Widespread activation and critical role of EMT and stemness in the neuroendocrine differentiation of prostate cancer (Review)

Abstract

Neuroendocrine (NE) prostate cancer (NEPC) is an aggressive and lethal subtype of prostate cancer. It is typically characterized by the expression of NE markers and the loss of androgen receptor expression. De novo NEPC is rare, accounting for <2% of all prostate cancer cases at diagnosis. More commonly, NEPC arises from prostate adenocarcinoma following androgen deprivation therapy, with 20‑25% of metastatic castration‑resistant prostate cancers undergoing NE differentiation due to lineage plasticity. During this transition, pathways associated with epithelial‑mesenchymal transition (EMT) and stemness are broadly activated, which is considered to be a key driver of NEPC's high metastatic potential, resistance to chemotherapy and radiotherapy and poor prognosis. EMT facilitates metastasis by enhancing cellular motility and invasiveness, while stemness properties contribute to post‑metastatic colonization, immune evasion, therapy resistance and cellular dormancy. As manifestations of cellular plasticity, these processes share overlapping molecular mechanisms. Targeting key regulators within these pathways may offer promising therapeutic strategies for NEPC.

Keywords: epithelial‑mesenchymal transition; molecular mechanism androgen signaling; neuroendocrine prostate cancer; stemness.

Figure 1.

The development of NEPC which influenced by ADT, EMT and stemness. Normal prostate luminal epithelial cells and basal epithelial cells can undergo malignant transformation into normal tumor cells. After ADT, 10–20% of prostate adenocarcinomas transform into CRPC. With further ADT treatment, 20–25% of CRPC can transition into NEPC. During this process, while AR (androgen receptor) signaling is inhibited, the EMT process is activated and plays a critical role in castration resistance, metastasis and NED. Cancer cells often undergo dedifferentiation under the therapeutic pressure of ADT, chemotherapy and radiation oncology. CSCs may originate from malignant mutations of normal stem cells, with the TME playing a significant role in this process. Normal tumor cells can become CTCs through EMT and a small subset of CTCs survive by activating stemness, thereby acquiring immune evasion and dormancy, which gives them an opportunity to colonize. These surviving stem-like tumor cells, due to their multilineage differentiation potential, may be an important source of NEPC. NEPC, neuroendocrine prostate cancer; ADT, androgen deprivation therapy; EMT, epithelial-mesenchymal transition; CRPC, castration-resistant prostate cancer; NED neuroendocrine differentiation; TME, tumor microenvironment; CTCs, circulating tumor cells

Figure 2.

The simplified association among ADT, EMT, stemness and NED in prostate cancer. ADT concurrently promotes EMT, stemness and NED; EMT facilitates stemness and NED; and stemness drives NED. ADT, androgen deprivation therapy; EMT, epithelial-mesenchymal transition; NED neuroendocrine differentiation.