Prostate cancer cells, calcium metabolism and bone metastases: A complex balance.

S. Di Francesco 1,2 and E. Toniato 1

1 Department of Medical and Oral Sciences and Biotechnologies. G. D’Annunzio University of Chieti-Pescara ,Chieti Italy

2 Department of Urological, Biomedical and Translational Sciences. Federiciana University, Cosenza, Italy

The skeleton is involved in more than 80% of patients with advanced prostate cancer. It has been hypothesized how prostate cancer cells can alter bone homeostasis both directly, secreting osteogenic and osteoclastic proteins, both indirectly modulating the activity of the bone microenvironment. Reciprocal interactions between tumor cells and bone cells determine not only the activation of osteoclasts and subsequent bone resorption, but also the progression of tumor cells. The osteolysis process releases and activates growth factors stimulating further tumor proliferation, thus establishing a vicious circle. Particularly prostatic cell lines that induce osteolytic bone metastases express cytokines that include RANKL, IL-1, TNF-α, PTHrP, and cathepsin K, which are associated with increased osteoclastogenesis. The induction of osteoblastic metastases, instead, occurs through the expression of OPG, BMP-2, BMP-4, BMP-6, VEGF, ET-1, PDGF-BB, IGF-1, FGF- 2, Wnt. Other cytokines produced by prostatic tumor cells indirectly affect the production of osteoclasts by modulating the expression of RANKL on osteoblastic cells. In our experience, patients with prostate cancer and bone metastases revealed a condition of hypocalcaemia and systemic hypophosphatemia associated with increased bone anabolism. The continuous sequestration of calcium and phosphates and secondary hyperparathyroidism seem to be linked above all to the “osteomimetic” activity of prostatic tumor cells. The analysis of the immune system also reveals a condition of lymphopenia. In particular, by examining the correlation between the number of skeletal sites involved in bone metastases, calcium and lymphocytes, there is a direct relationship between the number of osteoblastic metastases, hypocalcaemia and lymphopenia. The reduction of the Catabolism / Anabolism bone ratio could represent a crucial step towards the evolution in a state of lymphopenia with alteration of the immunosurveillance and the humoral immune response. A combination therapy that targets prostate cancer cells, calcium and lymphocytes may represent an interesting therapeutic approach for the prevention and treatment of advanced metastatic prostate cancer.