Contributions of epithelial-mesenchymal transition and cancer stem cells to the development of castration resistance of prostate cancer

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Abstract

An important clinical challenge in prostate cancer therapy is the inevitable transition from androgen-sensitive to castration-resistant and metastatic prostate cancer. Albeit the androgen receptor (AR) signaling axis has been targeted, the biological mechanism underlying the lethal event of androgen independence remains unclear. New emerging evidences indicate that epithelial-to-mesenchymal transition (EMT) and cancer stem cells (CSCs) play crucial roles during the development of castration-resistance and metastasis of prostate cancer. Notably, EMT may be a dynamic process. Castration can induce EMT that may enhance the stemness of CSCs, which in turn results in castration-resistance and metastasis. Reverse of EMT may attenuate the stemness of CSCs and inhibit castration-resistance and metastasis. These prospective approaches suggest that therapies target EMT and CSCs may cast a new light on the treatment of castration-resistant prostate cancer (CRPC) in the future. Here we review recent progress of EMT and CSCs in CRPC.

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Poised chromatin at the ZEB1 promoter enables breast cancer cell plasticity and enhances tumorigenicity.

Christine L Chaffer, Nemanja D Marjanovic, Tony Lee … (2013)

The recent discovery that normal and neoplastic epithelial cells re-enter the stem cell state raised the intriguing possibility that the aggressiveness of carcinomas derives not from their existing content of cancer stem cells (CSCs) but from their proclivity to generate new CSCs from non-CSC populations. Here, we demonstrate that non-CSCs of human basal breast cancers are plastic cell populations that readily switch from a non-CSC to CSC state. The observed cell plasticity is dependent on ZEB1, a key regulator of the epithelial-mesenchymal transition. We find that plastic non-CSCs maintain the ZEB1 promoter in a bivalent chromatin configuration, enabling them to respond readily to microenvironmental signals, such as TGFβ. In response, the ZEB1 promoter converts from a bivalent to active chromatin configuration, ZEB1 transcription increases, and non-CSCs subsequently enter the CSC state. Our findings support a dynamic model in which interconversions between low and high tumorigenic states occur frequently, thereby increasing tumorigenic and malignant potential. Copyright © 2013 Elsevier Inc. All rights reserved.

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Hedgehog signalling in prostate regeneration, neoplasia and metastasis.

Sunil S. Karhadkar, G. Bova, Nadia Abdallah … (2004)

Metastatic cancers adopt certain properties of normal cells in developing or regenerating organs, such as the ability to proliferate and alter tissue organization. We find here that activity of the Hedgehog (Hh) signalling pathway, which has essential roles in developmental patterning, is required for regeneration of prostate epithelium, and that continuous pathway activation transforms prostate progenitor cells and renders them tumorigenic. Elevated pathway activity furthermore distinguishes metastatic from localized prostate cancer, and pathway manipulation can modulate invasiveness and metastasis. Pathway activity is triggered in response to endogenous expression of Hh ligands, and is dependent upon the expression of Smoothened, an essential Hh response component that is not expressed in benign prostate epithelial cells. Monitoring and manipulating Hh pathway activity may thus offer significant improvements in diagnosis and treatment of prostate cancers with metastatic potential.

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Normal and disease-related biological functions of Twist1 and underlying molecular mechanisms.

Shuang-tao He, Jianming Xu, Young-Xu Yinong … (2011)

This article reviews the molecular structure, expression pattern, physiological function, pathological roles and molecular mechanisms of Twist1 in development, genetic disease and cancer. Twist1 is a basic helix-loop-helix domain-containing transcription factor. It forms homo- or hetero-dimers in order to bind the Nde1 E-box element and activate or repress its target genes. During development, Twist1 is essential for mesoderm specification and differentiation. Heterozygous loss-of-function mutations of the human Twist1 gene cause several diseases including the Saethre-Chotzen syndrome. The Twist1-null mouse embryos die with unclosed cranial neural tubes and defective head mesenchyme, somites and limb buds. Twist1 is expressed in breast, liver, prostate, gastric and other types of cancers, and its expression is usually associated with invasive and metastatic cancer phenotypes. In cancer cells, Twist1 is upregulated by multiple factors including SRC-1, STAT3, MSX2, HIF-1α, integrin-linked kinase and NF-κB. Twist1 significantly enhances epithelial-mesenchymal transition (EMT) and cancer cell migration and invasion, hence promoting cancer metastasis. Twist1 promotes EMT in part by directly repressing E-cadherin expression by recruiting the nucleosome remodeling and deacetylase complex for gene repression and by upregulating Bmi1, AKT2, YB-1, etc. Emerging evidence also suggests that Twist1 plays a role in expansion and chemotherapeutic resistance of cancer stem cells. Further understanding of the mechanisms by which Twist1 promotes metastasis and identification of Twist1 functional modulators may hold promise for developing new strategies to inhibit EMT and cancer metastasis.

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Author and article information

Contributors

Ping Li

Ru Yang

Wei-Qiang Gao

Journal

Journal ID (nlm-ta): Mol Cancer

Journal ID (iso-abbrev): Mol. Cancer

Title: Molecular Cancer

Publisher: BioMed Central

ISSN (Electronic): 1476-4598

Publication date Collection: 2014

Publication date (Electronic): 12 March 2014

Volume: 13

Page: 55

Affiliations

[1 ]State Key Laboratory of Oncogenes and Related Genes, Stem Cell Research Center, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China

[2 ]Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China

Article

Publisher ID: 1476-4598-13-55

DOI: 10.1186/1476-4598-13-55

PMC ID: 3975176

PubMed ID: 24618337

SO-VID: d519687b-b7ed-4273-8b57-85e9bc640c80

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This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Contributions of epithelial-mesenchymal transition and cancer stem cells to the development of castration resistance of prostate cancer

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Karger: Oncology

Most cited references 80

Poised chromatin at the ZEB1 promoter enables breast cancer cell plasticity and enhances tumorigenicity.

Hedgehog signalling in prostate regeneration, neoplasia and metastasis.

Normal and disease-related biological functions of Twist1 and underlying molecular mechanisms.

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