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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (30 June 2017) | Viewed by 99169

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Prof. Dr. Hiroyuki Tomita

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Department of Tumor Pathology, Gifu University School of Medicine, 1-1 Yanagido, Gifu 501-1194, Japan
Interests: pathology; tumor microenvironment; carcinogenesis; stem cell; mouse models
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Prof. Dr. Masahito Shimizu

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First Department of Internal Medicine, Gifu University Hospital, Gifu 501-1194, Japan
Interests: liver carcinogenesis; cancer chemoprevention; chronic hepatitis; metabolic syndrome; retinoid; phytochemicals; clinical trial
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Prof. Dr. Takuji Tanaka

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Department of Diagnostic Pathology and Research Center of Diagnostic Pathology, Gifu Municipal Hospital, 7-1 Kashima-cho, Gifu 500-8513, Japan
Interests: colorectal carcinogenesis; cancer chemiprevention; inflammatory bowel disease; ulcerative colitis; Crohn’s disease; animal model
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The cancer stem cell (CSC) theory assumes that a small population of cells with stem cell like features is causative of tumor growth, resistance, and recurrence in many human malignancies. This theory could be a beneficial paradigm for producing innovative and targeted drug therapies.

Currently, controversial issues have arisen regarding the CSCs. First, it is unclear whether CSCs can give rise to multiple differentiated cell types. Second, it is unclear whether normal cellular precursors of CSCs are true normal tissue SCs; for example, the CSC model usually stands on the basis of experimental characterizations of cancer cell populations. In normal tissue SCs, the surrounding microenvironment is considered to be normal, however, CSCs usually have aberrant microenvironments, such as severe inflammation, hypoxia, and/or low nutrient conditions.

We expect that this Special Issue will provide hot information on the above-mentioned topics, and will be of interest to scientists and clinicians working in the area of cancer research.

Dr. Hiroyuki Tomita
Prof. Dr. Takuji Tanaka
Prof. Dr. Masahito Shimizu
Guest Editors

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Keywords

Cancer stem cell
Stem cell marker
Tissue stem cell
Carcinogenesis
Chemoprevention
Animal model
Inflammation
Tumor microenvironment

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Published Papers (12 papers)

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3395 KiB

Open AccessArticle

Podocalyxin-Like Protein 1 Regulates TAZ Signaling and Stemness Properties in Colon Cancer

by Wen-Ying Lee, Chih-Chia Kuo, Bo-Xing Lin, Chia-Hsiung Cheng, Ku-Chung Chen and Cheng-Wei Lin

Int. J. Mol. Sci. 2017, 18(10), 2047; https://doi.org/10.3390/ijms18102047 - 23 Sep 2017

Cited by 16 | Viewed by 5740

Abstract

Colon cancer is the third most common cancer in the world and the second most common cause of cancer-related mortality. Molecular biomarkers for colon cancer have undergone vigorous discovery and validation. Recent studies reported that overexpression of podocalyxin-like protein 1 (PODXL) is associated with distant metastasis and poor prognosis across several types of malignancies. Its role and underlying molecular mechanism, however, are not yet fully understood. In the present study, we revealed that the Hippo transducer, the transcriptional coactivator with PDZ-binding motif (TAZ), acts as a downstream mediator of PODXL in colon cancer. Inhibition of PODXL resulted in the suppression of TAZ signaling and the downregulation of Hippo downstream genes. Moreover, PODXL plays a critical role in cancer stemness, invasiveness, and sensitivity to chemotherapies in colon cancer HCT15 cells. Notably, expression of PODXL showed a positive correlation with stem-like and epithelial-mesenchymal transition (EMT) core signatures, and was associated with poor survival outcomes in patients with colon cancer. These findings provide novel insights into the molecular mechanism of PODXL-mediated tumorigenesis in colon cancer. Full article

(This article belongs to the Special Issue Cancer Stem Cells)

