differentially regulated. Given the function, it is not surprising that the WNT pathway is one of the most mutated pathways of all, and it contributes to the formation of solid and hematological malignancies, including colorectal, hepatocellular cancers, melanoma, AML, CLL, etc. [40,41]. Several constituents of the Wnt pathway, including LEF1, TCF-4, β-catenin, and cyclin D1, are upregulated in the CSCs compared to non-CSCs [42]. Both canonical and non-canonical WNT pathways were reported to play important roles in developing and maintaining CSCs and chemotherapy resistance. Pancreatic CSCs resistant to 5-FU showed aberrant regulation of the WNT pathway [43]. Pery and colleagues stated that leukemia stem cells with upregulated WNT pathway expanded under the stress of conventional chemotherapy, whereas targeted inhibition resulted in reduced tumorigenic activity [44]. Similar findings were reported in breast cancer studies. Inhibition of WNT signaling reduced the burden of self-renewal properties of CSCs, decreased expression of CSCs markers ALDH and CD44, and suppressed growth in vitro and in vivo [44]. Interesting findings were reported by Martins-Neves et al., who showed that low-dose doxorubicin used for the treatment of osteosarcoma, induced increased WNT signaling, measured by TCF/LEF-luciferase transcriptional activity and exhibited resistance. When treated with a WNT pathway inhibitor, these cells had a significantly decreased cell viability and decreased expression of stem cell markers [45]. Chemoresistant CD 133+ neuroblastoma cells were also reported to upregulate the Wnt pathway upon treatment with doxorubicin, which was proposed to contribute to enhanced survival. In the presence of pathway inhibitors, the number of live cells in the chemoresistant group significantly dropped [46]. Further, the role of different inhibitors in chemoresistance of CSCs are shown in Table 2.
Table
Table 2. Summary of evidence for the role of Wnt signaling in chemoresistance of cancer stem cells.
Table 2. Summary of evidence for the role of Wnt signaling in chemoresistance of cancer stem cells.
Cancer TypeInhibitorExperimental EvidenceReferences
Ovarian cancerXAV-939 Effectively reversed cisplatin chemoresistance in vitro[47,48]
CCT036477Inhibition of β-catenin transcriptional activity sensitized previously resistant cells to carboplatin in vitro[49]
ICG-001 Sensitized cells to cisplatin and decreased the number of cancer-initiating cells [50]
NeuroblastomaXAV-939 and ICG-001Combination treatment with doxorubicin enhanced cytotoxicity against cancer stem-like cells[49]
XAV-939Significantly enhanced the sensitivity of cells to doxorubicin in both 2D and 3D culture systems[51]
GliomasFRP4Increased apoptosis in combination with doxorubicin/cisplatin and significantly decreased number of glioma stem cells [52]
Colon cancerXAV939 Significantly increased apoptosis induced by 5-FU/DDP and decreased expression of stemness markers in vitro[53]
RNAi of TCF4Significantly sensitized CRC cells to radiotherapy[54]
IC-2Reduced sphere numbers of CD44 high cells and sensitized CSCs to 5FU in vitro[55]
Head and neck squamous cell carcinoma cellsXAV939 Combination with cisplatin acted synergistically to abrogate chemoresistance by increasing DNA damage in cells with CSCs phenotype[56,57]
HC-1Sensitized and significantly enhanced the cytotoxicity of 5-FU in CD44 CSCs [58]
sFRP4Inhibited HNSCC proliferation and increased efficacy of doxorubicin and cisplatin via an increase in apoptosis[59]
Hepatocellular carcinomaLentiviral miRNA against β-cateninSignificantly diminished growth of cisplatin chemoresistant colonies consisting of progenitor-like cells [60]
Nasopharyngeal carcinomaICG-001 Effectively inhibited the growth of a CSC-like population in combination with cisplatin[61]
ALLICG-001 Induced differentiation of ALL CSCs and sensitized them to VDL chemotherapy[62]
CMLICG-001 Eliminated drug-resistant CML leukemia-initiating cells and sensitized resistant cells to imatinib[63]
Breast cancer ICG-001 Decreased emergence of drug-resistant, highly aggressive cancer stem-like phenotype in vitro[64]
CWP232228Affected chemoresistant BCSC maintenance[65]

4. Hedgehog Signaling Pathway

The Hedgehog (Hh) signaling pathway initially identified in Drosophila melanogaster regulates essential processes during embryonic development, such as proliferation, survival, patterning, migration, and cell fate determination by altering protein trafficking, gene expression, and protein–protein interactions [66]. However, the HH pathway is subsequently silenced later in development in most tissues except for limited organ systems such as the central nervous system, the lungs, theca, and Leydig cells, which continue to rely on it for repair and homeostasis [67].
There are three primary HH homologs, namely Sonic Hedgehog (Shh), Indian Hedgehog (Ihh), and Desert Hedgehog (Dhh), that differ in the pattern of spatial and temporal expression and distribution. They subsequently undergo maturation through several autoproteolytic steps and covalent modifications before an active ligand is released [68]. Signaling is initiated when a ligand binds to a 12-pass transmembrane receptor called Patched (PTCH1), which in the absence of a ligand, represses GPCR-like protein Smoothened (SMO). Upon binding of HH ligand, SMO translocate to the plasma membrane and subsequently weakens the interaction of suppressor of fused homolog (Sufu) and glioma-associated oncogene homolog (Gli) transcription factors [69]. This alters the expression of Gli family proteins’ target genes such as SNAIL, c-MYC, BCL-2, and Prominin-1 (CD133) [70].
Given its many roles and target genes, it is not surprising that dysregulation of the pathway in a lifetime can potentially contribute to cancer development. HH pathway was proposed to be responsible for a cell population with stem cell-like properties, supporting self-renewal capacities and upregulating stemness-determining genes [69,70]. One of such master determinants, Nanog, is directly targeted by the HH pathway. Moreover, it drives expressions of Oct4, Bmi1, and SOX2 [71]. Numerous studies reported that small molecule pathway inhibitor cyclopamine effectively reduced self-renewal potential, promoted apoptosis, and prevented relapse in different cancers, including acute and chronic myeloid leukemia, breast cancer, small and non-small cell carcinoma, and pancreatic and prostate cancer [72,73,74,75].
It was also proposed to be implicated in cancer stem cell resistance to chemotherapy in different cancer types [76,77,78,79,80,81,82,83,84,85,86,87,88,89]. Inhibition of HH pathway was achieved in cyclopamine-sensitized paclitaxel-resistant breast cancer cells in vitro, presumably through antagonizing Smo action. Moreover, the tumor size decreased in the xenograft model [76]. A similar observation was reported in doxorubicin-resistant breast cancer cells, further supporting the idea of the HH pathway involvement in resistance development to conventional chemotherapy agents [77]. Another pathway inhibitor, GANT61, a derivative of hexahydro pyrimidone, selectively inhibits the action of GLI transcription factors. It was also demonstrated that GANT61 decreased resistance to the FOLFOX regimen in colorectal cancer cells [87]. Additionally, vismodegib, another selective inhibitor of the pathway, sensitized tamoxifen-resistant breast cancer cells and inhibited the growth of tumors in xenograft models [80]. Evidence supporting HH pathway implication in the chemoresistance of cancer stem cells is summarized in Table 3.
Table
Table 3. Summary of evidence for the role of Hedgehog signaling in chemoresistance of cancer stem cells.
Table 3. Summary of evidence for the role of Hedgehog signaling in chemoresistance of cancer stem cells.
Cancer TypeInhibitorExperimental EvidenceReferences
Breast cancerCyclopamineEnhanced paclitaxel-induced cell death in vitro and decreases tumor growth in a xenograft model[76,77]
Sensitized doxorubicin-resistant breast cancer cells evident from diminished tumor size in the xenograft model of nude mice[78,79]
VismodegibInhibited growth of tumors in tamoxifen-resistant xenografts
Downregulated CSC markers and sensitized cells to docetaxel		[80,81]
Pancreatic cancer CyclopamineRestored gemcitabine sensitivity in gemcitabine-resistant cells[82,83,84,85,86]
Smo knockdownDownregulated CSC markers
Gli1 shRNADownregulated CSC markers
Colorectal cancerGANT61Decreased the resistance to 5-FU, irinotecan, and oxaliplatin [87,88]
Glioblastoma multiformeCyclopamineCyclopamine potentiated temozolomide treatment in glioblastoma cell lines by inducing apoptosis[89,90,91,92,93,94]
Prostate cancer CyclopamineEnhanced paclitaxel-mediated growth suppression in previously resistant cells[95,96]
Gastric cancer CyclopamineSignificantly improved the tumor response to the drug in oxaliplatin-resistant gastric CSCs[97]
Gli1 knockdownEnhanced the efficacy of chemotherapy and significantly reduced self-renewing capacity [98]

5. Microenvironment

Cancer stem cells share a lot of similarities with normal adult stem cells. However, the latter reside at locations less exposed to external stimuli and damage. For example, intestinal stem cells reside at the bottom of the crypt, mammary stem cells are away from the lumen of the acinus, and hematopoietic stem cells are shielded with the bone. Like the normal counterparts, CSCs have their protected microenvironments, sometimes called “niches” [99,100]. The niche is a three-dimensional structure constituted by collagens, various glycoproteins, and other ECM components which provide tissue architecture, allow communication and create a barrier [101]. Numerous studies proposed that niches are essential for regulating stem cell state, prevention of differentiation, and response to treatment via cell-to-cell or extracellular matrix components-to-cell communication [40,102]. The complex interplay between CSCs and ECM components, stroma, tumor-associated fibroblasts, and hypoxic state balances proliferation-promoting and inhibiting signals to maintain homeostasis. However, under environmental stress in the form of cytotoxic therapy, tumor cells, and the microenvironment may respond in various ways, which might lead to chemoresistance development.
A growing body of evidence supports the idea that hypoxia is a powerful driver of therapeutic resistance [103,104,105]. This was proposed to result from the upregulation of stemness developmental pathways discussed above. Alternatively, chemoresistance may be induced by miRNA regulation of hypoxia-inducible factors [103]. For example, according to Xiao et al., under hypoxic conditions, miR-520-f-3p promotes stem cell properties and resistance to sorafenib in hepatocellular CSCs [106]. Roscigno et al., reported similar results with colleagues, who showed that another miRNA, miR-24, regulates stemness and reduces chemotherapy-induced apoptosis in breast CSCs [107].
CSCs were also reported to form unique immunosuppressive niches under the pressure of chemotherapy through increased Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) secretion from anti-inflammatory M2- macrophages [108]. At the same time, CSCs show enhanced production of pro-inflammatory cytokines such as IL-1β, IL-6, IL-8, and CCL2. The latter stimulates CCR2+ monocytes, which function as a precursor to the immunosuppressive microenvironment [109]. Similar to macrophages, fibroblasts may be converted to cancer-associated fibroblasts (CAFs) under the influence of TGF-β and platelet-derived growth factor (PDGF). Studies suggest that CAFs actively participate in resistance development via enhanced secretion of ECM components and metastasis through the production of fibronectin, periostin, and metalloproteinases, thereby acquiring mesenchymal properties [110].
Moreover, recent studies have shown that surrounding stroma consisting of endothelial cells and smooth muscle cells that nourish the tumor is commonly driven in a protumorigenic wound-healing state. Paracrine signaling and cross-talk in the niche promote the secretion of angiogenic factors and hence survival [111]. Ferguson et al., demonstrated that leukemia CSCs need CD98 for successful perivascular adhesion, and treatment with anti-CD98 antibody enhances response to therapy [112]. Similar results were obtained from another study, where aggressive chemoresistant leukemias were sensitized to tyrosine kinase inhibitors upon treatment with adhesion signal inhibitors [113]. Additional data were gathered on tumor microenvironment role in chemoresistance of CSCs in Table 4.
Table
Table 4. Summary of evidence for the role of tumor microenvironment in chemoresistance of cancer stem cells.
Table 4. Summary of evidence for the role of tumor microenvironment in chemoresistance of cancer stem cells.
Cancer TypeInterventionExperimental EvidenceReferences
Glioblastoma multiformeHypoxiaHypoxia induced increased expression of stemness markers (CD133, Sox-2, Bmi-1, podoplanin, nestin) and chemoresistance-associated markers
(MGMT, MRP1, MDR-1, TIMP-1, Lamp1)		[114]
Anti-GPR77 antibodyReduced tumor formation and restored sensitivity to chemotherapy by targeting CD10+GPR77+ cancer-associated fibroblasts[115]
Breast cancer CAFs treated with Smo-i (HH inhibitor) Reduced metastatic growth and sensitized to chemotherapy with taxanes [86]
HIF-2α overexpressionInduced expression of stem cell markers c-Myc, OCT4, and Nanog and the resistance to paclitaxel [86]
IL-6 antibodyRe-sensitized CSCs with acquired trastuzumab resistance[116]
IL4DM, IL-4 receptor antagonistCombined with fulvestrant for ER+ CSCs and with docetaxel for triple-negative CSCs, potentiated cell death, and chemotherapeutic action [117]
Colorectal cancer Antibody against IL-17A Augmented the cytotoxic efficacy of chemotherapy with 5-FU and Oxaliplatin [118]
Co-culture with CAFs secreting TGF-b2 and IL-6Increased resistance to 5-fluorouracil/oxaliplatin due to upregulation of Gli2[93]
MFG-E8 produced by tumor-associated macrophagesThe presence of MFG-E8 suppressed cisplatin-induced caspase-3 mediated apoptosis in vitro[119]
MelanomaHypoxiaPromoted partial resistance to dacarbazine, increased self-renewal capacity, and promoted invasion through upregulation of Nodal [120]
Ovarian cancerHIF-2α knockdownSubstantially decreased the resistance of ovarian cancer stem cells to adriamycin; HIF-2α overexpression restored chemoresistance[121]
Head and neck cancerPeriostin from CAFsCAF-secreted
periostin which activates protein kinase seven and enhances erlotinib chemoresistance		[122]
Glioma FibronectinCulture with increasing fibronectin concentrations increased chemoresistance to carmustine in glioma stem cells[123]

