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20 pages, 4637 KiB

Open AccessArticle

ERRα Up-Regulates Invadopodia Formation by Targeting HMGCS1 to Promote Endometrial Cancer Invasion and Metastasis

by Shuting Tang, Jincheng Ma, Pingping Su, Huifang Lei, Yao Tong, Liangzhi Cai, Shuxia Xu, Xiaodan Mao and Pengming Sun

Int. J. Mol. Sci. 2023, 24(4), 4010; https://doi.org/10.3390/ijms24044010 - 16 Feb 2023

Cited by 1 | Viewed by 2194

Abstract

Estrogen-related receptor alpha (ERRα) plays an important role in endometrial cancer (EC) progression. However, the biological roles of ERRα in EC invasion and metastasis are not clear. This study aimed to investigate the role of ERRα and 3-hydroxy-3-methylglutaryl-CoA synthase 1 (HMGCS1) in regulating [...] Read more.

Estrogen-related receptor alpha (ERRα) plays an important role in endometrial cancer (EC) progression. However, the biological roles of ERRα in EC invasion and metastasis are not clear. This study aimed to investigate the role of ERRα and 3-hydroxy-3-methylglutaryl-CoA synthase 1 (HMGCS1) in regulating intracellular cholesterol metabolism to promote EC progression. ERRα and HMGCS1 interactions were detected by co-immunoprecipitation, and the effects of ERRα/HMGCS1 on the metastasis of EC were investigated by wound-healing and transwell chamber invasion assays. Cellular cholesterol content was measured to verify the relationship between ERRα and cellular cholesterol metabolism. Additionally, immunohistochemistry was performed to confirm that ERRα and HMGCS1 were related to EC progression. Furthermore, the mechanism was investigated using loss-of-function and gain-of-function assays or treatment with simvastatin. High expression levels of ERRα and HMGCS1 promoted intracellular cholesterol metabolism for invadopodia formation. Moreover, inhibiting ERRα and HMGCS1 expression significantly weakened the malignant progression of EC in vitro and in vivo. Our functional analysis showed that ERRα promoted EC invasion and metastasis through the HMGCS1-mediated intracellular cholesterol metabolism pathway, which was dependent on the epithelial–mesenchymal transition pathway. Our findings suggest that ERRα and HMGCS1 are potential targets to suppress EC progression. Full article

(This article belongs to the Special Issue Cancer Cell Invasion and Metastases 2.0)

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34 pages, 13232 KiB

Open AccessArticle

Lectin-Based Study Reveals the Presence of Disease-Relevant Glycoepitopes in Bladder Cancer Cells and Ectosomes

by Magdalena Surman, Magdalena Wilczak and Małgorzata Przybyło

Int. J. Mol. Sci. 2022, 23(22), 14368; https://doi.org/10.3390/ijms232214368 - 19 Nov 2022

Cited by 6 | Viewed by 1952

Abstract

Bladder cancer is a malignancy that remains a therapeutic challenge and requires the identification of new biomarkers and mechanisms of progression. Several studies showed that extracellular vesicles promote angiogenesis, migration and metastasis, and inhibit apoptosis in bladder cancer. This effect may depend on [...] Read more.

Bladder cancer is a malignancy that remains a therapeutic challenge and requires the identification of new biomarkers and mechanisms of progression. Several studies showed that extracellular vesicles promote angiogenesis, migration and metastasis, and inhibit apoptosis in bladder cancer. This effect may depend on their glycosylation status. Thus, the aim of this study was to compare glycosylation profiles of T-24 urothelial bladder cancer cells, HCV-29 normal ureter epithelial cells, and ectosomes released by both cell lines using lectin blotting and flow cytometry. Ectosomes displayed distinct total and surface glycosylation profiles with abundance of β-1,6-branched glycans and sialilated structures. Then, it was investigated whether the glycosylation status of the T-24 and HCV-29 cells is responsible for the effect exerted by ectosomes on the proliferation and migration of recipient cells. Stronger proproliferative and promigratory activity of T-24-derived ectosomes was observed in comparison to ectosomes from HCV-29 cells. When ectosomes were isolated from DMJ-treated cells, the aforementioned effects were diminished, suggesting that glycans carried by ectosomes were involved in modulation of recipient cell function. HCV-29- and T-24-derived ectosomes also increased the viability and motility of endothelial HUVEC cells and Hs27 fibroblasts. This supports the hypothesis that ectosomes can modulate the function of various cells present in the tumor microenvironment. Full article