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Open AccessCommunication

Morphological Evaluation of Tumor-Infiltrating Lymphocytes (TILs) to Investigate Invasive Breast Cancer Immunogenicity, Reveal Lymphocytic Networks and Help Relapse Prediction: A Retrospective Study

by Gloria Romagnoli, Meike Wiedermann, Friederike Hübner, Antonia Wenners, Micaela Mathiak, Christoph Röcken, Nicolai Maass, Wolfram Klapper and Ibrahim Alkatout

Int. J. Mol. Sci. 2017, 18(9), 1936; https://doi.org/10.3390/ijms18091936 - 8 Sep 2017

Cited by 19 | Viewed by 7713

Abstract

Tumor-infiltrating lymphocytes (TILs) in breast cancer are a key representative of the tumor immune microenvironment and have been shown to provide prognostic and predictive biomarkers. The extent of lymphocytic infiltration in tumor tissues can be assessed by evaluating hematoxylin and eosin (H&E)-stained tumor sections. We investigated tissue microarrays of 31 invasive breast cancer patients, looking at quantity and topological distribution of CD3+, CD8+, CD20+, Ki67+, FoxP3+ TILs and CD3+/FoxP3+, CD8+/FoxP3+ cell ratios. We separately evaluated TILs at the invasive edge and at the center of the tumor, to find any clinical implications of tumor heterogeneity. No statistically significant difference was found in quantity and distribution of both TIL subsets and TIL ratios, by comparing patients who suffered from a local or distant recurrence of the tumor (relapse group: 13 patients) with patients not showing cancer relapse (non-relapse group: 18 patients). In the whole sample, we observed three main statistically significant positive correlations: (1) between CD3+ and CD8+ T-cells; (2) between FoxP3+ and Ki67+ lymphocyte infiltration; (3) between CD3+/FoxP3+ cell ratio (C3FR) and CD8+/FoxP3+ cell ratio (C8FR). Tumor heterogeneity and stronger positive TIL associations were found in the non-relapse group, where both CD3–CD8 and FoxP3-Ki67 inter-correlations were found to be significant at the center of the tumor, while the correlation between C3FR and C8FR was significant at the invasive edge. No correlations between TIL subsets were detected in the relapse group. Our findings suggest the existence of stronger inter-subtype lymphocytic networks in invasive breast cancer not showing recurrence. Further evaluations of clinical and topological correlations between and within TIL subsets are needed, in addition to the assessment of TIL quantification and distribution, in order to follow up on whether morphological evaluation of TILs might reveal the underlying lymphocytic functional connectivity and help relapse prediction. Full article

(This article belongs to the Special Issue Cancer Stem Cells)

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Open AccessArticle

Bromopropane Compounds Increase the Stemness of Colorectal Cancer Cells

by Young-Chang Cho, Thanh Thi Nguyen, So-Yeon Park, Kwonseop Kim, Hyung Sik Kim, Hye Gwang Jeong, Kyung Keun Kim and Hangun Kim

Int. J. Mol. Sci. 2017, 18(9), 1888; https://doi.org/10.3390/ijms18091888 - 1 Sep 2017

Cited by 5 | Viewed by 5208

Abstract

Bromopropane (BP) compounds, including 1-bromopropane, 2-bromopropane, and 1,2-dibromopropane, are used in industry for various purposes, and their deleterious effects on human health are becoming known. In this study, we examined the effects of BP compounds on the stemness of colorectal cancer cells. At low, non-cytotoxic concentrations, BP compounds significantly increased spheroid formation in CSC221, DLD1, Caco2, and HT29 cells. In addition, the levels of cancer stem cell markers, such as aldehyde dehydrogenase-1, cluster of differentiation 133 (CD133), CD44, Lgr5, Musashi-1, Ephrin receptor, and Bmi-1 increased after exposure to BP compounds. BP compounds increased the transcriptional activity of the TOPflash and glioma-associated oncogene homolog zinc finger protein (Gli) promoters in reporter assays and increased the expression of Gli-1, Gli-2, Smoothened (SMO), and β-catenin by RT-PCR. These results demonstrate for the first time that BP compounds have the potential to promote cancer stemness. Full article

