Tumor AvB3 Integrin Is a Therapeutic Target for Breast Cancer Bone Metastases (original) (raw)
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Tumor αvβ3 Integrin Is a Therapeutic Target for Breast Cancer Bone Metastases
Cancer Research, 2007
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 αvβ3 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 αvβ3 integrin would prevent bone metastasis formation. We first showed that, compared with mock-transfected cells, the i.v. inoculation of αvβ3-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 αvβ3-overexpressing transfectants into the tibial bone marrow cavity did not however enhance skeletal tumor burden and bone destruction, suggesting that αvβ3 controls earlier events during bone metastasis formation. We next examined whether a nonpeptide antago...
Tumor v 3 Integrin Is a Therapeutic Target for Breast Cancer Bone Metastases
Cancer Research, 2007
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]
New mechanistic insights of integrin β1 in breast cancer bone colonization
Oncotarget, 2015
Bone metastasis is a frequent and life-threatening complication of breast cancer. The molecular mechanisms supporting the establishment of breast cancer cells in the skeleton are still not fully understood, which may be attributed to the lack of suitable models that interrogate interactions between human breast cancer cells and the bone microenvironment. Although it is well-known that integrins mediate adhesion of malignant cells to bone extracellular matrix, their role during bone colonization remains unclear. Here, the role of β1 integrins in bone colonization was investigated using tissue-engineered humanized in vitro and in vivo bone models. In vitro, bone-metastatic breast cancer cells with suppressed integrin β1 expression showed reduced attachment, spreading, and migration within human bone matrix compared to control cells. Cell proliferation in vitro was not affected by β1 integrin knockdown, yet tumor growth in vivo within humanized bone microenvironments was significantly ...
Anticancer research
Osteoclast activation plays an essential role in the development of bone metastasis (BM). Integrin alpha(v)beta3 mediates the attachment of osteoclasts to bone matrix, and it is overexpressed in bone-residing breast cancer cells. We studied BM from breast cancer in relation to its Integrin alpha(v)beta3 expression. Integrin alpha(v)beta3 expression in 4 human breast cancer cell lines (MDA-MB-231, MDA-MB-435, MKL-4 and T-47D) was determined by immunohistochemistry, flow cytometry and reverse transcriptase-polymerase chain reaction (RT-PCR). Integrin alpha(v)beta3 was expressed in MDA-MB-231 and MDA-MB-435, but not in MKL-4 or T-47D, using both immunohistochemistry and flow cytometry. By RT-PCR, positive bands for both alpha(v) and beta3 subunits were identified in MDA-MB-231 and 435, while only the alpha(v) subunit mRNA was present in MKL-4 and T-47D. BM was common in vivo following inoculation with MDA-MB-231 or 435, but not with MKL-4. Integrin alpha(v)beta3 expression appears to p...
Integrin αvβ3 Signaling in Tumor-Induced Bone Disease
Cancers
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.
Journal of Cancer Research and Clinical Oncology, 2020
Integrin β3 (ITGB3) is probably related to skeletal metastasis, which is the most frequent complication in breast cancer progression. We aimed to define its role and suitability as target for anti-metastatic therapy. We generated two MDA-MB-231 cell clones with conditional miRNA-mediated ITGB3 knockdown for analyzing the resulting effects in vitro regarding mRNA expression, proliferation and migration, as well the impact on skeletal metastasis in a nude rat model. Furthermore, ITGB3 levels were analyzed in exosomes from plasma of rats with skeletal metastases, and from MDA-MB-231 cells incubated with these vesicles, as well as from exosomes secreted by cells with conditional ITGB3 knockdown. This inhibition of ITGB3 expression decreased cellular proliferation and more distinctly inhibited cellular migration. Reduction and even complete remissions of respective soft tissue and osteolytic lesions were detected after ITGB3 knockdown in vivo. Furthermore, ITGB3 levels were increased in ...
Biphasic α2β1 Integrin Expression in Breast Cancer Metastasis to Bone
International Journal of Molecular Sciences
Integrins participate in the pathogenesis and progression of tumors at many stages during the metastatic cascade. However, current evidence for the role of integrins in breast cancer progression is contradictory and seems to be dependent on tumor stage, differentiation status, and microenvironmental influences. While some studies suggest that loss of α2β1 enhances cancer metastasis, other studies suggest that this integrin is pro-tumorigenic. However, few studies have looked at α2β1 in the context of bone metastasis. In this study, we aimed to understand the role of α2β1 integrin in breast cancer metastasis to bone. To address this, we utilized in vivo models of breast cancer metastasis to bone using MDA-MB-231 cells transfected with an α2 expression plasmid (MDA-OEα2). MDA cells overexpressing the α2 integrin subunit had increased primary tumor growth and dissemination to bone but had no change in tumor establishment and bone destruction. Further in vitro analysis revealed that tum...
Breast cancer research : BCR, 2006
Studies in xenograft models and experimental models of metastasis have implicated several beta3 integrin-expressing cell populations, including endothelium, platelets and osteoclasts, in breast tumor progression. Since orthotopic human xenograft models of breast cancer are poorly metastatic to bone and experimental models bypass the formation of a primary tumor, however, the precise contribution of tumor-specific alphavbeta3 to the spontaneous metastasis of breast tumors from the mammary gland to bone remains unclear. We used a syngeneic orthotopic model of spontaneous breast cancer metastasis to test whether exogenous expression of alphavbeta3 in a mammary carcinoma line (66cl4) that metastasizes to the lung, but not to bone, was sufficient to promote its spontaneous metastasis to bone from the mammary gland. The tumor burden in the spine and the lung following inoculation of alphavbeta3-expressing 66cl4 (66cl4beta3) tumor cells or control 66cl4pBabe into the mammary gland was anal...
Integrin activation controls metastasis in human breast cancer
Proceedings of The National Academy of Sciences, 2001
Metastasis is the primary cause of death in human breast cancer. Metastasis to bone, lungs, liver, and brain involves dissemination of breast cancer cells via the bloodstream and requires adhesion within the vasculature. Blood cell adhesion within the vasculature depends on integrins, a family of transmembrane adhesion receptors, and is regulated by integrin activation. Here we show that integrin v3
A small molecule antagonist of the αvβ3 integrin suppresses MDA-MB-435 skeletal metastasis
2004
Introduction: Breast cancer is one of the most common malignancies affecting women in the United States and Europe. Approximately three out of every four women with breast cancer develop metastases in bone which, in turn, diminishes quality of life. The α v β 3 integrin has previously been implicated in multiple aspects of tumor progression, metastasis and osteoclast bone resorption. Therefore, we hypothesized that the α v β 3 -selective inhibitor, S247, would decrease the development of osteolytic breast cancer metastases. Materials and methods: Cells were treated in vitro with S247 and assessed for viability and adhesion to matrix components. Athymic mice received intracardiac (left ventricle) injections of human MDA-MB-435 breast carcinoma cells expressing enhanced green-fluorescent protein.