6. Autophagy

The stress of chemotherapy and hypoxia drives CSCs to alter metabolism and utilize alternative sources for energy production to maintain viability. One of the evolutionarily conserved mechanisms potentially implicated in enhanced survival and chemoresistance is autophagy. It is an essential housekeeper system that is important for cellular homeostasis. Intracellular proteins and organelles are degraded in autolysosomes that form upon the fusion of autophagosomes with lysosomes. Contents are degraded by lysosomal enzymes of the cathepsins family [124].
Autophagy was reported to enhance tumorigenesis and maintenance of stemness in multiple cancers, including colorectal, hepatocellular, CNS tumors, and melanoma [125,126,127,128]. Targeted blocking of autophagy in ex vivo studies has been shown to decrease stem cell properties of breast CSCs as well as a result in inhibited growth in vivo [129,130]. Chemotherapeutic agents such as oxaliplatin were shown to enrich the resistant CSCs pool in colorectal cancer [131]. Inhibiting autophagy in resistant CSCs dramatically increased susceptibility to conventional chemotherapeutic drugs and decreased stem cell properties. In glioblastoma, multiform targeted inhibition of the main autophagy regulator, ATG4B, has sensitized CSCs to radiotherapy. Smith et al., suggested that a particular subtype of autophagy, namely mitophagy, is required for the self-renewal of CSCs [132]. Mitophagy is the selective degradation of mitochondria to maintain low levels of oxidative phosphorylation hence leaving the cell dependent on glycolysis as a significant source of ATP. This is proposed to contribute to a slow self-renewing state. Anti-cancer medications induce autophagy, which in many cases promotes tumorigenesis and resistance to therapy. It was reported that autophagy promotes chemoresistance in ovarian CSCs treated with cisplatin [133].
Moreover, selective inhibition of autophagy in cisplatin-resistant CSCs resulted in enhanced apoptosis [134,135]. In chemoresistant non-small cell carcinoma xenograft tumors, combination treatment with autophagy inhibitor decreased the growth of the tumor and promoted apoptosis more effectively [136]. ER-positive breast cancer was also reported to be sensitized to tamoxifen after inhibition of autophagy [137]. Similar results were reported in previously enzalutamide-resistant prostate cancer and imatinib-resistant gastrointestinal stromal tumors [138,139]. The importance of autophagy microenvironment in chemoresistance of CSCs is demonstrated in Table 5.
Table
Table 5. Summary of evidence for the role of autophagy microenvironment in chemoresistance of cancer stem cells.
Table 5. Summary of evidence for the role of autophagy microenvironment in chemoresistance of cancer stem cells.
Cancer TypeIntervention/InhibitorExperimental EvidenceReferences
CMLLys05Sensitized leukemia CSCs to tyrosine-kinase inhibitor treatment in vitro and in vivo[140]
Chloroquine
RNAi		Combination with tyrosine kinase inhibitor treatment results in almost complete eradication of CML CSCs[141]
LV-320, ATG4B inhibitorSensitized imatinib-nonresponding progenitor cells to tyrosine-kinase inhibitors[142]
Endometrial cancerChloroquine, 3-MAEnhanced sensitivity of endometrial CSCs to paclitaxel[143]
Colon cancer36-077, a novel autophagy inhibitorCombined treatment with 5-FU enhanced cytotoxic effect in cells expressing stemness markers [144]
Cdx1 siRNASensitized colon CD44+ CSCs to the therapeutic effect of paclitaxel [145]
Knockdown of Atg5Autophagy deficiency reversed the protective effect of autophagy and enhanced the action of oxaliplatin[131]
BNIP3L silencing (mitophagy)Enhanced the sensitivity of CSCs to doxorubicin[146]
Atg5 silencingPromoted apoptosis in previously resistant CSCs[147]
Breast cancerChloroquineDiminished DNA repair response in CSC, thereby increasing carboplatin sensitivity[148]
Reduced ‘stemness’ markers expression and sensitized ALDH+ CSCs to doxorubicin and docetaxel [149]
GlioblastomaChloroquineSignificantly increased the therapeutic effect of bevacizumab [150]
Ovarian cancerChloroquine
CRISPR-Cas9		Enhanced cytotoxicity effect of carboplatin in vitro and decreased its tumorigenic abilities in vivo[151]
Non-small cell lung carcinomaChloroquineCombination treatment with cisplatin decreased the expression of stemness markers in CD133+ cells and enhanced its antitumor action[136]
Gastric cancer ChloroquineEnhanced inhibitory action of 5-FU on CSCs [152]
Bladder cancerChloroquineSignificantly increased apoptotic cell death in previously gemcitabine and mitomycin-resistant cells[153]
Pancreatic cancershATG5, shATG7Enhanced the sensitivity of pancreatic CSCs to gemcitabine [154]

7. Epigenetics

Over the last decades, significant progress has been made in cancer genetics, identifying mutations and chromosomal alterations responsible for tumorigenesis and cancer progression [155]. A great body of evidence supports the idea that epigenetic changes such as DNA methylation, histone modifications, miRNAs, and chromatin remodeling might also be significant in the tumor initiation process [156,157,158]. Past advancements shifted the narrative to consider carcinogenesis a dynamic process of complex interactions between epigenetic and genetic factors. Since epigenetic alterations are important for the programming of cells during development, abnormal regulation of these processes was proposed to be involved in transforming normal stem cells to cancer stem cells with distinct properties such as enhanced chemotherapy resistance [159,160,161]. Chemotherapy-resistant cancer stem cells were commonly reported to have altered DNA methylation patterns. Therefore, hypomethylating agents were tested to restore sensitivity. Indeed, platinum-resistant ovarian cancer stem cells had significantly higher DNMT 3A and 3B expression than their non-resistant counterparts [162]. These cells were further re-sensitized to chemotherapy and essentially depleted in the presence of second-generation DNA methyltransferase inhibitor, SGI-110, supporting the role of epigenetic modification in the chemoresistance of CSCs.
miRNAs, small noncoding RNA molecules, are important regulators of gene expression and were also reported to be aberrantly expressed in cancer stem cells. For example, pancreatic cancer stem cells resistant to gemcitabine significantly downregulated specific clusters of miRNA 17-92 [163]. Overexpression of miR17-92 restored chemosensitivity to gemcitabine, abraxane, and 5-FU. Sensitivity to gemcitabine were also demonstrated in TSA, SAHA and for the pancreatic cancer specific inhibitors [164,165]. Interestingly, when differentiated cancer cells had been knocked down of miR 17-92 by an antisense inhibitor, they started to express stemness-related markers such as CD133 and ABC transporters and exhibited enhanced tumorigenesis. Another miRNA, miR-34a, was also found to be downregulated but in another cancer type. Overexpression of miR-34a in chemoresistant breast cancer stem cells showed to sensitize them to paclitaxel [166]. Authors suggest that this effect is due to the downregulation of Notch1 signaling pathway-related proteins, which indicates that epigenetic mechanisms may indirectly contribute to the chemoresistance of CSCs through the regulation of developmental pathways. These findings were consistent with another study where breast CSCs were re-sensitized to doxorubicin by ectopic expression of miR-34a [167]. Several other epigenetic mechanisms reported to be involved in the pathogenesis of chemoresistance of CSCs are summarized in Table 6.
Table
Table 6. Summary of evidence for the role of epigenetics microenvironment in chemoresistance of cancer stem cells.
Table 6. Summary of evidence for the role of epigenetics microenvironment in chemoresistance of cancer stem cells.
Cancer TypeInhibitorExperimental EvidenceReferences
Ovarian cancerSGI-110Low-dose DNA methyltransferase inhibitor limited the tumor-initiating capacity of stem cells and sensitized them to platinum-based therapy, promoting differentiation[162]
Pancreatic cancerOverexpression of miR-17-92Increased sensitivity to gemcitabine, abraxane, and 5-FU in vitro, possibly through targeting Alk4[163]
TSA and SAHAEnhanced action of gemcitabine against cancer stem cells[164]
UNC0638, G9a specific inhibitor Sensitized previously resistant stem cells to gemcitabine[165]
Breast cancermiR-34a overexpressionSignificantly increased cytotoxic effect of paclitaxel (PTX) on breast cancer stem cells, likely through downregulation of the Notch1 pathway[166]
Ectopic expression of miR-34a Sensitized CSCs to doxorubicin[167]
microRNA-200 knockdownReversed paclitaxel resistance and stem cell properties[168]
miR-873Adriamycin resistance was attenuated by activation of miR-873 signaling [169]
miR-128Ectopic expression of miR-128 enhanced cytotoxicity of doxorubicin through the downregulation of
Bmi-1 and ABCC5 protein levels		[170]
Lnc-LBCS overexpressionLnc-LBCS suppresses the chemoresistance of BCSCs in vitro and in vivo to gemcitabine and cisplatin[171]
Adenoid cystic carcinomaVorinostatReduced the load of CSCs in vivo and in vitro alone and combination with cisplatin effectively depleted CSC[172]
Glioblastoma multiformeKDM2B knockdownEnhanced cytotoxic effect in combination with both lomustine and etoposide augmented chemotherapy-induced apoptosis [173]
Testicular cancerGSKJ4Treatment with the specific demethylase inhibitor resulted in the sensitization of the cells to cisplatin [174]
CMLSIRT1 knockdown Enhanced activity of imatinib, increased apoptosis in leukemia stem cells in vitro and in vivo[175]

8. The Heterogeneity of CSCs, Hybrid Epithelial/Mesenchymal States and Stemness

Cancer stem cell heterogeneity can be found both in different cancer types and within the same tumor, causing the failure of drug treatment and disease relapse [176]. A better understanding of the CSC heterogeneity can promote the development of advanced therapeutic strategies against chemotherapy resistance [177]. Breast cancer tumor studies are a good example of the illustration of CSC plasticity and heterogeneity. It was shown that in the breast cancer tumor CD24−CD44+ and ALDH markers determine two distinct intra-tumor cell populations, where CD24−CD44+ is invasive with a mesenchymal-like state and ALDH is a more proliferative and epithelial-like state [178]. Another research group has found that ALDH can be identified in normal and breast cancer stem cells [179]. This CD44+CD24−/low breast cancer cells phenotype was highly resistant to lapatinib [180]. Intriguingly, isoforms of CD44 can be found among a variety of breast cancer cell populations and correlated with different levels of cancer cell tumorigenicity [181]. Similarly, in prostate cancer, ALDH isoforms were detected in both primary tumors and metastasized prostate cancer cells [182]. Another example demonstrated that TGF-β signaling contributes to cancer stem cell heterogeneity in tumor cells. TGF- β responding cells of squamous carcinoma cells illustrated cisplatin resistance. In contrast, non-responding cell population induced proliferative and growth characteristics [183]. Later, Futakuchi et al., showed that TGF- β signaling pathway plays an important role in the characterization of CSC, proliferating cells, and therapy resistance [184]. The heterogeneity of the CSC is a complex phenomenon that needs solid markers and criteria to differentiate and identify the cancer stem cells in the tumor. EMT is a reversible evolutional process during which epithelial cells undertake temporary changes losing their phenotype and gaining a mesenchymal-like phenotype. The process when mesenchymal cells undergo opposite changes is called mesenchymal–epithelial transition (MET) [185]. The first concept of EMT was associated with embryogenesis [186]. However, recently the importance of EMT in various physiological and pathological processes, including wound healing, fibrosis, and cancer is highlighted [187]. Moreover, EMT has been proven to be involved in both resistance to therapy and the generation of CSC. Notably, the hybrid E/M state, when cancer cells are found to co-express both epithelial and mesenchymal markers, is linked with high metastatic potential and stemness [188]. For example, a pre-existing population of colorectal cancer cells with EMT-related ZEB2+ demonstrated stemness and mesenchymal characteristics driving resistance to chemotherapy [189]. Another study by Bontemps et al., published in 2022, showed that loss of CD24 by breast cancer cells facilitates stemness characteristics linked with hybrid E/M states, thereby fostering resistance to radio and chemotherapy [190]. Therefore, it might be concluded that hybrid E/M state CSC play a crucial role in therapy resistance; however, additional research is necessary.