(This article belongs to the Special Issue Cancer Stem Cells)

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3883 KiB

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Targeting Apoptotic Activity Against Prostate Cancer Stem Cells

by Dagmara Jaworska and Ewelina Szliszka

Int. J. Mol. Sci. 2017, 18(8), 1648; https://doi.org/10.3390/ijms18081648 - 29 Jul 2017

Cited by 15 | Viewed by 6172

Abstract

Numerous data suggest that an increase of cancer stem cells (CSCs) in tumor mass can be the reason for failure of conventional therapies because of their resistance. CD44+/CD24− cells are a putative cancer stem cells subpopulation in prostate cancer. TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) is an activator of apoptosis in tumor cells. However, some tumors are TRAIL-resistant. Cancer cells can be re-sensitized to TRAIL induced apoptosis by a combination of TRAIL and taxanes. The aim of this work was to analyze the enhancement of the anticancer effect of TRAIL by paclitaxel, cabazitaxel and docetaxel in the whole population of PC3 and DU145 prostate cancer cells, but also in CD44+/CD24− prostate cancer stem cells. We examined the apoptotic effect of TRAIL and taxanes using flow cytometry and Annexin-V-PE staining. The co-treatment with taxanes and TRAIL enhanced significantly the apoptosis in CD44+/CD24− cells only in PC3 cell line but not in DU145 cells. We discovered also that taxanes can increase the expression of death receptor TRAIL-R2 in PC3 prostate cancer cells. The results of our study show that treatment with paclitaxel, cabazitaxel and docetaxel is able to enhance the apoptosis induced by TRAIL even in prostate cancer stem cells. Full article

(This article belongs to the Special Issue Cancer Stem Cells)

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Hypoxia Mediates Differential Response to Anti-EGFR Therapy in HNSCC Cells

by Emilia Wiechec, Katharina Tiefenböck Hansson, Lisa Alexandersson, Jan-Ingvar Jönsson and Karin Roberg

Int. J. Mol. Sci. 2017, 18(5), 943; https://doi.org/10.3390/ijms18050943 - 29 Apr 2017

Cited by 23 | Viewed by 5517

Abstract

Despite advances in the head and neck squamous cell carcinoma (HNSCC) treatment modalities, drug resistance and cancer recurrence are often reported. Hypoxia signaling through hypoxia-inducible factor 1 (HIF-1) promotes angiogenesis and metastasis by inducing epithelial-mesenchymal-transition (EMT). The aim of this study was to evaluate the impact of hypoxia on response to therapy as well as EMT and expression of stem cell markers in HNSCC cells. Five HNSCC cell lines (UT-SCC-2, UT-SCC-14, LK0412, LK0827, and LK0923) were selected for this study. The treatment sensitivity for radiation, cisplatin, cetuximab, and dasatinib was assessed by crystal violet assay. Gene expression of EMT and cancer stem cell (CSC) markers as well as protein level of EGFR signaling molecules were analyzed by qPCR and western blotting, respectively. Unlike UT-SCC-14 and LK0827, the LK0412 cell line became significantly more sensitive to cetuximab in hypoxic conditions. This cetuximab sensitivity was efficiently reversed after suppression of HIF-1α with siRNA. Additionally, hypoxia-induced EMT and expression of stem cell markers in HNSCC cells was partially revoked by treatment with cetuximab or knockdown of HIF-1α. In summary, our study shows that hypoxia might have a positive influence on the anti-EGFR therapy effectiveness in HNSCC. However, due to heterogeneity of HNSCC lesions, targeting HIF-1α may not be sufficient to mediate such a response. Further studies identifying a trait of hypoxia-specific response to cetuximab in HNSCC are advisable. Full article

