Integrins and bone metastasis: Integrating tumor cell and stromal cell interactions

Integrins on both tumor cells and the supporting host stromal cells in bone (osteoclasts, new blood vessels, inflammatory cells, platelets and bone marrow stromal cells) play key roles in enhancing bone metastasis. Tumor cells localize to specific tissues through integrin-mediated contacts with extracellular matrix and stromal cells. Integrin expression and signaling are perturbed in cancer cells, allowing them to “escape” from cell–cell and cell–matrix tethers, invade, migrate and colonize within new tissues and matrices. Integrin signaling through αvβ3 and VLA-4 on tumor cells can promote tumor metastasis to and proliferation in the bone microenvironment. Osteoclast (OC) mediated bone resorption is a critical component of bone metastasis and can promote tumor growth in bone and αvβ3 integrins are critical to OC function and development. Tumors in the bone microenvironment can recruit new blood vessel formation, platelets, pro-tumor immune cells and bone marrow stromal cells that promote tumor growth and invasion in bone. Integrins and their ligands play critical roles in platelet aggregation (αvβ3 and αIIbβ3), hematopoietic cell mobilization (VLA-4 and osteopontin), neoangiogenesis (αvβ3, αvβ5, α6β4, and β1 integrin) and stromal function (osteopontin and VLA-4). Integrins are involved in the pathogenesis of bone metastasis at many levels and further study to define integrin dysregulation by cancer will yield new therapeutic targets for the prevention and treatment of bone metastasis.

Research Highlights
► Integrin expression on both tumor cells and host cells are involved in invasion, migration and colonization of tumor cells in the bone microenvironment.
► Targeting skeletal metastases with bisphosphonates may have pleiotropic effects on tumor growth and angiogenesis in addition to reducing OC mediated bone resorption.
► Targeting integrins may be a promising target to treat and prevent skeletal metastasis but could lead to unexpected and undesired site effects.
► Platelet integrins are critical mediators of cancer induced skeletal metastasis, hence targeting platelet adhesion may represent a novel strategy to inhibit bone metastasis.