Cancer Stemness/Epithelial–Mesenchymal Transition Axis Influences Metastasis and Castration Resistance in Prostate Cancer: Potential Therapeutic Target

Abstract

Prostate cancer (PCa) is a leading cause of cancer death in men, worldwide. Mortality is highly related to metastasis and hormone resistance, but the molecular underlying mechanisms are poorly understood. We have studied the presence and role of cancer stem cells (CSCs) and the Epithelial–Mesenchymal transition (EMT) in PCa, using both in vitro and in vivo models, thereby providing evidence that the stemness–mesenchymal axis seems to be a critical process related to relapse, metastasis and resistance. These are complex and related processes that involve a cooperative action of different cancer cell subpopulations, in which CSCs and mesenchymal cancer cells (MCCs) would be responsible for invading, colonizing pre-metastatic niches, initiating metastasis and an evading treatments response. Manipulating the stemness–EMT axis genes on the androgen receptor (AR) may shed some light on the effect of this axis on metastasis and castration resistance in PCa. It is suggested that the EMT gene SNAI2/Slug up regulates the stemness gene Sox2, and vice versa, inducing AR expression, promoting metastasis and castration resistance. This approach will provide new sight about the role of the stemness–mesenchymal axis in the metastasis and resistance mechanisms in PCa and their potential control, contributing to develop new therapeutic strategies for patients with metastatic and castration-resistant PCa.

A prognostic signature consisting of N6-methyladenosine modified mRNAs demonstrates clinical potential in prediction of biochemical recurrence and guidance on precision therapy in prostate cancer

“…The aberrant m6A peaks representing mRNAs were enriched in hallmarks such as early estrogen response, EMT, TNFa signaling via NF-κB and angiogenesis, which are related to cancer metastasis ( Fig. 2B ) [ [13] , [14] , [15] ]. In addition, the 3164 hypermethylated m6A modification peaks representing mRNAs in the metastasis group were found to be enriched in KEGG pathway terms such as ECM-receptor interaction, protein digestion and absorption, cell adhesion molecules and proteoglycans in cancer ( Fig.…”

Pseudo-grading of tumor subpopulations from single-cell transcriptomic data using Phenotype Algebra

“…Specifically, CL2 showed downregulation of the genes involved in drug metabolism and cellular response while upregulation of the genes associated with drug resistance. In cancer cells, the acquisition of stemness-like as well as cell dedifferentiation (mesenchymal) traits can facilitate the formation of metastases and lead to the development of drug resistance 76 . Further analysis of the metastatic potential of CL2 indicated that the cluster is enriched with genes associated with vasculature and angiogenesis.…”

Microbiome Dysbiosis Is Associated with Castration Resistance and Cancer Stemness in Metastatic Prostate Cancer

“…Metastatic contributors have been identified too, and they include the loss of PTEN, aberrations in the PI3K-AKT signaling pathway, and the acquisition of DNA repair defects [ 18 ]. The degree of stemness observed in a cancer is also known to influence CR and metastasis [ 19 , 20 , 21 ]. Cancer stem cells (CSC) are thought to compose only about 1% of a tumor’s mass, though they are crucial in the tumor’s growth and proliferation [ 22 ].…”

“…In this process, malignant epithelial cells gain mesenchymal-like traits and become highly invasive in doing so [ 24 ]. The formation of CSCs through the process of EMT provides a tumor with a high capacity for colonization, ultimately promoting the cancer’s metastasis [ 19 , 20 , 21 ].…”