Proteases, growth factors, chemokines, and the microenvironment in prostate cancer bone metastasis.

The arrival of cancer cells in the marrow upsets the delicate homeostatic nature of the bone microenvironment. Cell surface or secreted factors brought in by cancer cells perturb the web-like communication network between different bone cell types and bone matrix. Chemokines not only attract cancer cells from the circulation into the marrow, they also stimulate a cell signaling process leading to attachment, invasion, and further stimulation of bone matrix turnover. Cancer cell surface-associated proteases have also been associated with tumor growth and bone matrix turnover. Recent data indicate that autocrine proteolytic shedding of cell surface chemokines further promotes osteoclastogenesis. Proteases also contribute to autocrine and paracrine shedding of growth factors, another mechanism of promoting growth and expansion of the metastatic deposit. Studies of the bone microenvironment have thus revealed multiple potential targets of intervention with regard to the expanding metastatic deposit.