New Insights in the Role of Androgen-to-Estrogen Ratios, Specific Growth Factors and Bone Cell Microenvironment to Potentiate Prostate Cancer Bone Metastasis

Abstract

Abstract. Prostate cancer progression to bone metastasis is an early event that remains dormant when the androgen ratio to estrogen is high.Only 40% of patients with bone metastasis and skeletal involvement survive past the first year. During andropause, changes in hormone ratios and nuclear receptor coregulator expression, in conjunction with crosstalk with fibroblast growth factors and bone stroma signaling pathways, reactivate the early metastasis. This review will provide insights into how this interplay induces changes in the osteolytic microenvironment to promote prostate cancer metastasis to the bone. While both AR and ER induce changes in the osteolytic microenvironment to promote bone metastasis, it is ER?? overexpression that stimulates osteoblast differentiation, proliferation, osteoclast-mediated bone resorption, and the release of bone matrix factors. Loss of ER??1 enhances VEGF expression and tumor cell survival through stimulation of osteoblast differentiation. Aberrant expression of FGFs and FGF receptors (FGFRs) initiates MAPK, PI3K, and PLC?? pathways, resulting in proliferation, dedifferentiation, angiogenesis and survival. The paracrine action of FGF10 may be required for bone metastasis reactivation due to interaction with bone stromal cells when E2/T ratio increases. This ratio change provides a potential mechanism for estrogen signal activation when prostate cancer cells express ER?? in the presence of bone stromal cells, resulting in ER?? predominance over the AR activity due to changes in coactivator/corepressor recruitment by ER?? when circulating androgens are reduced during hormonal deprivation therapies.