(This article belongs to the Special Issue Cancer Stem Cells)

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Open AccessArticle

NANOG Expression as a Responsive Biomarker during Treatment with Hedgehog Signal Inhibitor in Acute Myeloid Leukemia

by Seiji Kakiuchi, Yosuke Minami, Yoshiharu Miyata, Yu Mizutani, Hideaki Goto, Shinichiro Kawamoto, Kimikazu Yakushijin, Keiji Kurata, Hiroshi Matsuoka and Hironobu Minami

Int. J. Mol. Sci. 2017, 18(3), 486; https://doi.org/10.3390/ijms18030486 - 24 Feb 2017

Cited by 18 | Viewed by 5199

Abstract

Aberrant activation of the Hedgehog (Hh) signaling pathway is involved in the maintenance of leukemic stem cell (LSCs) populations. PF-0444913 (PF-913) is a novel inhibitor that selectively targets Smoothened (SMO), which regulates the Hh pathway. Treatment with PF-913 has shown promising results in an early phase study of acute myeloid leukemia (AML). However, a detailed mode of action for PF-913 and relevant biomarkers remain to be elucidated. In this study, we examined bone marrow samples derived from AML patients under PF-913 monotherapy. Gene set enrichment analysis (GSEA) revealed that PF-913 treatment affected the self-renewal signature and cell-cycle regulation associated with LSC-like properties. We then focused on the expression of a pluripotency factor, NANOG, because previous reports showed that a downstream effector in the Hh pathway, GLI, directly binds to the NANOG promoter and that the GLI-NANOG axis promotes stemness and growth in several cancers. In this study, we found that a change in NANOG transcripts was closely associated with GLI-target genes and NANOG transcripts can be a responsive biomarker during PF-913 therapy. Additionally, the treatment of AML with PF-913 holds promise, possibly through inducing quiescent leukemia stem cells toward cell cycling. Full article

(This article belongs to the Special Issue Cancer Stem Cells)

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3970 KiB

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Heat Shock Factor 1 Depletion Sensitizes A172 Glioblastoma Cells to Temozolomide via Suppression of Cancer Stem Cell-Like Properties

by Chang-Nim Im, Hye Hyeon Yun and Jeong-Hwa Lee

Int. J. Mol. Sci. 2017, 18(2), 468; https://doi.org/10.3390/ijms18020468 - 22 Feb 2017

Cited by 18 | Viewed by 9067

Abstract

Heat shock factor 1 (HSF1), a transcription factor activated by various stressors, regulates proliferation and apoptosis by inducing expression of target genes, such as heat shock proteins and Bcl-2 (B-cell lymphoma 2) interacting cell death suppressor (BIS). HSF1 also directly interacts with BIS, although it is still unclear whether this interaction is critical in the regulation of glioblastoma stem cells (GSCs). In this study, we examined whether small interfering RNA-mediated BIS knockdown decreased protein levels of HSF1 and subsequent nuclear localization under GSC-like sphere (SP)-forming conditions. Consistent with BIS depletion, HSF1 knockdown also reduced sex determining region Y (SRY)-box 2 (SOX2) expression, a marker of stemness, accompanying the decrease in SP-forming ability and matrix metalloprotease 2 (MMP2) activity. When HSF1 or BIS knockdown was combined with temozolomide (TMZ) treatment, a standard drug used in glioblastoma therapy, apoptosis increased, as measured by an increase in poly (ADP-ribose) polymerase (PARP) cleavage, whereas cancer stem-like properties, such as colony-forming activity and SOX2 protein expression, decreased. Taken together, our findings suggest that targeting BIS or HSF1 could be a viable therapeutic strategy for GSCs resistant to conventional TMZ treatment. Full article

(This article belongs to the Special Issue Cancer Stem Cells)

