An Approach for the Identification of Targets Specific to Bone Metastasis Using Cancer Genes Interactome and Gene Ontology Analysis
Bone metastasis results from imbalance of normal bone remodeling process involving osteolytic (leading to bone destruction) and osteoblastic (leading to aberrant bone formation) mechanisms. Breast cancer metastases are usually osteolytic, whereas prostate cancer metastases are usually osteoblastic. Osteolytic metastasis: Osteolytic metastasis of tumor cells involves a “vicious cycle” between tumor cells and the skeleton. The vicious cycle is propagated by four contributors: tumor cells, bone-forming osteoblasts, bone resorbing osteoclasts and stored factors within bone matrix. Osteoclast formation and activity are regulated by the osteoblast, adding complexity to the vicious cycle. Tumor cells release certain factors including IL-1, IL-6, IL-8, IL-11, PTHrP and TNF that stimulate osteoclastic bone resorption. These factors enhance the expression of RANKL over OPG by osteoblasts, tipping the balance toward osteoclast activation thus causing bone resorption. This bone lysis stimulates the release of BMPs, TGFβ, IGFs and FGFs for stimulating the growth of metastatic cancer cells to bone. Osteoblastic metastasis: Factors released by osetoblastic cells, such as ET-1, Wnt, ERBB3, VEGF play an important role in osteoblastic metastasis by increasing cancer cell proliferation and enhance the effect of other growth factors including PDGF, FGFs, IGF-1. Osteoblast differentiation is also increased by BMPs through the activation of certain transcription factors. Urokinase Plasminogen Activator (uPA), a protease, also acts as mediator for osteoblastic bone metastasis by cleaving osteoclast-mediated bone resorption factors responsible for regulation of osteoclast differentiation; thereby blocking the bone resorption.