(This article belongs to the Special Issue Cancer Cell Invasion and Metastases 2.0)

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19 pages, 15905 KiB

Open AccessArticle

Adiponectin Suppresses Metastasis of Nasopharyngeal Carcinoma through Blocking the Activation of NF-κB and STAT3 Signaling

by Zongmeng Zhang, Jinlin Du, Qihua Xu, Chaofeng Xing, Yuyu Li, Sujin Zhou, Zhenggang Zhao, Yunping Mu, Zijian (Allan) Zhao, Sumei Cao and Fanghong Li

Int. J. Mol. Sci. 2022, 23(21), 12729; https://doi.org/10.3390/ijms232112729 - 22 Oct 2022

Cited by 8 | Viewed by 1885

Abstract

Adiponectin is an adipocytokine with anti-inflammatory and anticancer properties. Our previous study has shown that blood adiponectin levels were inversely correlated to the risk of nasopharyngeal carcinoma (NPC), and that adiponectin could directly suppress the proliferation of NPC cells. However, the effect of [...] Read more.

Adiponectin is an adipocytokine with anti-inflammatory and anticancer properties. Our previous study has shown that blood adiponectin levels were inversely correlated to the risk of nasopharyngeal carcinoma (NPC), and that adiponectin could directly suppress the proliferation of NPC cells. However, the effect of adiponectin on NPC metastasis remains unknown. Here, we revealed in clinical studies that serum adiponectin level was inversely correlated with tumor stage, recurrence, and metastasis in NPC patients, and that low serum adiponectin level also correlates with poor metastasis-free survival. Coculture with recombinant adiponectin suppressed the migration and invasion of NPC cells as well as epithelial–mesenchymal transition (EMT). In addition, recombinant adiponectin dampened the activation of NF-κB and STAT3 signaling pathways induced by adipocyte-derived proinflammatory factors such as leptin, IL-6, and TNF-α. Pharmacological activation of adiponectin receptor through its specific agonist, AdipoRon, largely stalled the metastasis of NPC cells. Taken together, these findings demonstrated that adiponectin could not only regulate metabolism and inhibit cancer growth, but also suppress the metastasis of NPC. Pharmacological activation of adiponectin receptor may be a promising therapeutic strategy to stall NPC metastasis and extend patients’ survival. Full article

(This article belongs to the Special Issue Cancer Cell Invasion and Metastases 2.0)

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12 pages, 4264 KiB

Open AccessCommunication

Kaposi’s Sarcoma Lesion Progression in BKV-Tat Transgenic Mice Is Increased by Inflammatory Cytokines and Blocked by Treatment with Anti-Tat Antibodies

by Egidio Brocca-Cofano, Cecilia Sgadari, Orietta Picconi, Clelia Palladino, Antonella Caputo and Barbara Ensoli

Int. J. Mol. Sci. 2022, 23(4), 2081; https://doi.org/10.3390/ijms23042081 - 14 Feb 2022

Viewed by 1820

Abstract

Kaposi’s sarcoma (KS) is an angioproliferative tumor showing an increased frequency and aggressiveness in HIV-infected subjects (AIDS-KS), due to the combined effects of inflammatory cytokines (IC), angiogenic factors, and the HIV-1 Tat protein. While the introduction of effective combined antiretroviral regimens greatly improved [...] Read more.

