Prostate cancer (PCa) metastasizes to bone and soft tissues, greatly decreasing quality of life, causing bone pain, skeletal complications, and mortality in PCa patients. While new treatment strategies are being developed, the molecular and cellular basis of PCa metastasis and the "cross-talk" between cancer cells and their microenvironment and crucial cell signaling pathways need to be successfully dissected for intervention. In this review, we introduce a new concept of the mechanism of PCa metastasis, the recruitment and reprogramming of bystander and dormant cells (DCs) by a population of metastasis-initiating cells (MICs). We provide evidence that recruited and reprogrammed DCs gain MICs phenotypes and can subsequently metastasize to bone and soft tissues. We show that MICs can also recruit and reprogram circulating tumor cells (CTCs) and this could contribute to cancer cell evolution and the acquisition of therapeutic resistance. We summarize relevant molecular signaling pathways, including androgen receptors (ARs) and their variants and growth factors (GFs) and cytokines that could contribute to the predilection of PCa for homing to bone and soft tissues. To understand the etiology and the biology of PCa and the effectiveness of therapeutic targeting, we briefly summarize the animal and cell models that have been employed. We also report our experience in the use of three-dimensional (3-D) culture and co-culture models to understand cell signaling networks and the use of these attractive tools to conduct drug screening exercises against already-identified molecular targets. Further research into PCa growth and metastasis will improve our ability to target cancer metastasis more effectively and provide better rationales for personalized oncology.
Keywords: Metastasis-initiating cells (MICs); cell signaling network in tumor microenvironment; dormant cells (DCs); recruitment and reprogramming; three-dimensional cell culture.