9. Recent Developments in Combating CSCs Resistance

Over 19,000 online articles were published in PubMed in 2017–2019 only on CSCs and its resistance mechanisms to the various therapies demonstrating its advancements and significance to the research field. The strong self-renewal capacity of CSCs takes an important role in tumor relapse [191]. The existence of one CSC at the tumor site is capable to induce cancer development, relapse and metastasis. The latter changes lead to poor prognosis of the disease and play crucial role in resistance to therapies [191]. The mechanism of resistance of CSCs to traditional chemotherapy methods, through different ways, complicates destruction of cancer cells and tumors completely. Consequently, additional comprehensive studies should be done to understand novel mechanisms involved in CSCs resistance to therapies [192]. Russo et al., in 2019 suggested that de novo mutations might be caused by temporary enhancement of genetic instability during targeted therapy influenced by resistance. Their observation demonstrated temporal enhancement of mutagenesis, failure in DNA damage repair, in drug-tolerant tumor cells that endure and propagate with the EGFR/BRAF inhibition in colorectal cancer [193]. Das et al., reported in their study that CSCs number with CD133+ phenotype increases due to treatment by oxaliplatin. Cells carrying ESA+/CD44+/CD166+ stem cell surface markers demonstrated resistance to irinotecan. Both cases were reported in patients with colon cancer. Moreover, CSCs reported to show significant resistance to radiotherapy in HT-29 cells (human colon adenocarcinoma cells) [194]. Another study by Di Fiore et al., reported that significant increase in expression of ABC proteins, that function as a major CSCs mechanism of protection, play an important role in resistance to chemotherapy. This leads to the excretion of Hoechst dye and cytotoxic drugs that result in increase of resistance level to chemotherapy and cancer progression and poor prognosis [195].
Fumitremorgin C and verapamil drugs that are supposed to block ABC transporters demonstrate CSCs sensitivity in studies done using ovarian cancer [196]. Additionally, miRNAs play an important role in gene expression and are closely related to the biology of CSCs, as they regulate signaling pathways of stemness, EMT, cell differentiation processes, and tumorigenesis [195]. Di Fiore et al., claim that specific cluster of miRNAs found in tumor-initiating glioma cells (miR-302-367) might be used in future perspectives as a therapeutic agent since it demonstrated decreased level of growth of cervical cancer stem cells (CCSCs) through its involvement in regulation of cyclin D1 and AKT1 pathway [195]. As ECM components produce beneficial environment for CSCs, it is also possible to destroy their favorable niche through targeting therapy. Wang et al., reported that targeting hyaluronic acid, which is involved in enlargement of intra-tumoral pressure, might be beneficial against chemotherapy resistance and poor prognosis in patients [197], whereas Nawara et al., just recently (in 2021) argued that paclitaxel (PTX) if used in combination with other therapies might be beneficial against the resistance of cancer that are resistant to PTX alone. One of such examples is a study in which a combination of dasatinib with PTX resulted in partial reduction of breast CSCs proportion in the tumor, due to suppression of its self-renewal ability and hence, tumor growth [198]. Additionally, this combination demonstrated its inhibitory effect on pancreatic cancer cells by the phosphorylation of SRC, STAT3, AKT, and/or ERK protein [198]. Regardless of the enormous number of studies related to CSCs targeted therapy and variation of drug combination, it is important to enhance our in-depth understanding of these mechanisms in the future, in order to improve current therapies.

10. Future Perspectives

This article discusses the mechanism and potential re-sensitization of CSCs to the conventional chemotherapeutic drugs. CSCs can escape the cytotoxic effects of chemotherapeutic agents through various mechanisms, including those that were not included in this review. Mechanisms and examples discussed in this review may be useful in the identification of precise targeting strategies for various cancer types. A significant body of evidence and experimental data suggest that various developmental pathways and homeostasis mechanisms play a key role in chemoresistance development and mostly involve malfunction in pathway components. Therefore, novel, therapeutic approaches that aim to target particular pathway components for re-sensitization are an alternative approach that may have an important transitional effect, before new, advanced treatment strategies can be implemented. Studies provided in this review support the idea that CSCs can and should be re-sensitized using above mentioned pathway inhibitors, as an additional approach to improve outcomes in chemotherapy-resistant cancers. Other mechanisms, such as enhanced DNA repair response and CSCs metabolism, may be further explored to develop specific therapy and improve the survival of patients with highly aggressive chemoresistant cancers.

Author Contributions

Conceptualization, supervision—D.B., writing—M.K., L.B., A.A. and D.T. All authors have read and agreed to the published version of the manuscript.

Funding

The research was funded by the Science Committee of the Ministry of Education and Science of the Republic of Kazakhstan (Grant No. AP14872052). Ministry of Health of the Republic of Kazakhstan under the program-targeted funding of the Ageing and Healthy Lifespan research program (IRN: 51760/∏ЦΦ-M3 PK-19).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Acknowledgments