Kaposi’s sarcoma (KS) is an angioproliferative tumor showing an increased frequency and aggressiveness in HIV-infected subjects (AIDS-KS), due to the combined effects of inflammatory cytokines (IC), angiogenic factors, and the HIV-1 Tat protein. While the introduction of effective combined antiretroviral regimens greatly improved AIDS-KS incidence and course, it continues to be an incurable disease and the development of new rational targeted therapies is warranted. We used the BKV/Tat transgenic mouse model to evaluate the effects of IC and anti-Tat antibodies (Abs) treatment on KS-like lesions arising in BKV/Tat mice. We demonstrated here that IC-treatment increases the severity and delays the regression of KS-like lesions. Further, anti-Tat Abs reduced KS-like lesion severity developing in IC-treated mice when anti-Tat Abs were administered at an early-stage of lesion development as compared to more advanced lesions. Early anti-Tat Abs treatment also accelerated KS-like lesion regression and reduced the rate of severe-grade lesions. This effect was more evident in the first weeks after Ab treatment, suggesting that a longer treatment with anti-Tat Abs might be even more effective, particularly if administered just after lesion development. Although preliminary, these results are encouraging, and the approach deserves further studies for the development of anti-Tat Ab-based therapies for AIDS-KS. Clinical studies specifically addressing the effect of anti-Tat antibodies in treating AIDS-KS are not yet available. Nevertheless, the effectiveness of anti-Tat antibodies in controlling HIV/AIDS progression, likely due to the neutralization of extracellular Tat activities, is suggested by several cross-sectional and longitudinal clinical studies, indicating that anti-Tat Ab treatment or Tat-based vaccines may be effective to treat AIDS-KS patients or prevent the tumor in individuals at risk. Full article

(This article belongs to the Special Issue Cancer Cell Invasion and Metastases 2.0)

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14 pages, 2187 KiB

Open AccessArticle

Connexin46 Expression Enhances Cancer Stem Cell and Epithelial-to-Mesenchymal Transition Characteristics of Human Breast Cancer MCF-7 Cells

by Rodrigo A. Acuña, Manuel Varas-Godoy, Diego Herrera-Sepulveda and Mauricio A. Retamal

Int. J. Mol. Sci. 2021, 22(22), 12604; https://doi.org/10.3390/ijms222212604 - 22 Nov 2021

Cited by 17 | Viewed by 3442

Abstract

Connexins (Cxs) are a family of proteins that form two different types of ion channels: hemichannels and gap junction channels. These channels participate in cellular communication, enabling them to share information and act as a synchronized syncytium. This cellular communication has been considered [...] Read more.

Connexins (Cxs) are a family of proteins that form two different types of ion channels: hemichannels and gap junction channels. These channels participate in cellular communication, enabling them to share information and act as a synchronized syncytium. This cellular communication has been considered a strong tumor suppressor, but it is now recognized that some type of Cxs can be pro-tumorigenic. For example, Cx46 expression is increased in human breast cancer samples and correlates with cancer stem cell (CSC) characteristics in human glioma. Thus, we explored whether Cx46 and glioma cells, can set up CSC and epithelial-to-mesenchymal transition (EMT) properties in a breast cancer cell line. To this end, we transfected MCF-7 cells with Cx46 attached to a green fluorescent protein (Cx46GFP), and we determined how its expression orchestrates both the gene-expression and functional changes associated with CSC and EMT. We observed that Cx46GFP increased Sox2, Nanog, and OCT4 mRNA levels associated with a high capacity to form monoclonal colonies and tumorspheres. Similarly, Cx46GFP increased the mRNA levels of n-cadherin, Vimentin, Snail and Zeb1 to a higher migratory and invasive capacity. Furthermore, Cx46GFP transfected in MCF-7 cells induced the release of higher amounts of VEGF, which promoted angiogenesis in HUVEC cells. We demonstrated for the first time that Cx46 modulates CSC and EMT properties in breast cancer cells and thus could be relevant in the design of future cancer therapies. Full article

(This article belongs to the Special Issue Cancer Cell Invasion and Metastases 2.0)

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16 pages, 3743 KiB

Open AccessArticle

miR614 Expression Enhances Breast Cancer Cell Motility

by Tuyen T. Dang, Alec T. McIntosh, Julio C. Morales and Gray W. Pearson

Int. J. Mol. Sci. 2021, 22(1), 112; https://doi.org/10.3390/ijms22010112 - 24 Dec 2020

Cited by 1 | Viewed by 3592

Abstract

Using a data driven analysis of a high-content screen, we have uncovered new regulators of epithelial-to-mesenchymal transition (EMT) induced cell migration. Our results suggest that increased expression of miR614 can alter cell intrinsic gene expression to enhance single cell and collective migration in [...] Read more.

