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.

Keywords: androgen deprivation therapy (ADT); castration-resistant prostate cancer; lineage plasticity; neuroendocrine prostate cancer (NEPC); tumor microenvironment.

FIGURE 1

Role of non-cellular components in the NEPC microenvironment. (1) IL-8 activates NF-κB pathway signaling to increase levels of a series of stem cell transcription factors expression. (2) IL-6 induces neuroendocrine prostate cancer formation by activating STAT3 and MAPK/ERK signaling, and reducing the REST. Besides, IL-8 and IL-6 upregulate HIF-1 via PI3K/AKT/HIF-1α pathway and MAPK/HIF-1α pathway. (3) TGF-β/SMAD2 pathway signaling activates p38 MAPK and then induces neuroendocrine differentiation. (4) endostatin blocks androgen receptor signaling and then promotes the formation of epithelial tumor cells into androgen-independent cells.