We would like to thank Nazarbayev University School of Medicine for the publication support.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Zhao, J. Cancer stem cells and chemoresistance: The smartest survives the raid. Pharmacol. Ther. 2016, 160, 145–158. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  2. Espinosa-Sánchez, A.; Suárez-Martínez, E.; Sánchez-Díaz, L.; Carnero, A. Therapeutic Targeting of Signaling Pathways Related to Cancer Stemness. Front. Oncol. 2020, 10, 1533. [Google Scholar] [CrossRef] [PubMed]
  3. Jin, X.; Jin, X.; Kim, H. Cancer stem cells and differentiation therapy. Tumor Biol. 2017, 39, 1010428317729933. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  4. Provan, D.; Gribben, J. (Eds.) Molecular Hematology, 4th ed.; John Wiley & Sons Ltd.: London, UK, 2020. [Google Scholar]
  5. Zhao, W.; Li, Y.; Zhang, X. Stemness-Related Markers in Cancer. Cancer Transl. Med. 2017, 3, 87–95. [Google Scholar] [PubMed] [Green Version]
  6. Prieto-Vila, M.; Takahashi, R.U.; Usuba, W.; Kohama, I.; Ochiya, T. Drug Resistance Driven by Cancer Stem Cells and Their Niche. Int. J. Mol. Sci. 2017, 18, 2574. [Google Scholar] [CrossRef] [Green Version]
  7. Phi, L.; Sari, I.N.; Yang, Y.G.; Lee, S.H.; Jun, N.; Kim, K.S.; Lee, Y.K.; Kwon, H.Y. Cancer Stem Cells (CSCs) in Drug Resistance and their Therapeutic Implications in Cancer Treatment. Stem Cells Int. 2018, 2018, 5416923. [Google Scholar] [CrossRef] [Green Version]
  8. Hwang-Verslues, W.W.; Kuo, W.-H.; Chang, P.-H.; Pan, C.-C.; Wang, H.-H.; Tsai, S.-T.; Jeng, Y.-M.; Shew, J.-Y.; Kung, J.T.; Chen, C.-H.; et al. Multiple lineages of human breast cancer stem/progenitor cells identified by profiling with stem cell markers. PLoS ONE 2009, 4, e8377. [Google Scholar] [CrossRef] [Green Version]
  9. Chiou, S.-H.; Wang, M.-L.; Chou, Y.-T.; Chen, C.-J.; Hong, C.-F.; Hsieh, W.-J.; Chang, H.-T.; Chen, Y.-S.; Lin, T.-W.; Hsu, H.-S.; et al. Coexpression of Oct4 and Nanog enhances malignancy in lung adenocarcinoma by inducing cancer stem cell–like properties and epithelial–mesenchymal transdifferentiation. Cancer Res. 2010, 70, 10433–10444. [Google Scholar] [CrossRef] [Green Version]
  10. Liu, C.-G.; Lu, Y.; Wang, B.-B.; Zhang, Y.-J.; Zhang, R.-S.; Lu, Y.; Chen, B.; Xu, H.; Jin, F.; Lu, P. Clinical implications of stem cell gene Oct-4 expression in breast cancer. Ann. Surg. 2011, 253, 1165–1171. [Google Scholar] [CrossRef]
  11. Jeter, C.R.; Yang, T.; Wang, J.; Chao, H.P.; Tang, D.G. Concise review: NANOG in cancer stem cells and tumor development: An update and outstanding questions. Stem Cells 2015, 33, 2381–2390. [Google Scholar] [CrossRef]
  12. Leis, O.; Eguiara, A.; Lopez-Arribillaga, E.; Alberdi, M.J.; Hernandez-Garcia, S.; Elorriaga, K.; Pandiella, A.; Rezola, R.; Martin, A.G. Sox2 expression in breast tumours and activation in breast cancer stem cells. Oncogene 2012, 31, 1354–1365. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  13. Vlashi, E.; Pajonk, F. Cancer stem cells, cancer cell plasticity and radiation therapy. Semin. Cancer Biol. 2015, 31, 28–35. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  14. Pannuti, A.; Foreman, K.; Rizzo, P.; Osipo, C.; Golde, T.; Osborne, B.; Miele, L. Targeting Notch to target cancer stem cells. Clin. Cancer Res. 2010, 16, 3141–3152. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  15. Yang, L.; Shi, P.; Zhao, G.; Xu, J.; Peng, W.; Zhang, J.; Zhang, G.; Wang, X.; Dong, Z.; Chen, F.; et al. Targeting cancer stem cell pathways for cancer therapy. Signal Transduct. Target. Ther. 2020, 5, 8. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  16. Takebe, N.; Miele, L.; Harris, P.J.; Jeong, W.; Bando, H.; Kahn, M.G.; Yang, S.X.; Ivy, S.P. Targeting Notch, Hedgehog, and Wnt pathways in cancer stem cells: Clinical update. Nat. Rev. Clin. Oncol. 2015, 12, 445–464. [Google Scholar] [CrossRef] [PubMed]
  17. Vinson, K.E.; George, D.C.; Fender, A.W.; Bertrand, F.E.; Sigounas, G. The Notch pathway in colorectal cancer. Int. J. Cancer 2016, 138, 1835–1842. [Google Scholar] [CrossRef]
  18. Sahlgren, C.; Gustafsson, M.V.; Jin, S.; Poellinger, L.; Lendahl, U. Notch signaling mediates hypoxia-induced tumor cell migration and invasion. Proc. Natl. Acad. Sci. USA 2008, 105, 6392–6397. [Google Scholar] [CrossRef] [Green Version]
  19. Cohen, B.; Shimizu, M.; Izrailit, J.; Ng, N.F.; Buchman, Y.; Pan, J.G.; Dering, J.; Reedijk, M. Cyclin D1 is a direct target of JAG1-mediated Notch signaling in breast cancer. Breast Cancer Res. Treat. 2010, 123, 113–124. [Google Scholar] [CrossRef]
  20. Suman, S.; Das, T.P.; Damodaran, C. Silencing NOTCH signaling causes growth arrest in both breast cancer stem cells and breast cancer cells. Br. J. Cancer 2013, 109, 2587–2596. [Google Scholar] [CrossRef]
  21. BeLow, M.; Osipo, C. Notch Signaling in Breast Cancer: A Role in Drug Resistance. Cells 2020, 9, 2204. [Google Scholar] [CrossRef]
  22. Islam, S.S.; Aboussekhra, A. Sequential combination of cisplatin with eugenol targets ovarian cancer stem cells through the Notch-Hes1 signalling pathway. J. Exp. Clin. Cancer Res. 2019, 38, 382. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  23. Xie, M.; Zhang, L.; He, C.S.; Xu, F.; Liu, J.L.; Hu, Z.H.; Zhao, L.P.; Tian, Y. Activation of Notch-1 enhances epithelial-mesenchymal transition in gefitinib-acquired resistant lung cancer cells. J. Cell. Biochem. 2012, 113, 1501–1513. [Google Scholar] [CrossRef] [PubMed]
  24. Huang, R.; Wang, G.; Song, Y.; Tang, Q.; You, Q.; Liu, Z.; Chen, Y.; Zhang, Q.; Li, J.; Muhammand, S.; et al. Colorectal cancer stem cell and chemoresistant colorectal cancer cell phenotypes and increased sensitivity to Notch pathway inhibitor. Mol. Med. Rep. 2015, 12, 2417–2424. [Google Scholar] [CrossRef] [Green Version]
  25. Akiyoshi, T.; Nakamura, M.; Yanai, K.; Nagai, S.; Wada, J.; Koga, K.; Nakashima, H.; Sato, N.; Tanaka, M.; Katano, M. Gamma-secretase inhibitors enhance taxane-induced mitotic arrest and apoptosis in colon cancer cells. Gastroenterology 2008, 134, 131–144. [Google Scholar] [CrossRef] [PubMed]
  26. Meng, R.D.; Shelton, C.C.; Li, Y.M.; Qin, L.X.; Notterman, D.; Paty, P.B.; Schwartz, G.K. Gamma-Secretase inhibitors abrogate oxaliplatin-induced activation of the Notch-1 signaling pathway in colon cancer cells resulting in enhanced chemosensitivity. Cancer Res. 2009, 69, 573–582. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  27. Hoey, T.; Yen, W.C.; Axelrod, F.; Basi, J.; Donigian, L.; Dylla, S.; Fitch-Bruhns, M.; Lazetic, S.; Park, I.K.; Sato, A.; et al. DLL4 blockade inhibits tumor growth and reduces tumor-initiating cell frequency. Cell Stem Cell 2009, 5, 168–177. [Google Scholar] [CrossRef] [Green Version]
  28. Fan, X.; Matsui, W.; Khaki, L.; Stearns, D.; Chun, J.; Li, Y.M.; Eberhart, C.G. Notch pathway inhibition depletes stem-like cells and blocks engraftment in embryonal brain tumors. Cancer Res. 2006, 66, 7445–7452. [Google Scholar] [CrossRef] [Green Version]
  29. McAuliffe, S.M.; Morgan, S.L.; Wyant, G.A.; Tran, L.T.; Muto, K.W.; Chen, Y.S.; Chin, K.T.; Partridge, J.C.; Poole, B.B.; Cheng, K.-H.; et al. Targeting Notch, a key pathway for ovarian cancer stem cells, sensitizes tumors to platinum therapy. Proc. Natl. Acad. Sci. USA 2012, 109, E2939–E2948. [Google Scholar] [CrossRef] [Green Version]
  30. Park, J.T.; Chen, X.; Tropè, C.G.; Davidson, B.; Shih, I.; Wang, T.L. Notch3 overexpression is related to the recurrence of ovarian cancer and confers resistance to carboplatin. Am. J. Pathol. 2010, 177, 1087–1094. [Google Scholar] [CrossRef] [PubMed]
  31. Capodanno, Y.; Buishand, F.O.; Pang, L.Y.; Kirpensteijn, J.; Mol, J.A.; Argyle, D.J. Notch pathway inhibition targets chemoresistant insulinoma cancer stem cells. Endocr.-Relat. Cancer 2018, 25, 131–144. [Google Scholar] [CrossRef]
  32. Li, Z.L.; Chen, C.; Yang, Y.; Wang, C.; Yang, T.; Yang, X.; Liu, S.C. Gamma secretase inhibitor enhances sensitivity to doxorubicin in MDA-MB-231 cells. Int. J. Clin. Exp. Pathol. 2015, 8, 4378–4387. [Google Scholar] [PubMed]
  33. Qiu, M.; Peng, Q.; Jiang, I.; Carroll, C.; Han, G.; Rymer, I.; Lippincott, J.; Zachwieja, J.; Gajiwala, K.; Kraynov, E.; et al. Specific inhibition of Notch1 signaling enhances the antitumor efficacy of chemotherapy in triple negative breast cancer through reduction of cancer stem cells. Cancer Lett. 2013, 328, 261–270. [Google Scholar] [CrossRef]
  34. Liu, J.; Fan, H.; Ma, Y.; Liang, D.; Huang, R.; Wang, J.; Zhou, F.; Kan, Q.; Ming, L.; Li, H.; et al. Notch1 is a 5-fluorouracil resistant and poor survival marker in human esophagus squamous cell carcinomas. PLoS ONE 2013, 8, e56141. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  35. Wang, L.; Zi, H.; Luo, Y.; Liu, T.; Zheng, H.; Xie, C.; Wang, X.; Huang, X. Inhibition of Notch pathway enhances the antitumor effect of docetaxel in prostate cancer stem-like cells. Stem Cell Res. Ther. 2020, 11, 258. [Google Scholar] [CrossRef] [PubMed]
  36. Domingo-Domenech, J.; Vidal, S.J.; Rodriguez-Bravo, V.; Castillo-Martin, M.; Quinn, S.A.; Rodriguez-Barrueco, R.; Bonal, D.M.; Charytonowicz, E.; Gladoun, N.; de la Iglesia-Vicente, J.; et al. Suppression of acquired docetaxel resistance in prostate cancer through depletion of notch-and hedgehog-dependent tumor-initiating cells. Cancer Cell 2012, 22, 373–388. [Google Scholar] [CrossRef] [Green Version]
  37. Clara, J.A.; Monge, C.; Yang, Y.; Takebe, N. Targeting signalling pathways and the immune microenvironment of cancer stem cells—A clinical update. Nature reviews. Clin. Oncol. 2020, 17, 204–232. [Google Scholar]
  38. Reya, T.; Clevers, H. Wnt signalling in stem cells and cancer. Nature 2005, 434, 843–850. [Google Scholar] [CrossRef]
  39. Katoh, M. Canonical and non-canonical WNT signaling in cancer stem cells and their niches: Cellular heterogeneity, omics reprogramming, targeted therapy and tumor plasticity (Review). Int. J. Oncol. 2017, 51, 1357–1369. [Google Scholar] [CrossRef] [Green Version]
  40. Zhan, T.; Rindtorff, N.; Boutros, M. Wnt signaling in cancer. Oncogene 2017, 36, 1461–1473. [Google Scholar] [CrossRef]
  41. Duchartre, Y.; Kim, Y.M.; Kahn, M. The Wnt signaling pathway in cancer. Crit. Rev. Oncol./Hematol. 2016, 99, 141–149. [Google Scholar] [CrossRef] [Green Version]
  42. Matsui, W.H. Cancer stem cell signaling pathways. Medicine 2016, 95 (Suppl. S1), S8–S19. [Google Scholar] [CrossRef] [PubMed]
  43. Cao, J.; Ma, J.; Sun, L.; Li, J.; Qin, T.; Zhou, C.; Cheng, L.; Chen, K.; Qian, W.; Duan, W.; et al. Targeting glypican-4 overcomes 5-FU resistance and attenuates stem cell-like properties via suppression of Wnt/β-catenin pathway in pancreatic cancer cells. J. Cell. Biochem. 2018, 119, 9498–9512. [Google Scholar] [CrossRef] [PubMed]