Using a data driven analysis of a high-content screen, we have uncovered new regulators of epithelial-to-mesenchymal transition (EMT) induced cell migration. Our results suggest that increased expression of miR614 can alter cell intrinsic gene expression to enhance single cell and collective migration in multiple contexts. Interestingly, miR614 specifically increased the expression of the EMT transcription factor Slug while not altering existing epithelial character or inducing other canonical EMT regulatory factors. Analysis of two different cell lines identified a set of genes whose expression is altered by the miR614 through direct and indirect mechanisms. Prioritization driven by functional testing of 25 of the miR614 suppressed genes uncovered the mitochondrial small GTPase Miro1 and the transmembrane protein TAPT1 as miR614 suppressed genes that inhibit migration. Notably, the suppression of either Miro1 or TAPT1 was sufficient to increase Slug expression and the rate of cell migration. Importantly, reduced TAPT1 expression correlated with an increased risk of relapse in breast cancer patients. Together, our results reveal how increased miR614 expression and the suppression of TAPT1 and Miro1 modulate the EMT state and migratory properties of breast cancer cells. Full article

(This article belongs to the Special Issue Cancer Cell Invasion and Metastases 2.0)

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Review

Jump to: Research

14 pages, 563 KiB

Open AccessReview

Is Melanoma Progression Affected by Thyroid Diseases?

by Salvatore Ulisse, Enke Baldini, Daniele Pironi, Federica Gagliardi, Domenico Tripodi, Augusto Lauro, Sabino Carbotta, Danilo Tarroni, Matteo D’Armiento, Aldo Morrone, Flavio Forte, Flaminia Frattaroli, Severino Persechino, Teresa Odorisio, Vito D’Andrea, Eleonora Lori and Salvatore Sorrenti

Int. J. Mol. Sci. 2022, 23(17), 10036; https://doi.org/10.3390/ijms231710036 - 2 Sep 2022

Cited by 6 | Viewed by 2515

Abstract

Clinical and epidemiological evidence indicate a relationship between thyroid diseases and melanoma. In particular, the hypothyroidism condition appears to promote melanoma spread, which suggests a protective role of thyroid hormones against disease progression. In addition, experimental data suggest that, in addition to thyroid [...] Read more.

Clinical and epidemiological evidence indicate a relationship between thyroid diseases and melanoma. In particular, the hypothyroidism condition appears to promote melanoma spread, which suggests a protective role of thyroid hormones against disease progression. In addition, experimental data suggest that, in addition to thyroid hormones, other hormonal players of the hypothalamic–pituitary–thyroid (HPT) axis, namely the thyrotropin releasing hormone and the thyrotropin, are likely to affect melanoma cells behavior. This information warrants further clinical and experimental studies in order to build a precise pattern of action of the HPT hormones on melanoma cells. An improved knowledge of the involved molecular mechanism(s) could lead to a better and possibly personalized clinical management of these patients. Full article

(This article belongs to the Special Issue Cancer Cell Invasion and Metastases 2.0)

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26 pages, 2026 KiB

Open AccessReview

The Role of Histology-Agnostic Drugs in the Treatment of Metastatic Castration-Resistant Prostate Cancer

by Giovanni Maria Iannantuono, Francesco Torino, Roberto Rosenfeld, Simona Guerriero, Manuela Carlucci, Stefano Sganga, Barbara Capotondi, Silvia Riondino and Mario Roselli

Int. J. Mol. Sci. 2022, 23(15), 8535; https://doi.org/10.3390/ijms23158535 - 1 Aug 2022

Cited by 15 | Viewed by 4217

Abstract

Precision medicine has opened up a new era in the development of anti-cancer agents that is focused on identifying biomarkers predictive of treatment response regardless of tumor histology. Since 2017, the Food and Drug Administration has approved six drugs with histology-agnostic indications: pembrolizumab [...] Read more.

