Abstract
Tumor-induced bone disease is common among patients with advanced solid cancers, especially those with breast, prostate, and lung malignancies. The tendency of these cancers to metastasize to bone and induce bone destruction is, in part, due to alterations in integrin expression and signaling. Substantial evidence from preclinical studies shows that increased expression of integrin αvβ3 in tumor cells promotes the metastatic and bone-invasive phenotype. Integrin αvβ3 mediates cell adhesion to several extracellular matrix proteins in the bone microenvironment which is necessary for tumor cell colonization as well as the transmission of mechanical signals for tumor progression. This review will discuss the αvβ3 integrin receptor in the context of tumor-induced bone disease. Specifically, the focus will be the role of αvβ3 in modulating cancer metastasis to bone and tumor cell response to the bone microenvironment, including downstream signaling pathways that contribute to tumor-induced osteolysis. A better understanding of integrin dysregulation in cancer is critical to developing new therapeutics for the prevention and treatment of bone metastases.
Highlights
Advanced solid tumors frequently metastasize to bone, occurring in approximately 70–80% of patients with breast or prostate cancer, and in 30–40% of lung cancer patients [1]
Current therapies focus on inhibiting osteoclast-mediated bone resorption to reduce the risk of skeletal-related events (SREs), but there is a compelling need for therapies directly targeting metastatic tumor cells in bone
Despite the failure of existing drugs against advanced soft tissue tumors in clinical trials, integrin αvβ3 may be a promising therapeutic target for patients with tumor-induced bone disease (TIBD) as it is highly expressed in several bone-metastatic tumors including breast, prostate, and lung cancer
Summary
Advanced solid tumors frequently metastasize to bone, occurring in approximately 70–80% of patients with breast or prostate cancer, and in 30–40% of lung cancer patients [1]. Metastatic tumors can secrete factors (e.g., bone morphogenetic proteins, insulin-like growth factors, endothelin-1) that promote osteoblast proliferation and differentiation, resulting in bone formation and sclerotic lesions [4]. This vicious cycle of tumor-induced bone disease (TIBD) results in severe comorbidities including extreme bone pain, spinal cord compression, hypercalcemia, and pathological fractures that significantly decrease patient quality of life and increase mortality [5,6,7]. Numerous preclinical studies have shown that the expression of specific integrin heterodimers, and their downstream signaling pathways, are perturbed in cancers that metastasize to bone. This review will discuss integrin αvβ in the context of metastatic cancers in bone, how αvβ modulates tumor cell response to the bone microenvironment as well as downstream signaling pathways that promote tumor-induced bone destruction
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