Molecular Regulation of Bone Marrow Metastasis in Prostate and Breast Cancer

Figure 1

The mechanism of bone resorption in bone marrow metastasis. Tumor cells highly express CXCR4, causing their homing to BM by CXCL12/CXCR4 signaling. Metastatic tumor cells in bone release PTHrP, which induces OCL formation and bone resorption. Bone resorption releases the growth factors stored in bone such as TGF-β, IGF-1, PDGF, and FGF. TGF-β increases the expression of PTHrP, IL-1, IL-6, IL-8, IL-11, PGE2, M-CSF, and TNF-α by direct impact on cancer cells. These factors induce OCL formation by increasing RANKL expression on OB cells. RANKL binds to RANK on OCL precursor. The expression CTGF/CCN2 gene is triggered by PTHrP and TGF-β released by tumor cells through PKA-PKC-dependent activation of ERK1/2 pathway. TGF-β also increases jagged-1 expression in tumor cell through the Smad pathway. Cancer cells expressing jagged-1 activate Notch signaling in OB, stimulating the secretion of IL-6, which stimulates tumor cell growth. VCAM-1 is expressed in tumor cells and binds α4β7 and α4β1 integrins on OCL progenitors, causing OCL differentiation. Platelet-derived TGF-β and direct contact between platelets and tumor cells increase invasion and metastasis. platelet-derived lysophosphatidic acid (LPA) induces the release of IL-6 and IL-8 from tumor cells, which eventually leads to osteoclastic activation and bone resorption. Abbreviations: BM, bone marrow; CXCL12, C-X-C motif chemokine 12; CXCR4, C-X-C chemokine receptor 4; TGF-β, transforming growth factor β; LPA, lysophosphatidic acid; PTHrP, parathyroid hormone-related protein; PGE2, prostaglandin E-2; M-CSF, macrophage colony stimulating factor, TNF-α, and tumor necrosis factor α; IGF-1, Insulin-like growth factor; PDGF, platelet-derived growth factor; FGF, fibroblast growth factor; VCAM-1, vascular-endothelial molecule-1; CTGF, connective tissue growth factor; RANKL, receptor activator of nuclear factor-κB ligand; OCL, osteoclast; OB, osteoblast.