Tumor αvβ3 Integrin Is a Therapeutic Target for Breast Cancer Bone Metastases

Abstract

In breast cancer bone metastasis, tumor cells stimulate osteoclast-mediated bone resorption, and bone-derived growth factors released from resorbed bone stimulate tumor growth. The A v B 3 integrin is an adhesion receptor expressed by breast cancer cells and osteoclasts. It is implicated in tumor cell invasion and osteoclast-mediated bone resorption. Here, we hypothesized that the therapeutic targeting of tumor A v B 3 integrin would prevent bone metastasis formation. We first showed that, compared with mock-transfected cells, the i.v. inoculation of A v B 3 -overexpressing MDA-MB-231 breast cancer cells in animals increased bone metastasis incidence and promoted both skeletal tumor burden and bone destruction. The direct inoculation of A v B 3 -overexpressing transfectants into the tibial bone marrow cavity did not however enhance skeletal tumor burden and bone destruction, suggesting that A v B 3 controls earlier events during bone metastasis formation. We next examined whether a nonpeptide antagonist of A v B 3 (PSK1404) exhibits meaningful antitumor effects in experimental breast and ovarian cancer bone metastasis. A continuous PSK1404 treatment, which inhibited osteoclast-mediated bone resorption in an animal model of bone loss, substantially reduced bone destruction and decreased skeletal tumor burden. Importantly, a short-term PSK1404 treatment that did not inhibit osteoclast activity also decreased skeletal tumor burden and bone destruction. This dosing regimen caused a profound and specific inhibition of bone marrow colonization by green fluorescent protein, A v B 3 -expressing tumor cells in vivo and blocked tumor cell invasion in vitro. Overall, our data show that tumor A v B 3 integrin stands as a therapeutic target for the prevention of skeletal metastases. [Cancer Res 2007;67(12):5821-30]

Homing of Cancer Cells to the Bone

“…ET-1 antagonists such as atrasentan (ABT-627) and ZD4054 are currently being clinically evaluated as a biological therapy for prostate cancer bone metastasis [185]. PSK1404, an antagonist of α5β3 integrin significantly inhibits bone metastasis in animal models of metastatic breast and ovarian cancer [186]. In myeloma administration of anti-VLA-4 antibodies reduces bone destruction and the number of osteoclasts in a nude mice model [187].…”

Contribution of Bone Tissue Modulus to Breast Cancer Metastasis to Bone

“…Integrin α v β 3 , which is a receptor for the bone matrix proteins osteopontin, FN, and vitronectin, has been identified as a critical integrin in breast cancer and prostate cancer skeletal metastasis [35][36][37][38][39][40][41]. Overexpression of α v β 3 in breast cancer cells has been associated with increased levels of bone metastasis, tumor burden, and subsequent osteolysis [36,[42][43][44][45]. Considering the role of FN in tumor-induced bone disease, in vitro studies investigating the role of matrix rigidity on osteolytic gene expression have utilized FN as the matrix protein supporting binding of the tumor cells to the matrix [4,46].…”

“…3, our recent findings point to similar solid-state and soluble growth factor signaling pathways driving expression of osteolytic factors by tumor cells when they initially become established in the bone microenvironment. As discussed in Section "The Bone MicroEnvironment", active α v β 3 integrin in breast tumor cells binds to FN [90], thereby enabling cancer cells to adhere to and interact with bone matrix to control early events in bone metastasis [45]. Furthermore, α v β 3 integrin is required by osteoclasts to resorb the mineralized bone matrix, and antagonists of α v β 3 integrins have been successfully used to inhibit osteoclasts and reduce bone loss in models of osteoporosis and metastatic bone disease [45,91].…”

“…As discussed in Section "The Bone MicroEnvironment", active α v β 3 integrin in breast tumor cells binds to FN [90], thereby enabling cancer cells to adhere to and interact with bone matrix to control early events in bone metastasis [45]. Furthermore, α v β 3 integrin is required by osteoclasts to resorb the mineralized bone matrix, and antagonists of α v β 3 integrins have been successfully used to inhibit osteoclasts and reduce bone loss in models of osteoporosis and metastatic bone disease [45,91]. Thus blocking α v β 3 has the potential to block osteolysis in addition to inhibiting the stimulatory effect of TGFβ on PTHrP expression.…”

“…Thus changes in both the expression and clustering of integrins, as well as integrin-mediated signaling pathways induced by the rigid mineralized bone matrix, can activate SFKs, which might be essential for the ability of the cell to sense the rigidity of the matrix [96]. Specific inhibitors to Src tyrosine kinases, which are required to regulate integrin-cytoskeleton interactions, have shown promise in preclinical studies, reducing both tumor burden and incidence in bone [97,98] as well as metastasis to bone [99]. After activation, SFKs promote coupling of the cytoskeleton to integrins through talin [100][101][102], which enables mechanical forces on the integrins to engage the integrin/matrix catch bond [50].…”