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Review

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Drug Resistance Driven by Cancer Stem Cells and Their Niche

by Marta Prieto-Vila, Ryou-u Takahashi, Wataru Usuba, Isaku Kohama and Takahiro Ochiya

Int. J. Mol. Sci. 2017, 18(12), 2574; https://doi.org/10.3390/ijms18122574 - 1 Dec 2017

Cited by 389 | Viewed by 12089

Abstract

Drug resistance represents one of the greatest challenges in cancer treatment. Cancer stem cells (CSCs), a subset of cells within the tumor with the potential for self-renewal, differentiation and tumorigenicity, are thought to be the major cause of cancer therapy failure due to their considerable chemo- and radioresistance, resulting in tumor recurrence and eventually metastasis. CSCs are situated in a specialized microenvironment termed the niche, mainly composed of fibroblasts and endothelial, mesenchymal and immune cells, which also play pivotal roles in drug resistance. These neighboring cells promote the molecular signaling pathways required for CSC maintenance and survival and also trigger endogenous drug resistance in CSCs. In addition, tumor niche components such as the extracellular matrix also physically shelter CSCs from therapeutic agents. Interestingly, CSCs contribute directly to the niche in a bilateral feedback loop manner. Here, we review the recent advances in the study of CSCs, the niche and especially their collective contribution to resistance, since increasingly studies suggest that this interaction should be considered as a target for therapeutic strategies. Full article

(This article belongs to the Special Issue Cancer Stem Cells)

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Open AccessReview

Metaplasia in the Stomach—Precursor of Gastric Cancer?

by Hiroto Kinoshita, Yoku Hayakawa and Kazuhiko Koike

Int. J. Mol. Sci. 2017, 18(10), 2063; https://doi.org/10.3390/ijms18102063 - 27 Sep 2017

Cited by 67 | Viewed by 11716

Abstract

Despite a significant decrease in the incidence of gastric cancer in Western countries over the past century, gastric cancer is still one of the leading causes of cancer-related deaths worldwide. Most human gastric cancers develop after long-term Helicobacter pylori infection via the Correa pathway: the progression is from gastritis, atrophy, intestinal metaplasia, dysplasia, to cancer. However, it remains unclear whether metaplasia is a direct precursor of gastric cancer or merely a marker of high cancer risk. Here, we review human studies on the relationship between metaplasia and cancer in the stomach, data from mouse models of metaplasia regarding the mechanism of metaplasia development, and the cellular responses induced by H. pylori infection. Full article

(This article belongs to the Special Issue Cancer Stem Cells)

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1785 KiB

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Activation of Matrix Hyaluronan-Mediated CD44 Signaling, Epigenetic Regulation and Chemoresistance in Head and Neck Cancer Stem Cells

by Lilly Y. W. Bourguignon, Christine Earle and Marisa Shiina

Int. J. Mol. Sci. 2017, 18(9), 1849; https://doi.org/10.3390/ijms18091849 - 24 Aug 2017