  44. Perry, J.M.; Tao, F.; Roy, A.; Lin, T.; He, X.C.; Chen, S.; Lu, X.; Nemechek, J.; Ruan, L.; Yu, X.; et al. Overcoming Wnt-β-catenin dependent anti-cancer therapy resistance in leukaemia stem cells. Nat. Cell Biol. 2020, 22, 689–700. [Google Scholar] [CrossRef]
  45. Martins-Neves, S.R.; Paiva-Oliveira, D.I.; Wijers-Koster, P.M.; Abrunhosa, A.J.; Fontes-Ribeiro, C.; Bovée, J.V.; Cleton-Jansen, A.-M.; Gomes, C.M. Chemotherapy induces stemness in osteosarcoma cells through activation of Wnt/β-catenin signaling. Cancer Lett. 2016, 370, 286–295. [Google Scholar] [CrossRef] [PubMed]
  46. Vangipuram, S.D.; Buck, S.A.; Lyman, W.D. Wnt pathway activity confers chemoresistance to cancer stem-like cells in a neuroblastoma cell line. Tumor Biol. 2012, 33, 2173–2183. [Google Scholar] [CrossRef] [PubMed]
  47. Huang, L.; Jin, Y.; Feng, S.; Zou, Y.; Xu, S.; Qiu, S.; Li, L.; Zheng, J. Role of Wnt/β-catenin, Wnt/c-Jun N-terminal kinase and Wnt/Ca2+ pathways in cisplatin-induced chemoresistance in ovarian cancer. Exp. Ther. Med. 2016, 12, 3851–3858. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  48. Li, J.; Yang, S.; Su, N.; Wang, Y.; Yu, J.; Qiu, H.; He, X. Overexpression of long noncoding RNA HOTAIR leads to chemoresistance by activating the Wnt/β-catenin pathway in human ovarian cancer. Tumour Biol. J. Int. Soc. Oncodevelopmental Biol. Med. 2016, 37, 2057–2065. [Google Scholar] [CrossRef] [PubMed]
  49. Barghout, S.H.; Zepeda, N.; Xu, Z.; Steed, H.; Lee, C.H.; Fu, Y. Elevated β-catenin activity contributes to carboplatin resistance in A2780cp ovarian cancer cells. Biochem. Biophys. Res. Commun. 2015, 468, 173–178. [Google Scholar] [CrossRef]
  50. Nagaraj, A.B.; Joseph, P.; Kovalenko, O.; Singh, S.; Armstrong, A.; Redline, R.; Resnick, K.; Zanotti, K.; Waggoner, S.; DiFeo, A. Critical role of Wnt/β-catenin signaling in driving epithelial ovarian cancer platinum resistance. Oncotarget 2015, 6, 23720–23734. [Google Scholar] [CrossRef] [Green Version]
  51. Suebsoonthron, J.; Jaroonwitchawan, T.; Yamabhai, M.; Noisa, P. Inhibition of WNT signaling reduces differentiation and induces sensitivity to doxorubicin in human malignant neuroblastoma SH-SY5Y cells. Anti-Cancer Drugs 2017, 28, 469–479. [Google Scholar] [CrossRef]
  52. Warrier, S.; Balu, S.K.; Kumar, A.P.; Millward, M.; Dharmarajan, A. Wnt antagonist, secreted frizzled-related protein 4 (sFRP4), increases chemotherapeutic response of glioma stem-like cells. Oncol. Res. Featur. Preclin. Clin. Cancer Ther. 2014, 21, 93–102. [Google Scholar] [CrossRef] [PubMed]
  53. Wu, X.; Luo, F.; Li, J.; Zhong, X.; Liu, K. Tankyrase 1 inhibitior XAV939 increases chemosensitivity in colon cancer cell lines via inhibition of the Wnt signaling pathway. Int. J. Oncol. 2016, 48, 1333–1340. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  54. Kendziorra, E.; Ahlborn, K.; Spitzner, M.; Rave-Fränk, M.; Emons, G.; Gaedcke, J.; Kramer, F.; Wolff, H.A.; Becker, H.; Beissbarth, T.; et al. Silencing of the Wnt transcription factor TCF4 sensitizes colorectal cancer cells to (chemo-) radiotherapy. Carcinogenesis 2011, 32, 1824–1831. [Google Scholar] [CrossRef]
  55. Urushibara, S.; Tsubota, T.; Asai, R.; Azumi, J.; Ashida, K.; Fujiwara, Y.; Shiota, G. WNT/β-catenin signaling inhibitor IC-2 suppresses sphere formation and sensitizes colorectal cancer cells to 5-fluorouracil. Anti-Cancer Res. 2017, 37, 4085–4091. [Google Scholar]
  56. Roy, S.; Roy, S.; Kar, M.; Chakraborty, A.; Kumar, A.; Delogu, F.; Asthana, S.; Hande, M.P.; Banerjee, B. Combined treatment with cisplatin and the tankyrase inhibitor XAV-939 increases cytotoxicity, abrogates cancer-stem-like cell phenotype and increases chemosensitivity of head-and-neck squamous-cell carcinoma cells. Mutation research. Genet. Toxicol. Environ. Mutagen. 2019, 846, 503084. [Google Scholar] [CrossRef]
  57. Lee, S.H.; Koo, B.S.; Kim, J.M.; Huang, S.; Rho, Y.S.; Bae, W.J.; Kang, H.J.; Kim, Y.S.; Moon, J.H.; Lim, Y.C. Wnt/β-catenin signalling maintains self-renewal and tumourigenicity of head and neck squamous cell carcinoma stem-like cells by activating Oct4. J. Pathol. 2014, 234, 99–107. [Google Scholar] [CrossRef]
  58. Yokogi, S.; Tsubota, T.; Kanki, K.; Azumi, J.; Itaba, N.; Oka, H.; Morimoto, M.; Ryoke, K.; Shiota, G. Wnt/Beta-Catenin Signal Inhibitor HC-1 Sensitizes Oral Squamous Cell Carcinoma Cells to 5-Fluorouracil through Reduction of CD44-Positive Population. Yonago Acta Med. 2016, 59, 93–99. [Google Scholar] [PubMed]
  59. Warrier, S.; Bhuvanalakshmi, G.; Arfuso, F.; Rajan, G.; Millward, M.; Dharmarajan, A. Cancer stem-like cells from head and neck cancers are chemosensitized by the Wnt antagonist, sFRP4, by inducing apoptosis, decreasing stemness, drug resistance and epithelial to mesenchymal transition. Cancer Gene Ther. 2014, 21, 381–388. [Google Scholar] [CrossRef] [Green Version]
  60. Yang, W.; Yan, H.X.; Chen, L.; Liu, Q.; He, Y.Q.; Yu, L.X.; Zhang, S.H.; Huang, D.D.; Tang, L.; Kong, X.N.; et al. Wnt/beta-catenin signaling contributes to activation of normal and tumorigenic liver progenitor cells. Cancer Res. 2008, 68, 4287–4295. [Google Scholar] [CrossRef] [Green Version]
  61. Chan, K.C.; Chan, L.S.; Ip, J.C.; Lo, C.; Yip, T.T.; Ngan, R.K.; Wong, R.N.; Lo, K.W.; Ng, W.T.; Lee, A.W.; et al. Therapeutic targeting of CBP/β-catenin signaling reduces cancer stem-like population and synergistically suppresses growth of EBV-positive nasopharyngeal carcinoma cells with cisplatin. Sci. Rep. 2015, 5, 9979. [Google Scholar] [CrossRef] [Green Version]
  62. Gang, E.J.; Hsieh, Y.T.; Pham, J.; Zhao, Y.; Nguyen, C.; Huantes, S.; Park, E.; Naing, K.; Klemm, L.; Swaminathan, S.; et al. Small-molecule inhibition of CBP/catenin interactions eliminates drug-resistant clones in acute lymphoblastic leukemia. Oncogene 2014, 33, 2169–2178. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  63. Zhao, Y.; Masiello, D.; McMillian, M.; Nguyen, C.; Wu, Y.; Melendez, E.; Smbatyan, G.; Kida, A.; He, Y.; Teo, J.L.; et al. CBP/catenin antagonist safely eliminates drug-resistant leukemia-initiating cells. Oncogene 2016, 35, 3705–3717. [Google Scholar] [CrossRef] [PubMed]
  64. He, K.; Xu, T.; Xu, Y.; Ring, A.; Kahn, M.; Goldkorn, A. Cancer cells acquire a drug resistant, highly tumorigenic, cancer stem-like phenotype through modulation of the PI3K/Akt/β-catenin/CBP pathway. Int. J. Cancer 2014, 134, 43–54. [Google Scholar] [CrossRef]
  65. Jang, G.B.; Hong, I.S.; Kim, R.J.; Lee, S.Y.; Park, S.J.; Lee, E.S.; Park, J.H.; Yun, C.H.; Chung, J.U.; Lee, K.J.; et al. Wnt/β-Catenin Small-Molecule Inhibitor CWP232228 Preferentially Inhibits the Growth of Breast Cancer Stem-like Cells. Cancer Res. 2015, 75, 1691–1702. [Google Scholar] [CrossRef] [Green Version]
  66. Lee, D.H.; Lee, S.Y.; Oh, S.C. Hedgehog signaling pathway as a potential target in the treatment of advanced gastric cancer. In Tumor Biology; SAGE Publications Ltd.: Thousand Oaks, CA, USA, 2017. [Google Scholar]
  67. Cochrane, C.R.; Szczepny, A.; Watkins, D.N.; Cain, J.E. Hedgehog Signaling in the Maintenance of Cancer Stem Cells. Cancers 2015, 7, 1554–1585. [Google Scholar] [CrossRef] [PubMed]
  68. Sari, I.N.; Phi, L.T.H.; Jun, N.; Wijaya, Y.T.; Lee, S.; Kwon, H.Y. Hedgehog signaling in cancer: A prospective therapeutic target for eradicating cancer stem cells. Cells 2018, 7, 208. [Google Scholar] [CrossRef] [Green Version]
  69. Giroux-Leprieur, E.; Costantini, A.; Ding, V.W.; He, B. Hedgehog signaling in lung cancer: From oncogenesis to cancer treatment resistance. Int. J. Mol. Sci. 2018, 19, 2835. [Google Scholar] [CrossRef] [Green Version]
  70. McMillan, R.; Matsui, W. Molecular pathways: The hedgehog signaling pathway in cancer. Clin. Cancer Res. 2012, 18, 4883–4888. [Google Scholar] [CrossRef] [Green Version]
  71. Ma, Y.; Yu, W.; Shrivastava, A.; Alemi, F.; Lankachandra, K.; Srivastava, R.; Shankar, S. Sanguinarine inhibits pancreatic cancer stem cell characteristics by inducing oxidative stress and suppressing sonic hedgehog-Gli-Nanog pathway. Carcinogenesis 2017, 38, 1047–1056. [Google Scholar] [CrossRef] [Green Version]
  72. Merchant, A.A.; Matsui, W. Targeting HedgehogHedgehog—A cancer stem cell pathway. Clin. Cancer Res. 2010, 16, 3130–3140. [Google Scholar] [CrossRef] [Green Version]
  73. Campbell, V.; Copland, M. Hedgehog signaling in cancer stem cells: A focus on hematological cancers. Stem Cells Cloning Adv. Appl. 2015, 8, 27. [Google Scholar]
  74. Po, A.; Abballe, L.; Sabato, C.; Gianno, F.; Chiacchiarini, M.; Catanzaro, G.; De Smaele, E.; Giangaspero, F.; Ferretti, E.; Miele, E.; et al. Sonic hedgehog medulloblastoma cancer stem cells mirnome and transcriptome highlight novel functional networks. Int. J. Mol. Sci. 2018, 19, 2326. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  75. Leprieur, E.G.; Tolani, B.; Li, H.; Leguay, F.; Hoang, N.T.; Acevedo, L.A.; Jin, J.Q.; Tseng, H.-H.; Yue, D.; Kim, I.-J.; et al. Membrane-bound full-length Sonic Hedgehog identifies cancer stem cells in human non-small cell lung cancer. Oncotarget 2017, 8, 103744. [Google Scholar] [CrossRef] [PubMed]
  76. Chai, F.; Zhou, J.; Chen, C.; Xie, S.; Chen, X.; Su, P.; Shi, J. The Hedgehog inhibitor cyclopamine antagonizes chemoresistance of breast cancer cells. OncoTargets Ther. 2013, 6, 1643. [Google Scholar]
  77. He, M.; Fu, Y.; Yan, Y.; Xiao, Q.; Wu, H.; Yao, W.; Zhao, H.; Zhao, L.; Jiang, Q.; Yu, Z.; et al. The Hedgehog signalling pathway mediates drug response of MCF-7 mammosphere cells in breast cancer patients. Clin. Sci. 2015, 129, 809–822. [Google Scholar] [CrossRef]
  78. Lu, Y.-L.; Ma, Y.-B.; Feng, C.; Zhu, D.-L.; Liu, J.; Chen, L.; Liang, S.-J.; Dong, C.-Y. Co-delivery of cyclopamine and doxorubicin mediated by bovine serum albumin nanoparticles reverses doxorubicin resistance in breast cancer by down-regulating P-glycoprotein expression. J. Cancer 2019, 10, 2357. [Google Scholar] [CrossRef] [Green Version]
  79. Hu, K.; Zhou, H.; Liu, Y.; Liu, Z.; Liu, J.; Tang, J.; Li, J.; Zhang, J.; Sheng, W.; Zhao, Y.; et al. Hyaluronic acid functional amphipathic and redox-responsive polymer particles for the co-delivery of doxorubicin and cyclopamine to eradicate breast cancer cells and cancer stem cells. Nanoscale 2015, 7, 8607–8618. [Google Scholar] [CrossRef]
