Focus on the tumor microenvironment: A seedbed for neuroendocrine prostate cancer

Abstract

The tumor microenvironment (TME) is a microecology consisting of tumor and mesenchymal cells and extracellular matrices. The TME plays important regulatory roles in tumor proliferation, invasion, metastasis, and differentiation. Neuroendocrine differentiation (NED) is a mechanism by which castration resistance develops in advanced prostate cancer (PCa). NED is induced after androgen deprivation therapy and neuroendocrine prostate cancer (NEPC) is established finally. NEPC has poor prognosis and short overall survival and is a major cause of death in patients with PCa. Both the cellular and non-cellular components of the TME regulate and induce NEPC formation through various pathways. Insights into the roles of the TME in NEPC evolution, growth, and progression have increased over the past few years. These novel insights will help refine the NEPC formation model and lay the foundation for the discovery of new NEPC therapies targeting the TME.

Epithelial-to-Mesenchymal Transition-Related Markers in Prostate Cancer: From Bench to Bedside

“…Some of the key players within the stroma include mesenchymal stem/progenitor cells, stromal-derived mediators of inflammation, regulators of angiogenesis, connective tissue growth factors, wingless homologs (Wnts), and integrins [ 17 ]. A study by Zhou et al referred to the mechanism of neuroendocrine differentiation that occurs in parallel with castration resistance development in advanced PCa [ 99 ]. In addition, it is noteworthy mentioning that the TME evolves in parallel with the PCa clones, where the ECM and vasculature architecture is altered, recruiting specialized tumor-supporting cells that favor tumor spread and colonization at distant sites, particularly the bones where a premetastatic niche is orchestrated [ 100 ].…”

Targeting Key Players of Neuroendocrine Differentiation in Prostate Cancer

“…In addition to the intrinsic characteristics of tumors, components of the tumor microenvironment, such as immune cells, tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs) and cancer associated fibroblasts (CAFs) can establish communications with PC cells and are critical in shaping PC progression [98]. PC cells secrete BMP6 (Bone Morphogenic Protein-6), which triggers the release of IL-6 (Interleukin 6) by TAMs [99], thus promoting NEPC through various pathways, including activation of the STAT3, TGF-β (Transforming Growth Factor Beta)/SMAD2 (SMAD Family Member 2) and MAPK (Mitogen-Activated Protein Kinase) pathways [100][101][102] and suppression of REST [103].…”

A bibliometric study of the top 100 most-cited papers in neuroendocrine prostate cancer

“…Thus, next-generation AR pathway inhibitors (ARPIs), such as enzalutamide and abiraterone, have been developed. Patients with PCa may nonetheless acquire resistance to ARPIs, whose long-term use can lead to epithelial-mesenchymal transition (EMT) and neuroendocrine differentiation (NED) in some prostate tumor cells (6)(7)(8)(9)(10). This type of pathology that has undergone NED is classified as neuroendocrine prostate cancer (NEPC) (11).…”