Molecular and Functional Links between Neurodevelopmental Processes and Treatment-Induced Neuroendocrine Plasticity in Prostate Cancer Progression

Abstract

Neuroendocrine plasticity and treatment-induced neuroendocrine phenotypes have recently been proposed as important resistance mechanisms underlying prostate cancer progression. Treatment-induced neuroendocrine prostate cancer (t-NEPC) is highly aggressive subtype of castration-resistant prostate cancer which develops for one fifth of patients under prolonged androgen deprivation. In recent years, understanding of molecular features and phenotypic changes in neuroendocrine plasticity has been grown. However, there are still fundamental questions to be answered in this emerging research field, for example, why and how do the prostate cancer treatment-resistant cells acquire neuron-like phenotype. The advantages of the phenotypic change and the role of tumor microenvironment in controlling cellular plasticity and in the emergence of treatment-resistant aggressive forms of prostate cancer is mostly unknown. Here, we discuss the molecular and functional links between neurodevelopmental processes and treatment-induced neuroendocrine plasticity in prostate cancer progression and treatment resistance. We provide an overview of the emergence of neurite-like cells in neuroendocrine prostate cancer cells and whether the reported t-NEPC pathways and proteins relate to neurodevelopmental processes like neurogenesis and axonogenesis during the development of treatment resistance. We also discuss emerging novel therapeutic targets modulating neuroendocrine plasticity.

Neuroendocrine Carcinoma as an Independent Prognostic Factor for Patients With Prostate Cancer: A Population-Based Study

“…ADTs is still first-line treatment for metastatic prostate cancer. However, after initial response to ADT, the tumor develops an androgen-insensitive form known as CRPC ( 34 ). ARPIs including abiraterone, enzalutamide, apalutamide and darolutamide have been developed for CRPC treatment.…”

The Role of Perineural Invasion in Prostate Cancer and Its Prognostic Significance

“…Mucin 1 (MUC1) has been found as a robust regulator of lineage plasticity in PCa that promotes the progression to NEPC [ 47 ]. Intriguingly, MUC1 is also considered a key player in the development of both EMT and PNI [ 48 ], which supports the connection between PNI and PCa lineage plasticity. Furthermore, it has been shown that the high expression of NeuroD1, a neuronal transcription factor that facilitates neuroendocrine differentiation, is a significant risk factor for PNI.…”

Killing SCLC: insights into how to target a shapeshifting tumor

“…Analysis of these samples suggest that adeno-to-SCLC conversion has the capacity to give rise to all four subtypes, albeit YAP1 expression was higher in the lung adenocarcinoma component ( Quintanal-Villalonga et al 2021 ). Prostate adenocarcinoma treated with androgen deprivation therapy can also convert to neuroendocrine prostate carcinoma (NEPC) that shares many similarities to SCLC, including expression of ASCL1 and NEUROD1 ( Cejas et al 2021 ; Kaarijärvi et al 2021 ). Whether non-NE subtypes of SCLC can use similar mechanisms of plasticity to transition to an NE-high state remains an open question.…”