Integrin ␤ 4 signaling promotes tumor angiogenesis

Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Cancer Cell (Impact Factor: 23.52). 12/2004; 6(5):471-83. DOI: 10.1016/j.ccr.2004.09.029
Source: PubMed


Mice carrying a targeted deletion of the signaling portion of the integrin beta4 subunit display drastically reduced angiogenesis in response to bFGF in the Matrigel plug assay and to hypoxia in the retinal neovascularization model. Molecular cytology indicates that alpha6beta4 signaling promotes branching of beta4+ medium- and small-size vessels into beta4- microvessels without exerting a direct effect on endothelial cell proliferation or survival. Signaling studies reveal that alpha6beta4 signaling induces endothelial cell migration and invasion by promoting nuclear translocation of P-ERK and NF-kappaB. Upon subcutaneous implantation of various cancer cells, the mutant mice develop smaller and significantly less vascularized tumors than wild-type controls. These results provide genetic evidence that alpha6beta4 signaling promotes the onset of the invasive phase of pathological angiogenesis and hence identify a novel target for antiangiogenic therapy.

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Available from: Sotiris Nikolopoulos, Jan 15, 2015
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    • "Integrins comprise a large family of cell adhesion molecules; they are transmembrane glycoproteins that play a key role in the interaction between cells and components of the interstitial space. Integrin-mediated interactions between cells or between cells and the extracellular matrix play an important role in tumor growth, invasion, metastasis, drug resistance, and many other processes [5]. Many studies have confirmed that carbohydrate antigens on the cell surface are closely related to integrins. "
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    Journal of Experimental & Clinical Cancer Research 06/2013; 32(1):36. DOI:10.1186/1756-9966-32-36 · 4.43 Impact Factor
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    • "In contrast to mice lacking the entire b4 cytoplasmic domain, which display extensive skin blistering because of the absence of hemidesmosomes (Murgia et al. 1998), mice with a more restricted truncation do not show these defects. However, they show delayed wound healing and defective neoangiogenesis in tumor xenografts (Nikolopoulos et al. 2004, 2005). In addition, when crossed to the MMTV-Neu mice that carry an activated form of epidermal growth factor receptor-2 (ErbB2) driven by a mouse mammary tumor virus (MMTV) promoter leading to mammary tumors , the b4 mutant mice display delayed tumor onset, impaired tumor growth and decreased metastatic potential (Guo et al. 2006). "
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    Cold Spring Harbor perspectives in biology 02/2011; 3(2). DOI:10.1101/cshperspect.a005116 · 8.68 Impact Factor
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    • "Genetic evidence has implicated that α6β4 integrin signaling in promoting tumor angiogenesis and invasion [50]. These can be enhanced by HIF-1α and Ras up-expression as well [51-54]. "
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