Antiintegrin alpha v beta 3 blocks human breast cancer growth and angiogenesis in human skin.

Brooks, Peter C.; Strömblad, Staffan; Klemke, Richard L.; Visscher, Daniel W.; Sarkar, Fazlul H.; Cheresh, David A.

doi:10.1172/jci118227

Cited by 757 publications

(417 citation statements)

References 25 publications

(16 reference statements)

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“…Consistent with other studies implicating α v β 3 integrin in tumor progression [121], our unpublished data suggest that α v β 3 integrin is the prevalent integrin complex involved in tumor response to matrix rigidity [122]. Therefore, monoclonal antibodies have been developed to inhibit integrin activity [121], such as LM-609, which has been shown to inhibit tumor growth in pre-clinical studies [123]. Etaracizumab (the humanized form of LM609) is currently in clinical trials for metastatic melanoma, where it has been used successfully [124].…”

Section: Clinical Perspectivessupporting

confidence: 87%

Contribution of Bone Tissue Modulus to Breast Cancer Metastasis to Bone

Guelcher

Sterling

2011

Cancer Microenvironment

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Certain tumors, such as breast, frequently metastasize to bone where they can induce bone destruction. Currently, it is well-accepted that the tumor cells are influenced by other cells and growth factors present in the bone microenvironment that lead to tumor-induced bone disease. Over the past 20 years, many groups have studied this process and determined the major contributing factors; however, these results do not fully explain the changes in gene expression and cell behavior that occur when tumor cells metastasize to bone. More recently, groups studying metastasis from soft tissue sites have determined that the rigidity of the microenvironment, which increases during tumor progression in soft tissue, can regulate tumor cell behavior and gene expression. Therefore, we began to investigate the role of the rigid bone extracellular matrix in the regulation of genes that stimulate tumor-induced bone disease. We found that the rigidity of bone specifically regulates parathyroid hormone-related protein (PTHrP) and Gli2 expression in a transforming growth factor β (TGF-β) and mechanotransduction-dependent mechanism. In this review, we summarize the mechanotransduction signaling pathway and how this influences TGF-β signaling and osteolytic gene expression.

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Section: Clinical Perspectivessupporting

confidence: 87%

Contribution of Bone Tissue Modulus to Breast Cancer Metastasis to Bone

Guelcher

Sterling

2011

Cancer Microenvironment

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“…The same anti-integrin antibody was also reported to inhibit human breast cancer growth and angiogenesis in human skin (8).…”

mentioning

confidence: 88%

Integrin αvβ3 Expression in Colon Carcinoma Correlates with Survival

Vonlaufen¹,

Wiedle²,

Borisch³

et al. 2001

Modern Pathology

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Integrin ␣ v ␤ 3 is expressed by newly formed blood vessels in diseased and neoplastic tissue and can therefore be used as a marker for angiogenesis. We investigated its expression on the vasculature of 40 colon carcinomas using the anti-␣ v ␤ 3 -specific monoclonal antibody LM609. The average relapsefree interval and overall survival in patients suffering from colon carcinomas with high vascular expression of ␣ v ␤ 3 integrin was significantly reduced compared with that in patients with low ␣ v ␤ 3 integrin expressing tumor vasculature. Moreover, the expression level of ␣ v ␤ 3 integrin correlated with the presence of liver metastases. In conclusion, we propose vascular expression of ␣ v ␤ 3 integrin as a prognostic indicator for colon carcinoma.

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“…40 Integrin ␣v␤3 is minimally expressed in normal epithelial cells and in normal blood vessels and is significantly upregulated within human tumors. 44 In several malignancies, tumor cells express ␣v␤3, and this expression correlates with tumor progression in melanoma, glioma and ovarian, prostate and breast cancer. 40,45 In breast, ␣v␤3 characterizes the metastatic phenotype as this integrin is upregulated in invasive tumors and in distant metastases.…”

Section: Growth-inhibitory Functions Of Ilkmentioning

confidence: 99%

Suppression of malignant growth of human breast cancer cells by ectopic expression of integrin‐linked kinase

Chen

Shen

Karnik

2004

Intl Journal of Cancer

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Allelic loss at the short arm of chromosome 11 is one of the most common and potent events in the progression and metastasis of breast cancer. Here, we present evidence that the Integrin-Linked Kinase (ILK) gene maps to the commonly deleted chromosome 11p15. Genetic alterations that occur in breast cancer are believed to be of importance for initiation as well as progression of the disease. These genetic alterations lead to the loss or activation of a number of critical genes, such as those involved in cell proliferation, differentiation, apoptosis and genetic stability. The genetic abnormalities most frequently observed in breast tumors are amplification of proto-oncogenes (MYC, ERBB2 and CCND1), mutations of TP53 and loss of heterozygosity (LOH) on chromosomes 3p, 6q, 7q, 8p, 9p, 11, 13q, 17, 18q and 22q. 1,2 Metastatic phenotypes have been linked to such genes as NME1 (17q), CDH1 (16q), BRMS1 (11q) and KISS1 (1q). 1,3-5 LOH analyses have defined regions of deletion associated with metastasis on chromosomes 3p21, 15q14, 16q22 and 11p15. 2,6 Frequent genetic alterations on chromosome 11p15 suggest a crucial role for this region in breast 6,7 and other adult 8 -12 and childhood cancers. [13][14][15][16][17] More recently, we have mapped 2 distinct regions on chromosome 11p15.5 that are subject to LOH during breast tumor progression and metastasis. 6 LOH at region 1 correlated with tumors that contain ductal carcinoma in situ, suggesting that the loss of a critical gene in this region may be responsible for early events in malignancy. LOH at region 2 correlated with a more aggressive tumor and an ominous outlook for the patient, such as aneuploidy, high S-phase fraction and the presence of metastasis in regional lymph nodes. Although considerable advances have been made in the fine-mapping of chromosome 11p15.5, the tumor/metastasis suppressor gene(s) encoded by this region has evaded identification.Integrin-linked kinase (ILK) is an intriguing serine/threonine kinase that has been implicated in integrin-, growth-factor-and Wnt-signaling pathways. 18 It binds to the cytoplasmic domains of ␤1 and ␤3 integrins and mediates the downstream signaling events in integrin function. 19 Interactions between integrins and their ligands are involved in the regulation of many cellular functions, including embryonic development, cell proliferation, tumor growth and the ability to metastasize. 20 In Drosophila, the absence of ILK function causes defects similar to loss of integrin adhesion, and ILK mutations cause embryonic lethality and defects in muscle attachment. 21 Although ILK maps to the commonly deleted chromosome 11p, the potential of this gene in tumor/metastasis suppression has not been evaluated. We have therefore analyzed the effect of ILK expression on the in vitro and in vivo tumor growth and invasion of human mammary carcinoma cells. MATERIAL AND METHODS Mapping of ILK to LOH region 2Two YAC clones (847a12 and 696H10), a BAC clone (BAC 1760) and a PAC clone (PAC1331) overlapped the LOH region 2 and were used to...

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Antiintegrin alpha v beta 3 blocks human breast cancer growth and angiogenesis in human skin.

Cited by 757 publications

References 25 publications

Contribution of Bone Tissue Modulus to Breast Cancer Metastasis to Bone

Contribution of Bone Tissue Modulus to Breast Cancer Metastasis to Bone

Integrin αvβ3 Expression in Colon Carcinoma Correlates with Survival

Suppression of malignant growth of human breast cancer cells by ectopic expression of integrin‐linked kinase

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