  80. Bhateja, P.; Cherian, M.; Majumder, S.; Ramaswamy, B. The Hedgehog Signaling Pathway: A Viable Target in Breast Cancer? Cancers 2019, 11, 1126. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  81. Cazet, A.S.; Hui, M.N.; Elsworth, B.L.; Wu, S.Z.; Roden, D.; Chan, C.L.; Skhinas, J.N.; Collot, R.; Yang, J.; Harvey, K.; et al. Targeting stromal remodeling and cancer stem cell plasticity overcomes chemoresistance in triple negative breast cancer. Nat. Commun. 2018, 9, 2897. [Google Scholar] [CrossRef] [Green Version]
  82. Yao, J.; An, Y.; Wie, J.; Ji, Z.; Lu, Z.; Wu, J.; Jiang, K.; Chen, P.; Xu, Z.; Miao, Y. Cyclopamine reverts acquired chemoresistance and down-regulates cancer stem cell markers in pancreatic cancer cell lines. Swiss Med. Wkly. 2011, 141, w13208. [Google Scholar] [CrossRef]
  83. Huang, F.T.; Zhuan-Sun, Y.X.; Zhuang, Y.Y.; Wei, S.L.; Tang, J.; Chen, W.B.; Zhang, S.N. Inhibition of hedgehog signaling depresses self-renewal of pancreatic cancer stem cells and reverses chemoresistance. Int. J. Oncol. 2012, 41, 1707–1714. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  84. Mueller, M.; Hermann, P.C.; Witthauer, J.; Rubio–Viqueira, B.; Leicht, S.F.; Huber, S.; Ellwart, J.W.; Mustafa, M.; Bartenstein, P.; D’Haese, J.G.; et al. Combined targeted treatment to eliminate tumorigenic cancer stem cells in human pancreatic cancer. Gastroenterology 2009, 137, 1102–1113. [Google Scholar] [CrossRef] [PubMed]
  85. Wang, F.; Ma, L.; Zhang, Z.; Liu, X.; Gao, H.; Zhuang, Y.; Yang, P.; Kornmann, M.; Tian, X.; Yang, Y. Hedgehog Signaling Regulates Epithelial-Mesenchymal Transition in Pancreatic Cancer Stem-Like Cells. J. Cancer 2016, 7, 408–417. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  86. Jia, Y.; Gu, D.; Wan, J.; Yu, B.; Zhang, X.; Chiorean, E.G.; Wang, Y.; Xie, J. The role of GLI-SOX2 signaling axis for gemcitabine resistance in pancreatic cancer. Oncogene 2019, 38, 1764–1777. [Google Scholar] [CrossRef] [PubMed]
  87. Usui, T.; Sakurai, M.; Umata, K.; Elbadawy, M.; Ohama, T.; Yamawaki, H.; Hazama, S.; Takenouchi, H.; Nakajima, M.; Tsunedomi, R.; et al. Hedgehog Signals Mediate Anti-Cancer Drug Resistance in Three-Dimensional Primary Colorectal Cancer Organoid Culture. Int. J. Mol. Sci. 2018, 19, 1098. [Google Scholar] [CrossRef] [Green Version]
  88. Tang, Y.A.; Chen, Y.F.; Bao, Y.; Mahara, S.; Yatim, S.; Oguz, G.; Lee, P.L.; Feng, M.; Cai, Y.; Tan, E.Y.; et al. Hypoxic tumor microenvironment activates GLI2 via HIF-1α and TGF-β2 to promote chemoresistance in colorectal cancer. Proc. Natl. Acad. Sci. USA 2018, 115, E5990–E5999. [Google Scholar] [CrossRef] [Green Version]
  89. Carballo, G.B.; Matias, D.; Ribeiro, J.H.; Pessoa, L.S.; Arrais-Neto, A.M. Cyclopamine sensitizes glioblastoma cells to temozolomide treatment through Sonic hedgehog pathway. Life Sci. 2020, 257, 118027. [Google Scholar] [CrossRef]
  90. Bar, E.E.; Chaudhry, A.; Lin, A.; Fan, X.; Schreck, K.; Matsui, W.; Piccirillo, S.; Vescovi, A.L.; DiMeco, F.; Olivi, A.; et al. Cyclopamine-mediated hedgehog pathway inhibition depletes stem-like cancer cells in glioblastoma. Stem Cells 2007, 25, 2524–2533. [Google Scholar] [CrossRef] [Green Version]
  91. Clement, V.; Sanchez, P.; de Tribolet, N.; Radovanovic, I.; Ruiz i Altaba, A. HEDGEHOG-GLI1 signaling regulates human glioma growth, cancer stem cell self-renewal, and tumorigenicity. Curr. Biol. CB 2007, 17, 165–172. [Google Scholar] [CrossRef]
  92. Wang, K.; Chen, D.; Qian, Z.; Cui, D.; Gao, L.; Lou, M. Hedgehog/Gli1 signaling pathway regulates MGMT expression and chemoresistance to temozolomide in human glioblastoma. Cancer Cell Int. 2017, 17, 117. [Google Scholar] [CrossRef] [Green Version]
  93. Nanta, R.; Shrivastava, A.; Sharma, J.; Shankar, S.; Srivastava, R.K. Inhibition of sonic HedgehogHedgehog and PI3K/Akt/mTOR pathways cooperate in suppressing survival, self-renewal and tumorigenic potential of glioblastoma-initiating cells. Mol. Cell. Biochem. 2019, 454, 11–23. [Google Scholar] [CrossRef] [PubMed]
  94. Doheny, D.; Sirkisoon, S.; Carpenter, R.L.; Aguayo, N.R.; Regua, A.T.; Anguelov, M.; Manore, S.G.; Arrigo, A.; Jalboush, S.A.; Wong, G.L.; et al. Combined inhibition of JAK2-STAT3 and SMO-GLI1/tGLI1 pathways suppresses breast cancer stem cells, tumor growth, and metastasis. Oncogene 2020, 39, 6589–6605. [Google Scholar] [CrossRef] [PubMed]
  95. Yang, R.; Mondal, G.; Wen, D.; Mahato, R.I. Combination therapy of paclitaxel and cyclopamine polymer-drug conjugates to treat advanced prostate cancer. Nanomed. Nanotechnol. Biol. Med. 2017, 13, 391–401. [Google Scholar] [CrossRef]
  96. Singh, S.; Chitkara, D.; Mehrazin, R.; Behrman, S.W.; Wake, R.W.; Mahato, R.I. Chemoresistance in prostate cancer cells is regulated by miRNAs and Hedgehog pathway. PLoS ONE 2012, 7, e40021. [Google Scholar] [CrossRef] [PubMed]
  97. Song, Z.; Yue, W.; Wei, B.; Wang, N.; Li, T.; Guan, L.; Shi, S.; Zeng, Q.; Pei, X.; Chen, L. Sonic hedgehog pathway is essential for maintenance of cancer stem-like cells in human gastric cancer. PLoS ONE 2011, 6, e17687. [Google Scholar] [CrossRef] [Green Version]
  98. Xu, M.; Gong, A.; Yang, H.; George, S.K.; Jiao, Z.; Huang, H.; Jiang, X.; Zhang, Y. Sonic hedgehog-glioma associated oncogene homolog 1 signaling enhances drug resistance in CD44+/Musashi-1+ gastric cancer stem cells. Cancer Lett. 2015, 369, 124–133. [Google Scholar] [CrossRef]
  99. Plaks, V.; Kong, N.; Werb, Z. The cancer stem cell niche: How essential is the niche in regulating stemness of tumor cells? Cell Stem Cell 2015, 16, 225–238. [Google Scholar] [CrossRef] [Green Version]
  100. Borovski, T.; De Sousa E Melo, F.; Vermeulen, L.; Medema, J.P. Cancer stem cell niche: The place to be. Cancer Res. 2011, 71, 634–639. [Google Scholar] [CrossRef] [Green Version]
  101. Hynes, R.O.; Naba, A. Overview of the matrisome--an inventory of extracellular matrix constituents and functions. Cold Spring Harb. Perspect. Biol. 2012, 4, a004903. [Google Scholar] [CrossRef] [Green Version]
  102. Senthebane, D.A.; Rowe, A.; Thomford, N.E.; Shipanga, H.; Munro, D.; Mazeedi, M.; Almazyadi, H.; Kallmeyer, K.; Dandara, C.; Pepper, M.S.; et al. The Role of Tumor Microenvironment in Chemoresistance: To Survive, Keep Your Enemies Closer. Int. J. Mol. Sci. 2017, 18, 1586. [Google Scholar] [CrossRef] [Green Version]
  103. Sun, X.; Lv, X.; Yan, Y.; Zhao, Y.; Ma, R.; He, M.; Wei, M. Hypoxia-mediated cancer stem cell resistance and targeted therapy. Biomed. Pharmacother. 2020, 130, 110623. [Google Scholar] [CrossRef]
  104. Qin, J.; Liu, Y.; Lu, Y.; Liu, M.; Li, M.; Li, J.; Wu, L. Hypoxia-inducible factor 1 alpha promotes cancer stem cells-like properties in human ovarian cancer cells by upregulating SIRT1 expression. Sci. Rep. 2017, 7, 10592. [Google Scholar] [CrossRef] [Green Version]
  105. Nejad, A.E.; Najafgholian, S.; Rostami, A.; Sistani, A.; Shojaeifar, S.; Esparvarinha, M.; Nedaeinia, R.; Javanmard, S.H.; Taherian, M.; Ahmadlou, M.; et al. The role of hypoxia in the tumor microenvironment and development of cancer stem cell: A novel approach to developing treatment. Cancer Cell Int. 2021, 21, 62. [Google Scholar] [CrossRef] [PubMed]
  106. Xiao, Y.; Sun, Y.; Liu, G.; Zhao, J.; Gao, Y.; Yeh, S.; Gong, L.; Chang, C. Androgen receptor (AR)/miR-520f-3p/SOX9 signaling is involved in altering hepatocellular carcinoma (HCC) cell sensitivity to the Sorafenib therapy under hypoxia via increasing cancer stem cells phenotype. Cancer Lett. 2019, 444, 175–187. [Google Scholar] [CrossRef] [PubMed]
  107. Roscigno, G.; Puoti, I.; Giordano, I.; Donnarumma, E.; Russo, V.; Affinito, A.; Adamo, A.; Quintavalle, C.; Todaro, M.; Vivanco, M.D.; et al. MiR-24 induces chemotherapy resistance and hypoxic advantage in breast cancer. Oncotarget 2017, 8, 19507–19521. [Google Scholar] [CrossRef] [Green Version]
  108. Jinushi, M. Role of cancer stem cell-associated inflammation in creating pro-inflammatory tumorigenic microenvironments. OncoImmunology 2014, 3, e28862. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  109. Qian, B.Z.; Li, J.; Zhang, H.; Kitamura, T.; Zhang, J.; Campion, L.R.; Kaiser, E.A.; Snyder, L.A.; Pollard, J.W. CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis. Nature 2011, 475, 222–225. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  110. Valkenburg, K.C.; de Groot, A.E.; Pienta, K.J. Targeting the tumour stroma to improve cancer therapy. Nature reviews. Clin. Oncol. 2018, 15, 366–381. [Google Scholar]
  111. Kalluri, R. The biology and function of fibroblasts in cancer. Nat. Rev. Cancer 2016, 16, 582–598. [Google Scholar] [CrossRef]
  112. Ferguson, L.P.; Diaz, E.; Reya, T. The Role of the Microenvironment and Immune System in Regulating Stem Cell Fate in Cancer. Trends Cancer 2021, 7, 624–634. [Google Scholar] [CrossRef]
  113. Cogle, C.R.; Bosse, R.C.; Brewer, T.; Migdady, Y.; Shirzad, R.; Kampen, K.R.; Saki, N. Acute myeloid leukemia in the vascular niche. Cancer Lett. 2016, 380, 552–560. [Google Scholar] [CrossRef] [PubMed]
  114. Kolenda, J.; Jensen, S.S.; Aaberg-Jessen, C.; Christensen, K.; Andersen, C.; Brünner, N.; Kristensen, B.W. Effects of hypoxia on expression of a panel of stem cell and chemoresistance markers in glioblastoma-derived spheroids. J. Neuro-Oncol. 2011, 103, 43–58. [Google Scholar] [CrossRef] [PubMed]
  115. Su, S.; Chen, J.; Yao, H.; Liu, J.; Yu, S.; Lao, L.; Wang, M.; Luo, M.; Xing, Y.; Chen, F.; et al. CD10+GPR77+ Cancer-Associated Fibroblasts Promote Cancer Formation and Chemoresistance by Sustaining Cancer Stemness. Cell 2018, 172, 841–856.e16. [Google Scholar] [CrossRef]
  116. Korkaya, H.; Kim, G.I.; Davis, A.; Malik, F.; Henry, N.L.; Ithimakin, S.; Quraishi, A.A.; Tawakkol, N.; D’Angelo, R.; Paulson, A.K.; et al. Activation of an IL6 inflammatory loop mediates trastuzumab resistance in HER2+ breast cancer by expanding the cancer stem cell population. Mol. Cell 2012, 47, 570–584. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  117. Gaggianesi, M.; Turdo, A.; Chinnici, A.; Lipari, E.; Apuzzo, T.; Benfante, A.; Sperduti, I.; Di Franco, S.; Meraviglia, S.; Lo Presti, E.; et al. IL4 Primes the Dynamics of Breast Cancer Progression via DUSP4 Inhibition. Cancer Res. 2017, 77, 3268–3279. [Google Scholar] [CrossRef]
  118. Lotti, F.; Jarrar, A.M.; Pai, R.K.; Hitomi, M.; Lathia, J.; Mace, A.; Gantt, G.A.; Sukhdeo, K.; DeVecchio, J.; Vasanji, A.; et al. Chemotherapy activates cancer-associated fibroblasts to maintain colorectal cancer-initiating cells by IL-17A. J. Exp. Med. 2013, 210, 2851–2872. [Google Scholar] [CrossRef] [Green Version]
  119. Jinushi, M.; Chiba, S.; Yoshiyama, H.; Masutomi, K.; Kinoshita, I.; Dosaka-Akita, H.; Yagita, H.; Takaoka, A.; Tahara, H. Tumor-associated macrophages regulate tumorigenicity and anti-cancer drug responses of cancer stem/initiating cells. Proc. Natl. Acad. Sci. USA 2011, 108, 12425–12430. [Google Scholar] [CrossRef] [Green Version]
