Prostate cancer and bone: the elective affinities

Abstract

The onset of metastases dramatically changes the prognosis of prostate cancer patients, determining increased morbidity and a drastic fall in survival expectancy. Bone is a common site of metastases in few types of cancer, and it represents the most frequent metastatic site in prostate cancer. Of note, the prevalence of tumor relapse to the bone appears to be increasing over the years, likely due to a longer overall survival of prostate cancer patients. Bone tropism represents an intriguing challenge for researchers also because the preference of prostate cancer cells for the bone is the result of a sequential series of targetable molecular events. Many factors have been associated with the peculiar ability of prostate cancer cells to migrate in bone marrow and to determine mixed osteoblastic/osteolytic lesions. As anticipated by the success of current targeted therapy aimed to block bone resorption, a better understanding of molecular affinity between prostate cancer and bone microenvironment will permit us to cure bone metastasis and to improve prognosis of prostate cancer patients.

Figure 1

Schematic representation of molecular pathogenesis of osteoblastic metastases in prostatecancer. Once reached the bone, tumor cells produce factors that stimulate osteoblasts (OBLs) differentiation and activity. Tumor cells also produce factors that act on stromal cells and osteoblasts that in turn stimulate osteoclasts (OCL) differentiation, thus perturbing bone remodeling on both sides. Finally, osteoclasts resorb bone allowing the release of growth factors that stimulate tumor cells survival and growth, thus fuelling the vicious circle.

Figure 2

Proposed metastatic stroma associated with prostate cancer growth in the bone. Cancer cells can stimulate mesenchymal stem cells (MSCs) to differentiate in osteoblasts, fibroblasts, and adipocytes. Cancer associated fibroblasts (CAFs) release factors, including SDF-1 and TGFβ, which stimulate cancer cell invasion and proliferation. In addition, cancer associated adipocytes, through the release of lipids and cytokines, can sustain cancer growth and induce an osteotropic phenotype. These interactions could influence the crosstalk between cancer cells and osteoblasts/osteoclasts (OBLs, OCL) and the formation of bone lesions. The increased differentiation of MSCs in osteoblasts induced by PCa cells could shift the balance of bone homeostasis towards aberrant mineralization.

Figure 3

Potential therapeutic targets in the progression of bone metastasis in prostate cancer. In the figure the main final metastatic steps are schematically illustrated, including extravasation and secondary growth (see details in the text).