Application of Original Prostate Cancer Progression Model Interacting with Fibroblasts in Preclinical Research

Prostate cancer (PCa) is a heterogeneous disease that exhibits androgen sensitivity and responsiveness to androgen deprivation therapy (ADT). However, ADT induces only temporary remission, and the majority of PCa cases eventually progress to castration-resistant PCa (CRPC). During the development and progression of CRPC, androgen sensitivity and androgen receptor (AR) dependency in PCa cells are often deceased or lost due to ADT or spontaneously arising AR variants even before starting ADT. To prevent CRPC, a clinical PCa model derived from an AR-positive cancer cell line with weak or no androgen sensitivity is required. The human prostate LNCaP cell line is a good model for PCa because of its androgen sensitivity and AR dependency in terms of cell growth and gene expression. Notably, LNCaP cells are heterogeneous cells comprising different clones with natural variations in androgen sensitivity and AR dependency resulting from spontaneously occurring changes. In our group, to obtain androgen-insensitive or weakly sensitive clones spontaneously derived from parental LNCaP cells, we performed a limiting dilution of parental LNCaP cells and obtained several sublines with varying levels of androgen sensitivity and AR dependency. In addition, we established an androgen-insensitive subline from parental LNCaP cells by continuous passage under hormone-depleted conditions. This article provides a unique perspective on our original PCa progression model interacting with fibroblasts and its application in preclinical research.