The present studies were conducted to evaluate key serum proteins and other components that mediate anchorage-independent growth (3-D growth) of LNCaP prostate cancer cells as spheroids. The cells were cultured on ultra-low attachment plates in the absence and presence of fetuin-A and with or without extracellular vesicles. The data show that fetuin-A (alpha 2HS glycoprotein) is the serum protein that mediates 3-D growth in these cells. It does so by sequestering extracellular vesicles of various sizes on the surfaces of rounded cells that grow as spheroids. These vesicles in turn transmit growth signals such as the activation of AKT and MAP kinases in a pattern that differs from the activation of these key growth signaling pathways in adherent and spread cells growing in 2-D. In the process of orchestrating the movement and disposition of extracellular vesicles on these cells, fetuin-A is readily internalized in adhered and spread cells but remains on the surfaces of non-adherent cells. Taken together, our studies suggest the presence of distinct signaling domains or scaffolding platforms on the surfaces of prostate tumor cells growing in 3-D compared to 2-D.

Prostate cancer (PCa) is one of the leading causes of cancer-related deaths in American men. PCa patients often die of the aggressive forms of the malignancy at advanced stages such as distant metastasis. There are urgent need to understand the molecular mechanisms driving PCa progression and subsequently develop efficient therapeutics to improve men’s health in the US as well as the world. Tumor microenvironment (TME) has been realized to play a critical role in PCa progression and metastasis, and targeting key factors of the TME has become the logical strategy for efficiently controlling PCa malignancy. Stromal cells in prostate tumors secrete growth factors, cytokines, and extracellular matrix (ECM) proteins that provide the TME to fuel cell proliferation, invasion, and metastasis. This review will focus on several key factors influencing TME, which include cancer-associated fibroblasts (CAFs), ECM remodeling, androgen receptor (AR) signaling, inflammation, and hypoxia. We will explain and analyze the biological roles of these factors and their important contributions to PCa malignancy, targeted therapeutics, and drug resistance. Furthermore, we will discuss the contributions of the dysregulation of epigenetic regulators to the complexity of the TME in PCa.