  120. Li, H.; Chen, J.; Wang, X.; He, M.; Zhang, Z.; Cen, Y. Nodal induced by hypoxia exposure contributes to dacarbazine resistance and the maintenance of stemness in melanoma cancer stem-like cells. Oncol. Rep. 2018, 39, 2855–2864. [Google Scholar] [CrossRef] [Green Version]
  121. He, M.; Wu, H.; Jiang, Q.; Liu, Y.; Han, L.; Yan, Y.; Wei, B.; Liu, F.; Deng, X.; Chen, H.; et al. Hypoxia-inducible factor-2α directly promotes BCRP expression and mediates the resistance of ovarian cancer stem cells to adriamycin. Mol. Oncol. 2019, 13, 403–421. [Google Scholar] [CrossRef] [Green Version]
  122. Yu, B.; Wu, K.; Wang, X.; Zhang, J.; Wang, L.; Jiang, Y.; Zhu, X.; Chen, W.; Yan, M. Periostin secreted by cancer-associated fibroblasts promotes cancer stemness in head and neck cancer by activating protein tyrosine kinase 7. Cell Death Dis. 2018, 9, 1082. [Google Scholar] [CrossRef] [Green Version]
  123. Yu, Q.; Xue, Y.; Liu, J.; Xi, Z.; Li, Z.; Liu, Y. Fibronectin Promotes the Malignancy of Glioma Stem-Like Cells Via Modulation of Cell Adhesion, Differentiation, Proliferation and Chemoresistance. Front. Mol. Neurosci. 2018, 11, 130. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  124. Yun, C.W.; Lee, S.H. The roles of autophagy in cancer. Int. J. Mol. Sci. 2018, 19, 3466. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  125. Gong, C.; Bauvy, C.; Tonelli, G.; Yue, W.; Deloménie, C.; Nicolas, V.; Zhu, Y.; Domergue, V.; Marin-Esteban, V.; Tharinger, H.; et al. Beclin 1 and autophagy are required for the tumorigenicity of breast cancer stem-like/progenitor cells. Oncogene 2013, 32, 2261–2272e.11. [Google Scholar] [CrossRef] [Green Version]
  126. Lee, Y.J.; Jang, B.K. The role of autophagy in hepatocellular carcinoma. Int. J. Mol. Sci. 2015, 16, 26629–26643. [Google Scholar] [CrossRef] [Green Version]
  127. Simpson, J.E.; Gammoh, N. The impact of autophagy during the development and survival of glioblastoma. Open Biol. 2020, 10, 200184. [Google Scholar] [CrossRef] [PubMed]
  128. Di Leo, L.; Bodemeyer, V.; De Zio, D. The complex role of autophagy in melanoma evolution: New perspectives from mouse models. Front. Oncol. 2020, 9, 1506. [Google Scholar] [CrossRef] [Green Version]
  129. Han, Y.; Fan, S.; Qin, T.; Yang, J.; Sun, Y.; Lu, Y.; Mao, J.; Li, L. Role of autophagy in breast cancer and breast cancer stem cells. Int. J. Oncol. 2018, 52, 1057–1070. [Google Scholar] [CrossRef] [Green Version]
  130. Rao, R.; Balusu, R.; Fiskus, W.; Mudunuru, U.; Venkannagari, S.; Chauhan, L.; Smith, J.E.; Hembruff, S.L.; Ha, K.; Atadja, P.; et al. Combination of pan-histone deacetylase inhibitor and autophagy inhibitor exerts superior efficacy against triple-negative human breast cancer cells. Mol. Cancer Ther. 2012, 11, 973–983. [Google Scholar] [CrossRef] [Green Version]
  131. Yang, H.Z.; Ma, Y.; Zhou, Y.; Xu, L.M.; Chen, X.J.; Ding, W.B.; Zou, H.B. Autophagy contributes to the enrichment and survival of colorectal cancer stem cells under oxaliplatin treatment. Cancer Lett. 2015, 361, 128–136. [Google Scholar] [CrossRef]
  132. Smith, A.G.; Macleod, K.F. Autophagy, cancer stem cells and drug resistance. J. Pathol. 2019, 247, 708–718. [Google Scholar] [CrossRef] [Green Version]
  133. Kondo, Y.; Kanzawa, T.; Sawaya, R.; Kondo, S. The role of autophagy in cancer development and response to therapy. Nat. Rev. Cancer 2005, 5, 726–734. [Google Scholar] [CrossRef] [PubMed]
  134. Wang, J.; Wu, G.S. Role of autophagy in cisplatin resistance in ovarian cancer cells. J. Biol. Chem. 2014, 289, 17163–17173. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  135. Chen, S.; Rehman, S.K.; Zhang, W.; Wen, A.; Yao, L.; Zhang, J. Autophagy is a therapeutic target in anti-cancer drug resistance. Biochim. Biophys. Acta (BBA)-Rev. Cancer 2010, 1806, 220–229. [Google Scholar] [CrossRef]
  136. Hao, C.; Liu, G.; Tian, G. Autophagy inhibition of cancer stem cells promotes the efficacy of cisplatin against non-small cell lung carcinoma. Ther. Adv. Respir. Dis. 2019, 13, 1753466619866097. [Google Scholar] [CrossRef] [Green Version]
  137. Yao, J.; Deng, K.; Huang, J.; Zeng, R.; Zuo, J. Progress in the understanding of the mechanism of tamoxifen resistance in breast cancer. Front. Pharmacol. 2020, 11, 592912. [Google Scholar] [CrossRef] [PubMed]
  138. Zheng, S.; Shu, Y.; Lu, Y.; Sun, Y. Chloroquine Combined with Imatinib Overcomes Imatinib Resistance in Gastrointestinal Stromal Tumors by Inhibiting Autophagy via the MAPK/ERK Pathway. OncoTargets Ther. 2020, 13, 6433. [Google Scholar] [CrossRef]
  139. Nguyen, H.G.; Yang, J.C.; Kung, H.-J.; Shi, X.-B.; Tilki, D.; Lara, P.N.; White, R.W.D.; Gao, A.C.; Evans, C.P. Targeting autophagy overcomes Enzalutamide resistance in castration-resistant prostate cancer cells and improves therapeutic response in a xenograft model. Oncogene 2014, 33, 4521–4530. [Google Scholar] [CrossRef] [Green Version]
  140. Baquero, P.; Dawson, A.; Mukhopadhyay, A.; Kuntz, E.M.; Mitchell, R.; Olivares, O.; Helgason, G.V. Targeting quiescent leukemic stem cells using second generation autophagy inhibitors. Leukemia 2019, 33, 981–994. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  141. Bellodi, C.; Lidonnici, M.R.; Hamilton, A.; Helgason, G.V.; Soliera, A.R.; Ronchetti, M.; Galavotti, S.; Young, K.W.; Selmi, T.; Yacobi, R.; et al. Targeting autophagy potentiates tyrosine kinase inhibitor-induced cell death in Philadelphia chromosome-positive cells, including primary CML stem cells. J. Clin. Investig. 2009, 119, 1109–1123. [Google Scholar] [CrossRef] [PubMed]
  142. Rothe, K.; Watanabe, A.; Forrest, D.L.; Gorski, S.; Young, R.; Jiang, X. Inhibiting the core autophagy enzyme atg4b with novel drugs sensitizes resistant leukemic stem/progenitor cells to standard targeted therapy. Blood 2018, 132, 933. [Google Scholar] [CrossRef]
  143. Ran, X.; Zhou, P.; Zhang, K. Autophagy plays an important role in stemness mediation and the novel dual function of EIG121 in both autophagy and stemness regulation of endometrial carcinoma JEC cells. Int. J. Oncol. 2017, 51, 644–656. [Google Scholar] [CrossRef] [Green Version]
  144. Kumar, B.; Ahmad, R.; Sharma, S.; Gowrikumar, S.; Primeaux, M.; Rana, S.; Singh, A.B. Pik3c3 inhibition promotes sensitivity to colon cancer therapy by inhibiting cancer stem cells. Cancers 2021, 13, 2168. [Google Scholar] [CrossRef] [PubMed]
  145. Wu, S.; Wang, X.; Chen, J.; Chen, Y. Autophagy of cancer stem cells is involved with chemoresistance of colon cancer cells. Biochem. Biophys. Res. Commun. 2013, 434, 898–903. [Google Scholar] [CrossRef] [PubMed]
  146. Yan, C.; Luo, L.; Guo, C.Y.; Goto, S.; Urata, Y.; Shao, J.H.; Li, T.S. Doxorubicin-induced mitophagy contributes to drug resistance in cancer stem cells from HCT8 human colorectal cancer cells. Cancer Lett. 2017, 388, 34–42. [Google Scholar] [CrossRef] [PubMed]
  147. Wei, M.F.; Chen, M.W.; Chen, K.C.; Lou, P.J.; Lin, S.Y.; Hung, S.C.; Hsiao, M.; Yao, C.J.; Shieh, M.J. Autophagy promotes resistance to photodynamic therapy-induced apoptosis selectively in colorectal cancer stem-like cells. Autophagy 2014, 10, 1179–1192. [Google Scholar] [CrossRef] [PubMed]
  148. Liang, D.H.; Choi, D.S.; Ensor, J.E.; Kaipparettu, B.A.; Bass, B.L.; Chang, J.C. The autophagy inhibitor chloroquine targets cancer stem cells in triple negative breast cancer by inducing mitochondrial damage and impairing DNA break repair. Cancer Lett. 2016, 376, 249–258. [Google Scholar] [CrossRef] [Green Version]
  149. Sun, R.; Shen, S.; Zhang, Y.J.; Xu, C.F.; Cao, Z.T.; Wen, L.P.; Wang, J. Nanoparticle-facilitated autophagy inhibition promotes the efficacy of chemotherapeutics against breast cancer stem cells. Biomaterials 2016, 103, 44–55. [Google Scholar] [CrossRef]
  150. Huang, H.; Song, J.; Liu, Z.; Pan, L.; Xu, G. Autophagy activation promotes bevacizumab resistance in glioblastoma by suppressing Akt/mTOR signaling pathway. Oncol. Lett. 2018, 15, 1487–1494. [Google Scholar] [CrossRef] [Green Version]
  151. Pagotto, A.; Pilotto, G.; Mazzoldi, E.L.; Nicoletto, M.O.; Frezzini, S.; Pastò, A.; Amadori, A. Autophagy inhibition reduces chemoresistance and tumorigenic potential of human ovarian cancer stem cells. Cell Death Dis. 2017, 8, e2943. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  152. Li, L.Q.; Pan, D.; Zhang, S.W.; Xie, D.Y.; Zheng, X.L.; Chen, H. Autophagy regulates chemoresistance of gastric cancer stem cells via the Notch signaling pathway. Eur. Rev. Med. Pharmacol. Sci. 2018, 22, 3402–3407. [Google Scholar]
  153. Ojha, R.; Singh, S.K.; Bhattacharyya, S. JAK-mediated autophagy regulates stemness and cell survival in cisplatin resistant bladder cancer cells. Biochim. Biophys. Acta 2016, 1860, 2484–2497. [Google Scholar] [CrossRef] [PubMed]
  154. Yang, M.C.; Wang, H.C.; Hou, Y.C.; Tung, H.L.; Chiu, T.J.; Shan, Y.S. Blockade of autophagy reduces pancreatic cancer stem cell activity and potentiates the tumoricidal effect of gemcitabine. Mol. Cancer 2015, 14, 179. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  155. Crea, F.; Danesi, R.; Farrar, W.L. Cancer stem cell epigenetics and chemoresistance. Epigenomics 2009, 1, 63–79. [Google Scholar] [CrossRef] [PubMed]
  156. Jones, P.A.; Baylin, S.B. The fundamental role of epigenetic events in cancer. Nat. Rev. Genet. 2002, 3, 415–428. [Google Scholar] [CrossRef]
  157. Baylin, S.B.; Jones, P.A. Epigenetic Determinants of Cancer. Cold Spring Harb. Perspect. Biol. 2016, 8, a019505. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  158. Ilango, S.; Paital, B.; Jayachandran, P.; Padma, P.R.; Nirmaladevi, R. Epigenetic alterations in cancer. Front. Biosci. 2020, 25, 1058–1109. [Google Scholar]
  159. Keyvani-Ghamsari, S.; Khorsandi, K.; Rasul, A.; Zaman, M.K. Current understanding of epigenetics mechanism as a novel target in reducing cancer stem cells resistance. Clin. Epigenetics 2021, 13, 120. [Google Scholar] [CrossRef]
  160. Toh, T.B.; Lim, J.J.; Chow, E.K. Epigenetics in cancer stem cells. Mol. Cancer 2017, 16, 29. [Google Scholar] [CrossRef] [Green Version]
  161. Abdullah, L.N.; Chow, E.K. Mechanisms of chemoresistance in cancer stem cells. Clin. Transl. Med. 2013, 2, 3. [Google Scholar] [CrossRef] [Green Version]
  162. Wang, Y.; Cardenas, H.; Fang, F.; Condello, S.; Taverna, P.; Segar, M.; Liu, Y.; Nephew, K.P.; Matei, D. Epigenetic targeting of ovarian cancer stem cells. Cancer Res. 2014, 74, 4922–4936. [Google Scholar] [CrossRef] [Green Version]
