Prostate cancer is the most frequent cancer in men (over 75,000 new cases per year in France and 190,000 in United States), and it is the second leading cause of death among men and the first above 65 years-old. Indeed, prostate cancer is unique, often with an only detectable metastasis site, the bone (mostly the spine, back and pelvis). Skeletal metastases are also generally associated with poor prognosis. Only 23% of patients survived 5 years from initial diagnosis, and the 10-year survival rate is 10%. Bone metastasis in prostate cancer is a complex process, multifactorial and not very well-known producing complications for the patient like pain, hypercalcemia, anemia, fractures, susceptibility to infection, spinal cord compression or reduced mobility. These complications, known as skeletal-related events (SRE), increase morbidity and decrease patient quality of life. Therefore, a better comprehension of the molecular mecanisms implicated in prostate cancer bone metastasis and the development of new targeted therapies are urgently needed.
Although S1P has been reported to regulate remodeling in normal bone physiology, its role in the pathological context of bone metastasis has not been described to date. Prostate cancer metastasizes to the bone to predominantly produce an osteoblastic reaction (bone formation) by virtue of promoting proliferation and differentiation of osteoblasts.
Because we have recently shown that the SphK1/S1P signaling is highly expressed in osteoblastic MC3T3 cells and stimulated by androgens (Martin et al., 2010, BBRC), we investigated the putative role of S1P in the complex interactions between CaP and osteoblastic cells (Brizuela et al., Mol Oncol, 2014).
We have shown that S1P produced by osteoblasts promotes CaP cell proliferation and resistance to standard therapeutics, a paracrine mechanism exclusively driven to the S1P receptor subtype 1 (S1PR1).
Concomitantly osteoblast-borne S1P contributes to the osteoblastic differentiation, a hallmark of CaP bone metastasis, via an autocrine effect involving the osteoblastic S1P receptor subtype 3 (S1PR3). Of note, differentiated osteoblasts further enhanced proliferation and resistance to therapeutics of CaP cells in a S1P-dependent manner.
There is a need to understand the molecular mechanisms underlying prostate cancer bone metastasis as there is no effective therapy. These results support the notion that osteoblastic S1P could be a mediator of the dialogue between osteoblastic and CaP cells in the bone microenvironment, and the potential clinical value of anti-S1P antibodies (Sabbadini, 2011) which are currently in Phase 2 clinical trials for cancer, suggesting that metastatic CaP could be an important disease for S1P-directed therapy.