Cited by 66 | Viewed by 9674

Abstract

Head and neck squamous cell carcinoma (HNSCC) is a solid tumor composed by a genotypically and phenotypically heterogeneous population of neoplastic cells types. High recurrence rate and regional metastases lead to major morbidity and mortality. Recently, many studies have focused on cellular and molecular mechanisms of tumor progression that can help to predict prognosis and to choose the best therapeutic approach for HNSCC patients. Hyaluronan (HA), an important glycosaminoglycan component of the extracellular matrix (ECM), and its major cell surface receptor, CD44, have been suggested to be important cellular mediators influencing tumor progression and treatment resistance in head and neck cancer. HNSCC contains a small subpopulation of cells that exhibit a hallmark of CD44-expressing cancer stem cell (CSC) properties with self-renewal, multipotency, and a unique potential for tumor initiation. HA has been shown to stimulate a variety of CSC functions including self-renewal, clone formation and differentiation. This review article will present current evidence for the existence of a unique small population of CD44v3^highALDH^high-expressing CSCs in HNSCC. A special focus will be placed on the role of HA/CD44-induced oncogenic signaling and histone methyltransferase, DOT1L activities in regulating histone modifications (via epigenetic changes) and miRNA activation. Many of these events are essential for the CSC properties such as Nanog/Oct4/Sox2 expression, spheroid/clone formation, self-renewal, tumor cell migration/invasion, survival and chemotherapeutic drug resistance in HA-activated head and neck cancer. These newly-discovered HA/CD44-mediated oncogenic signaling pathways delineate unique tumor dynamics with implications for defining the drivers of HNSCC progression processes. Most importantly, the important knowledge obtained from HA/CD44-regulated CSC signaling and functional activation could provide new information regarding the design of novel drug targets to overcome current therapeutic drug resistance which will have significant treatment implications for head and neck cancer patients. Full article

(This article belongs to the Special Issue Cancer Stem Cells)

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1009 KiB

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Roles of Wnt Target Genes in the Journey of Cancer Stem Cells

by Jee-Heun Kim, So-Yeon Park, Youngsoo Jun, Ji-Young Kim and Jeong-Seok Nam

Int. J. Mol. Sci. 2017, 18(8), 1604; https://doi.org/10.3390/ijms18081604 - 25 Jul 2017

Cited by 72 | Viewed by 9305

Abstract

The importance of Wnt/β-catenin signaling in cancer stem cells (CSCs) has been acknowledged; however, the mechanism through which it regulates the biological function of CSCs and promotes cancer progression remains elusive. Hence, to understand the intricate mechanism by which Wnt controls stemness, the specific downstream target genes of Wnt were established by analyzing the genetic signatures of multiple types of metastatic cancers based on gene set enrichment. By focusing on the molecular function of Wnt target genes, the biological roles of Wnt were interpreted in terms of CSC dynamics from initiation to metastasis. Wnt signaling participates in cancer initiation by generating CSCs from normal stem cells or non-CSCs and augmenting persistent growth at the primary region, which is resistant to anti-cancer therapy. Moreover, it assists CSCs in invading nearby tissues and in entering the blood stream, during which the negative feedback of the Wnt signaling pathway maintains CSCs in a dormant state that is suitable for survival. When CSCs arrive at distant organs, another burst of Wnt signaling induces CSCs to succeed in re-initiation and colonization. This comprehensive understanding of Wnt target genes provides a plausible explanation for how Wnt allows CSCs variation during cancer progression. Full article

(This article belongs to the Special Issue Cancer Stem Cells)

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Multifaceted Interpretation of Colon Cancer Stem Cells

by Yuichiro Hatano, Shinya Fukuda, Kenji Hisamatsu, Akihiro Hirata, Akira Hara and Hiroyuki Tomita

Int. J. Mol. Sci. 2017, 18(7), 1446; https://doi.org/10.3390/ijms18071446 - 5 Jul 2017

Cited by 54 | Viewed by 10625

Abstract

Colon cancer is one of the leading causes of cancer-related deaths worldwide, despite recent advances in clinical oncology. Accumulating evidence sheds light on the existence of cancer stem cells and their role in conferring therapeutic resistance. Cancer stem cells are a minor fraction of cancer cells, which enable tumor heterogeneity and initiate tumor formation. In addition, these cells are resistant to various cytotoxic factors. Therefore, elimination of cancer stem cells is difficult but essential to cure the malignant foci completely. Herein, we review the recent evidence for intestinal stem cells and colon cancer stem cells, methods to detect the tumor-initiating cells, and clinical significance of cancer stem cell markers. We also describe the emerging problems of cancer stem cell theory, including bidirectional conversion and intertumoral heterogeneity of stem cell phenotype. Full article

(This article belongs to the Special Issue Cancer Stem Cells)

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