  163. Cioffi, M.; Trabulo, S.M.; Sanchez-Ripoll, Y.; Miranda-Lorenzo, I.; Lonardo, E.; Dorado, J.; Reis Vieira, C.; Ramirez, J.C.; Hidalgo, M.; Aicher, A.; et al. The miR-17-92 cluster counteracts quiescence and chemoresistance in a distinct subpopulation of pancreatic cancer stem cells. Gut 2015, 64, 1936–1948. [Google Scholar] [CrossRef] [PubMed]
  164. Cai, M.H.; Xu, X.G.; Yan, S.L.; Sun, Z.; Ying, Y.; Wang, B.K.; Tu, Y.X. Depletion of HDAC1, 7 and 8 by histone deacetylase inhibition confers elimination of pancreatic cancer stem cells in combination with gemcitabine. Sci. Rep. 2018, 8, 1621. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  165. Pan, M.R.; Hsu, M.C.; Luo, C.W.; Chen, L.T.; Shan, Y.S.; Hung, W.C. The histone methyltransferase G9a as a therapeutic target to override gemcitabine resistance in pancreatic cancer. Oncotarget 2016, 7, 61136–61151. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  166. Kang, L.; Mao, J.; Tao, Y.; Song, B.; Ma, W.; Lu, Y.; Zhao, L.; Li, J.; Yang, B.; Li, L. MicroRNA-34a suppresses the breast cancer stem cell-like characteristics by downregulating Notch1 pathway. Cancer Sci. 2015, 106, 700–708. [Google Scholar] [CrossRef] [Green Version]
  167. Park, E.Y.; Chang, E.; Lee, E.J.; Lee, H.W.; Kang, H.G.; Chun, K.H.; Woo, Y.M.; Kong, H.K.; Ko, J.Y.; Suzuki, H.; et al. Targeting of miR34a-NOTCH1 axis reduced breast cancer stemness and chemoresistance. Cancer Res. 2014, 74, 7573–7582. [Google Scholar] [CrossRef] [Green Version]
  168. Li, C.Y.; Miao, K.L.; Chen, Y.; Liu, L.Y.; Zhao, G.B.; Lin, M.H.; Jiang, C. Jagged2 promotes cancer stem cell properties of triple negative breast cancer cells and paclitaxel resistance via regulating microRNA-200. Eur. Rev. Med. Pharmacol. Sci. 2018, 22, 6008–6014. [Google Scholar]
  169. Gao, L.; Guo, Q.; Li, X.; Yang, X.; Ni, H.; Wang, T.; Zhao, Q.; Liu, H.; Xing, Y.; Xi, T.; et al. MiR-873/PD-L1 axis regulates the stemness of breast cancer cells. EBioMedicine 2019, 41, 395–407. [Google Scholar] [CrossRef] [Green Version]
  170. Zhu, Y.; Yu, F.; Jiao, Y.; Feng, J.; Tang, W.; Yao, H.; Gong, C.; Chen, J.; Su, F.; Zhang, Y.; et al. Reduced miR-128 in breast tumor-initiating cells induces chemotherapeutic resistance via Bmi-1 and ABCC5. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 2011, 17, 7105–7115. [Google Scholar] [CrossRef]
  171. Chen, X.; Xie, R.; Gu, P.; Huang, M.; Han, J.; Dong, W.; Xie, W.; Wang, B.; He, W.; Zhong, G.; et al. Long Noncoding RNA LBCS Inhibits Self-Renewal and Chemoresistance of Bladder Cancer Stem Cells through Epigenetic Silencing of SOX2. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 2019, 25, 1389–1403. [Google Scholar] [CrossRef] [Green Version]
  172. Almeida, L.O.; Guimarães, D.M.; Martins, M.D.; Martins, M.; Warner, K.A.; Nör, J.E.; Castilho, R.M.; Squarize, C.H. Unlocking the chromatin of adenoid cystic carcinomas using HDAC inhibitors sensitize cancer stem cells to cisplatin and induces tumor senescence. Stem Cell Res. 2017, 21, 94–105. [Google Scholar] [CrossRef]
  173. Staberg, M.; Rasmussen, R.D.; Michaelsen, S.R.; Pedersen, H.; Jensen, K.E.; Villingshøj, M.; Skjoth-Rasmussen, J.; Brennum, J.; Vitting-Seerup, K.; Poulsen, H.S.; et al. Targeting glioma stem-like cell survival and chemoresistance through inhibition of lysine-specific histone demethylase KDM2B. Mol. Oncol. 2018, 12, 406–420. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  174. Singh, R.; Fazal, Z.; Corbet, A.K.; Bikorimana, E.; Rodriguez, J.C.; Khan, E.M.; Shahid, K.; Freemantle, S.J.; Spinella, M.J. Epigenetic Remodeling through Downregulation of Polycomb Repressive Complex 2 Mediates Chemotherapy Resistance in Testicular Germ Cell Tumors. Cancers 2019, 11, 796. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  175. Li, L.; Wang, L.; Li, L.; Wang, Z.; Ho, Y.; McDonald, T.; Holyoake, T.L.; Chen, W.; Bhatia, R. Activation of p53 by SIRT1 inhibition enhances elimination of CML leukemia stem cells in combination with imatinib. Cancer Cell 2012, 21, 266–281. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  176. Bedard, P.L.; Hansen, A.R.; Ratain, M.J.; Siu, L.L. Tumour heterogeneity in the Clinic. Nature 2013, 501, 355–364. [Google Scholar] [CrossRef] [Green Version]
  177. Tang, D.G. Understanding cancer stem cell heterogeneity and plasticity. Cell Res. 2012, 22, 457–472. [Google Scholar] [CrossRef] [Green Version]
  178. Liu, S.; Cong, Y.; Wang, D.; Sun, Y.; Deng, L.; Liu, Y.; Martin-Trevino, R.; Shang, L.; McDermott, S.P.; Landis, M.D.; et al. Breast cancer stem cells transition between epithelial and mesenchymal states reflective of their normal counterparts. Stem Cell Rep. 2014, 2, 78–91. [Google Scholar] [CrossRef]
  179. Ginestier, C.; Hur, M.H.; Charafe-Jauffret, E.; Monville, F.; Dutcher, J.; Brown, M.; Jacquemier, J.; Viens, P.; Kleer, C.G.; Liu, S.; et al. ALDH1 Is a Marker of Normal and Malignant Human Mammary Stem Cells and a Predictor of Poor Clinical Outcome. Cell Stem Cell 2007, 1, 555–567. [Google Scholar] [CrossRef] [Green Version]
  180. Li, X.; Lewis, M.T.; Huang, J.; Gutierrez, C.; Osborne, C.K.; Wu, M.-F.; Hilsenbeck, S.G.; Pavlick, A.; Zhang, X.; Chamness, G.C.; et al. Intrinsic Resistance of Tumorigenic Breast Cancer Cells to Chemotherapy. Gynecol. Oncol. 2008, 100, 672–679. [Google Scholar] [CrossRef]
  181. Olsson, E.; Honeth, G.; Bendahl, P.-O.; Saal, L.H.; Gruvberger-Saal, S.; Ringnér, M.; Vallon-Christersson, J.; Jönsson, G.; Holm, K.; Lövgren, K.; et al. CD44 isoforms are heterogeneously expressed in breast cancer and correlate with tumor subtypes and cancer stem cell markers. BMC Cancer 2011, 11, 418. [Google Scholar] [CrossRef] [Green Version]
  182. van den Hoogen, C.; van der Horst, G.; Cheung, H.; Buijs, J.T.; Lippitt, J.M.; Guzmán-Ramírez, N.; Hamdy, F.C.; Eaton, C.L.; Thalmann, G.N.; Cecchini, M.G.; et al. High Aldehyde Dehydrogenase Activity Identifies Tumor-Initiating and Metastasis-Initiating Cells in Human Prostate Cancer. Cancer Res. 2010, 70, 5163–5173. [Google Scholar] [CrossRef] [Green Version]
  183. Oshimori, N.; Oristian, D.; Fuchs, E. TGF-β promotes heterogeneity and drug resistance in squamous cell carcinoma. Cell 2015, 160, 963–976. [Google Scholar] [CrossRef] [Green Version]
  184. Futakuchi, M.; Lami, K.; Tachibana, Y.; Yamamoto, Y.; Furukawa, M.; Fukuoka, J. The Effects of TGF-β Signaling on Cancer Cells and Cancer Stem Cells in the Bone Microenvironment. Int. J. Mol. Sci. 2019, 20, 5117. [Google Scholar] [CrossRef] [Green Version]
  185. Kalluri, R.; Weinberg, R.A. The basics of epithelial-mesenchymal transition. J. Clin. Investig. 2009, 119, 1420–1428. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  186. Hay, E.D. An overview of epithelio-mesenchymal transformation. Cells Tissues Organs 1995, 154, 8–20. [Google Scholar] [CrossRef] [PubMed]
  187. Nieto, M.A.; Huang, R.Y.J.; Jackson, R.A.; Thiery, J.P. EMT: 2016. Cell 2016, 166, 21–45. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  188. Liao, T.T.; Yang, M.H. Hybrid epithelial/mesenchymal state in cancer metastasis: Clinical significance and regulatory mechanisms. Cells 2020, 9, 623. [Google Scholar] [CrossRef] [Green Version]
  189. Francescangeli, F.; Contavalli, P.; De Angelis, M.L.; Careccia, S.; Signore, M.; Haas, T.L.; Salaris, F.; Baiocchi, M.; Boe, A.; Giuliani, A.; et al. A pre-existing population of ZEB2+ quiescent cells with stemness and mesenchymal features dictate chemoresistance in colorectal cancer. J. Exp. Clin. Cancer Res. 2020, 39, 2. [Google Scholar] [CrossRef] [Green Version]
  190. Bontemps, I.; Lallemand, C.; Biard, D.; Dechamps, N.; Kortulewski, T.; Bourneuf, E.; Siberchicot, C.; Boussin, F.; Chevillard, S.; Campalans, A.; et al. Loss of CD24 promotes radiation-and chemo-resistance by inducing stemness properties associated with a hybrid E/M state in breast cancer cells. Oncol. Rep. 2022, 49, 4. [Google Scholar] [CrossRef]
  191. Najafi, M.; Mortezaee, K.; Majidpoor, J. Cancer stem cell (CSC) resistance drivers. Life Sci. 2019, 234, 116781. [Google Scholar] [CrossRef]
  192. Huang, T.; Song, X.; Xu, D.; Tiek, D.; Goenka, A.; Wu, B.; Sastry, N.; Hu, B.; Cheng, S.-Y. Stem cell programs in cancer initiation, progression, and therapy resistance. Theranostics 2020, 10, 8721. [Google Scholar] [CrossRef]
  193. Russo, M.; Crisafulli, G.; Sogari, A.; Reilly, N.M.; Arena, S.; Lamba, S.; Bardelli, A. Adaptive mutability of colorectal cancers in response to targeted therapies. Science 2019, 366, 1473–1480. [Google Scholar] [CrossRef] [PubMed]
  194. Das, P.K.; Islam, F.; Lam, A.K. The roles of cancer stem cells and therapy resistance in colorectal carcinoma. Cells 2020, 9, 1392. [Google Scholar] [CrossRef] [PubMed]
  195. Di Fiore, R.; Suleiman, S.; Drago-Ferrante, R.; Subbannayya, Y.; Pentimalli, F.; Giordano, A.; Calleja-Agius, J. Cancer Stem Cells and Their Possible Implications in Cervical Cancer: A Short Review. Int. J. Mol. Sci. 2022, 23, 5167. [Google Scholar] [CrossRef] [PubMed]
  196. Boesch, M.; Zeimet, A.G.; Reimer, D.; Schmidt, S.; Gastl, G.; Parson, W.; Spoeck, F.; Hatina, J.; Wolf, D.; Sopper, S. The side population of ovarian cancer cells defines a heterogeneous compartment exhibiting stem cell characteristics. Oncotarget 2014, 5, 7027. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  197. Wang, D.; Li, Y.; Ge, H.; Ghadban, T.; Reeh, M.; Güngör, C. The Extracellular Matrix: A Key Accomplice of Cancer Stem Cell Migration, Metastasis Formation, and Drug Resistance in PDAC. Cancers 2022, 14, 3998. [Google Scholar] [CrossRef] [PubMed]
  198. Nawara, H.M.; Afify, S.M.; Hassan, G.; Zahra, M.H.; Seno, A.; Seno, M. Paclitaxel-based chemotherapy targeting cancer stem cells from mono-to combination therapy. Biomedicines 2021, 9, 500. [Google Scholar] [CrossRef] [PubMed]
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Kim, M.; Bakyt, L.; Akhmetkaliyev, A.; Toktarkhanova, D.; Bulanin, D. Re-Sensitizing Cancer Stem Cells to Conventional Chemotherapy Agents. Int. J. Mol. Sci. 2023, 24, 2122. https://doi.org/10.3390/ijms24032122

AMA Style

Kim M, Bakyt L, Akhmetkaliyev A, Toktarkhanova D, Bulanin D. Re-Sensitizing Cancer Stem Cells to Conventional Chemotherapy Agents. International Journal of Molecular Sciences. 2023; 24(3):2122. https://doi.org/10.3390/ijms24032122

Chicago/Turabian Style

Kim, Mariyam, Laura Bakyt, Azamat Akhmetkaliyev, Dana Toktarkhanova, and Denis Bulanin. 2023. "Re-Sensitizing Cancer Stem Cells to Conventional Chemotherapy Agents" International Journal of Molecular Sciences 24, no. 3: 2122. https://doi.org/10.3390/ijms24032122

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