Precision medicine has opened up a new era in the development of anti-cancer agents that is focused on identifying biomarkers predictive of treatment response regardless of tumor histology. Since 2017, the Food and Drug Administration has approved six drugs with histology-agnostic indications: pembrolizumab (both for tumors with the mismatch-repair deficiency (dMMR)/high microsatellite instability (MSI-H) phenotype and for those with the high tumor mutational burden (TMB-H) phenotype), dostarlimab (for dMMR tumors), larotrectinib and entrectinib (for tumors harboring neurotrophic tyrosine receptor kinase (NTRK) fusions), and the combination of dabrafenib plus trametinib (for BRAF V600E-mutated tumors). The genomic alterations targeted by these antineoplastic agents are rare in metastatic castration-resistant prostate cancer (mCRPC). Furthermore, only a small number of mCRPC patients were enrolled in the clinical trials that led to the approval of the above-mentioned drugs. Therefore, we critically reviewed the literature on the efficacy of histology-agnostic drugs in mCRPC patients. Although the available evidence derives from retrospective studies and case reports, our results confirmed the efficacy of pembrolizumab in dMMR/MSI-H mCRPC. In contrast, few data are available for dostarlimab, larotrectinib, entrectinib, and dabrafenib-trametinib in this subset of patients. Large, multi-institutional registries aimed at collecting real-world data are needed to better comprehend the role of tissue-agnostic drugs in mCRPC patients. Full article

(This article belongs to the Special Issue Cancer Cell Invasion and Metastases 2.0)

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Graphical abstract

25 pages, 1058 KiB

Open AccessReview

Infection by High-Risk Human Papillomaviruses, Epithelial-to-Mesenchymal Transition and Squamous Pre-Malignant or Malignant Lesions of the Uterine Cervix: A Series of Chained Events?

by Giovanni Barillari, Roberto Bei, Vittorio Manzari and Andrea Modesti

Int. J. Mol. Sci. 2021, 22(24), 13543; https://doi.org/10.3390/ijms222413543 - 17 Dec 2021

Cited by 18 | Viewed by 3928

Abstract

Wound healing requires static epithelial cells to gradually assume a mobile phenotype through a multi-step process termed epithelial-to-mesenchymal transition (EMT). Although it is inherently transient and reversible, EMT perdures and is abnormally activated when the epithelium is chronically exposed to pathogens: this event [...] Read more.

Wound healing requires static epithelial cells to gradually assume a mobile phenotype through a multi-step process termed epithelial-to-mesenchymal transition (EMT). Although it is inherently transient and reversible, EMT perdures and is abnormally activated when the epithelium is chronically exposed to pathogens: this event deeply alters the tissue and eventually contributes to the development of diseases. Among the many of them is uterine cervical squamous cell carcinoma (SCC), the most frequent malignancy of the female genital system. SCC, whose onset is associated with the persistent infection of the uterine cervix by high-risk human papillomaviruses (HR-HPVs), often relapses and/or metastasizes, being resistant to conventional chemo- or radiotherapy. Given that these fearsome clinical features may stem, at least in part, from the exacerbated and long-lasting EMT occurring in the HPV-infected cervix; here we have reviewed published studies concerning the impact that HPV oncoproteins, cellular tumor suppressors, regulators of gene expression, inflammatory cytokines or growth factors, and the interactions among these effectors have on EMT induction and cervical carcinogenesis. It is predictable and desirable that a broader comprehension of the role that EMT inducers play in SCC pathogenesis will provide indications to flourish new strategies directed against this aggressive tumor. Full article

(This article belongs to the Special Issue Cancer Cell Invasion and Metastases 2.0)

