Studies of hormonal regulation, phenotype plasticity, bone metastasis, and experimental therapeutics in androgen-repressed human prostate cancer (ARCaP) model

摘要

First established by Dr. Leland W. K. Chung’s lab, the androgen-repressed prostate cancer cell (ARCaP) line is derived from the ascitic fluid of a prostate cancer (PCa) patient with widely metastatic disease. Based on its unique characteristic of growth suppression in the presence of androgen, ARCaP cell line has contributed to the research of PCa disease progression toward therapy- and castration-resistant PCa (t-CRPC). It has been widely applied in studies exploring experimental therapeutic reagents including Genistein, Vorinostat and Silibinin. ARCaP cells have showed increased metastatic potential to the bone and soft tissues. In addition, accumulating studies using ARCaP model have demonstrated the epithelial-to-mesenchymal transitional plasticity of PCa using epithelial-like ARCaP E line treated in vitro with growth factors derived from bone microenvironment. The resulting mesenchymal-like ARCaP M sub-clone derived from bone-metastasized tumor has high expression of several factors correlated with cancer metastasis, such as N-Cadherin, Vimentin, MCM3, Granzyme B, β2-microglobulin and RANKL. In particular, the increased secretion of RANKL in ARCaP M further facilitates its capacity of inducing osteoclastogenesis at the bone microenvironment, leading to bone resorption and tumor colonization. Meanwhile, sphingosine kinase 1 (SphK1) acts as a key molecule driver in the neuroendocrine differentiation (NED) of ARCaP sublines, suggesting the unique facet of ARCaP cells for insightful studies in more malignant neuroendocrine prostate cancer (NEPC). Overall, the establishment of ARCaP line has provided a valuable model to explore the mechanisms underlying PCa progression toward metastatic t-CRPC. In this review, we will focus on the contribution of ARCaP model in PCa research covering hormone receptor activity, skeletal metastasis, plasticity of epithelial-to-mesenchymal transition (EMT) and application of therapeutic strategies.