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

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.

Basal Cell Proliferation Induced by Chlormadinone Acetate Suggests Stem Cell Transformation of Prostatic Cells

“…Androgen deprivation causes EMT for both normal and malignant prostatic gland [10]. EMT induced by castration changes prostatic luminal cells into cancer stem cells (CSCs), and helps these cells to obtain apoptosis resistance by castration [5]. reported that CD133 did not enrich for stem cell activity in vivo in adult mouse prostates [16].…”

“…The EMT is also believed to be a critical step in the progression of cancers from both the pre-invasive to invasive state, and from organ confined to metastatic disease [2]. At prostatic tissue, EMT is reported to play an important role in progression of benign hyperplastic change [3] [4], carcinogenesis, acquiring apoptotic tolerance [5], neuroendocrine differentiation and chemotherapy resistance [6]. Among these roles, EMT at the first hormonal therapy is thought to play an essential role in obtaining castrate resistance for hormone naïve prostate cancer as well as benign prostatic tissues [7].…”

A comprehensive review of genomic landscape, biomarkers and treatment sequencing in castration-resistant prostate cancer

“…The cell plasticity with dedifferentiation leading to proliferation, apoptosis resistance and EMT is alternatively involved in the progression to CRPC through the AR activity independent pathway, even though some clones might still be dependent on AR signaling [23]. Activation of the EMT program is characterized by the loss of E-cadherin and the gain of mesenchymal markers such as Vimentin and N-cadherin, which increases the migratory ability of the cells and contribute notably to the interaction of tumors cells with the microenvironment at the bone [24][25][26].…”

Enhancement of HIFU Effect by Simultaneous Short Course Degarelix for Early Stage Prostate Cancer: A Pilot Study

“…Recent study revealed that small number of prostatic cancer cells can acquire an apoptotic tolerance by epithelial to mesenchymal transition (EMT) mechanism [8]. Moreover, some of these non-apoptotic cells will progress to castration resistant prostate cancer after obtaining ability to cell multiplication even under a hormonally castrated condition [9]. So if some other therapeutic modality such as HIFU is added at the timing when most of the cancer cells are dying by apoptosis and only small number of cells are obtaining apoptotic tolerance during the first hormonal exposure, complete cell kill may be performed.…”