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22 pages, 2055 KiB

Open AccessReview

MCAM/MUC18/CD146 as a Multifaceted Warning Marker of Melanoma Progression in Liquid Biopsy

by Maria Cristina Rapanotti, Elisa Cugini, Marzia Nuccetelli, Alessandro Terrinoni, Cosimo Di Raimondo, Paolo Lombardo, Gaetana Costanza, Terenzio Cosio, Piero Rossi, Augusto Orlandi, Elena Campione, Sergio Bernardini, Marcel Blot-Chabaud and Luca Bianchi

Int. J. Mol. Sci. 2021, 22(22), 12416; https://doi.org/10.3390/ijms222212416 - 17 Nov 2021

Cited by 12 | Viewed by 3604

Abstract

Human malignant melanoma shows a high rate of mortality after metastasization, and its incidence is continuously rising worldwide. Several studies have suggested that MCAM/MUC18/CD146 plays an important role in the progression of this malignant disease. MCAM/MUC18/CD146 is a typical single-spanning transmembrane glycoprotein, existing [...] Read more.

Human malignant melanoma shows a high rate of mortality after metastasization, and its incidence is continuously rising worldwide. Several studies have suggested that MCAM/MUC18/CD146 plays an important role in the progression of this malignant disease. MCAM/MUC18/CD146 is a typical single-spanning transmembrane glycoprotein, existing as two membrane isoforms, long and short, and an additional soluble form, sCD146. We previously documented that molecular MCAM/MUC18/CD146 expression is strongly associated with disease progression. Recently, we showed that MCAM/MUC18/CD146 and ABCB5 can serve as melanoma-specific-targets in the selection of highly primitive circulating melanoma cells, and constitute putative proteins associated with disease spreading progression. Here, we analyzed CD146 molecular expression at onset or at disease recurrence in an enlarged melanoma case series. For some patients, we also performed the time courses of molecular monitoring. Moreover, we explored the role of soluble CD146 in different cohorts of melanoma patients at onset or disease progression, rather than in clinical remission, undergoing immune therapy or free from any clinical treatment. We showed that MCAM/MUC18/CD146 can be considered as: (1) a membrane antigen suitable for identification and enrichment in melanoma liquid biopsy; (2) a highly effective molecular “warning” marker for minimal residual disease monitoring; and (3) a soluble protein index of inflammation and putative response to therapeutic treatments. Full article

(This article belongs to the Special Issue Cancer Cell Invasion and Metastases 2.0)

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26 pages, 1169 KiB

Open AccessReview

Extracellular Vesicles and Cancer Stem Cells in Tumor Progression: New Therapeutic Perspectives

by Maria Giovanna Scioli, Sonia Terriaca, Elena Fiorelli, Gabriele Storti, Giulia Fabbri, Valerio Cervelli and Augusto Orlandi

Int. J. Mol. Sci. 2021, 22(19), 10572; https://doi.org/10.3390/ijms221910572 - 29 Sep 2021

Cited by 16 | Viewed by 3606

Abstract

Tumor burden is a complex microenvironment where different cell populations coexist and have intense cross-talk. Among them, a heterogeneous population of tumor cells with staminal features are grouped under the definition of cancer stem cells (CSCs). CSCs are also considered responsible for tumor [...] Read more.

Tumor burden is a complex microenvironment where different cell populations coexist and have intense cross-talk. Among them, a heterogeneous population of tumor cells with staminal features are grouped under the definition of cancer stem cells (CSCs). CSCs are also considered responsible for tumor progression, drug resistance, and disease relapse. Furthermore, CSCs secrete a wide variety of extracellular vesicles (EVs) with different cargos, including proteins, lipids, ssDNA, dsDNA, mRNA, siRNA, or miRNA. EVs are internalized by other cells, orienting the microenvironment toward a protumorigenic and prometastatic one. Given their importance in tumor growth and metastasis, EVs could be exploited as a new therapeutic target. The inhibition of biogenesis, release, or uptake of EVs could represent an efficacious strategy to impair the cross-talk between CSCs and other cells present in the tumor microenvironment. Moreover, natural or synthetic EVs could represent suitable carriers for drugs or bioactive molecules to target specific cell populations, including CSCs. This review will discuss the role of CSCs and EVs in tumor growth, progression, and metastasis and how they affect drug resistance and disease relapse. Furthermore, we will analyze the potential role of EVs as a target or vehicle of new therapies. Full article

(This article belongs to the Special Issue Cancer Cell Invasion and Metastases 2.0)

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13 pages, 955 KiB

Open AccessReview

PI3K/PTEN/AKT Signaling Pathways in Germ Cell Development and Their Involvement in Germ Cell Tumors and Ovarian Dysfunctions

by Massimo De Felici and Francesca Gioia Klinger

Int. J. Mol. Sci. 2021, 22(18), 9838; https://doi.org/10.3390/ijms22189838 - 11 Sep 2021

Cited by 36 | Viewed by 5312

Abstract

Several studies indicate that the PI3K/PTEN/AKT signaling pathways are critical regulators of ovarian function including the formation of the germ cell precursors, termed primordial germ cells, and the follicular pool maintenance. This article reviews the current state of knowledge of the functional role [...] Read more.

Several studies indicate that the PI3K/PTEN/AKT signaling pathways are critical regulators of ovarian function including the formation of the germ cell precursors, termed primordial germ cells, and the follicular pool maintenance. This article reviews the current state of knowledge of the functional role of the PI3K/PTEN/AKT pathways during primordial germ cell development and the dynamics of the ovarian primordial follicle reserve and how dysregulation of these signaling pathways may contribute to the development of some types of germ cell tumors and ovarian dysfunctions. Full article

(This article belongs to the Special Issue Cancer Cell Invasion and Metastases 2.0)

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27 pages, 847 KiB

Open AccessReview

Non-Coding RNAs Set a New Phenotypic Frontier in Prostate Cancer Metastasis and Resistance

by Joshua Altschuler, Jennifer A. Stockert and Natasha Kyprianou

Int. J. Mol. Sci. 2021, 22(4), 2100; https://doi.org/10.3390/ijms22042100 - 20 Feb 2021

Cited by 20 | Viewed by 4209

Abstract

Prostate cancer (PCa) mortality remains a significant public health problem, as advanced disease has poor survivability due to the development of resistance in response to both standard and novel therapeutic interventions. Therapeutic resistance is a multifaceted problem involving the interplay of a number [...] Read more.

Prostate cancer (PCa) mortality remains a significant public health problem, as advanced disease has poor survivability due to the development of resistance in response to both standard and novel therapeutic interventions. Therapeutic resistance is a multifaceted problem involving the interplay of a number of biological mechanisms including genetic, signaling, and phenotypic alterations, compounded by the contributions of a tumor microenvironment that supports tumor growth, invasiveness, and metastasis. The androgen receptor (AR) is a primary regulator of prostate cell growth, response and maintenance, and the target of most standard PCa therapies designed to inhibit AR from interacting with androgens, its native ligands. As such, AR remains the main driver of therapeutic response in patients with metastatic castration-resistant prostate cancer (mCRPC). While androgen deprivation therapy (ADT), in combination with microtubule-targeting taxane chemotherapy, offers survival benefits in patients with mCRPC, therapeutic resistance invariably develops, leading to lethal disease. Understanding the mechanisms underlying resistance is critical to improving therapeutic outcomes and also to the development of biomarker signatures of predictive value. The interconversions between epithelial-to-mesenchymal transition (EMT) and mesenchymal-to-epithelial transition (MET) navigate the prostate tumor therapeutic response, and provide a novel targeting platform in overcoming therapeutic resistance. Both microRNA (miRNA)- and long non-coding RNA (lncRNA)-mediated mechanisms have been associated with epigenetic changes in prostate cancer. This review discusses the current evidence-based knowledge of the role of the phenotypic transitions and novel molecular determinants (non-coding RNAs) as contributors to the emergence of therapeutic resistance and metastasis and their integrated predictive value in prostate cancer progression to advanced disease. Full article

(This article belongs to the Special Issue Cancer Cell Invasion and Metastases 2.0)

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