Integrin β4 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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    ABSTRACT: Objective This study investigates the expression of Lewis y antigen, integrin αv, β3 in epithelial ovarian cancer tissues. We further evaluate the relationship between their expression and chemotherapy resistance of ovarian cancer and its possible clinical significance. Methods Tissues of 92 patients with ovarian cancer meeting the inclusion criteria with complete follow-up data were enrolled and divided into chemotherapy resistant group and sensitive group. The expression and relationship of Lewis y antigen and integrin αv, β3 are assessed in paraffin sections using immunohistochemistry and double-labeling immunofluorescence method. Multivariate logistic regression analysis was used to investigate the relationship between age, clinical stage, differentiation, histologic subtype, Lewis y antigen and integrin αv, β3 expression in ovarian cancer patients. Results The expression rates of Lewis y antigen and integrin αv in the resistant group, significantly higher than the rates found in the sensitive group (p <0.05). Multivariate analysis showed that the expression of Lewis y antigen, integrin αv and ovarian cancer’s clinical stage were independent, drug resistance-related risk factors. The expression levels of Lewis y antigen and integrin αv, β3 were positively correlated with each other. Conclusions A close correlation between Lewis y antigen, integrin αv, β3 and ovarian cancer was observed. Lewis y antigen can influence the biological behavior of a tumor cell as an important composition of integrin αv, β3 by some signal pathway. And the expression of Lewis y antigen, integrin αv and ovarian cancer’s clinical stage are both independent, drug resistance-related risk factors.
    Full-text · Article · Jun 2013 · Journal of Experimental & Clinical Cancer Research
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    • "The interaction of integrins with the extracellular matrix influences the assembly and organisation of the intracellular cytoskeleton, enhances cell survival and reduces the likelihood of apoptosis in a variety of tumour types (Janes and Watt, 2006; Le Tourneau et al., 2007; Moschos et al., 2007; Streuli, 2009). The centres of growing solid tumours can become hypoxic, which prompts the generation of new blood supply for the tumour through angiogenesis, in which integrins expressed by the growing endothelia influence migration to and entry into the tumour (Nikolopoulos et al., 2004; Varner and Cheresh, 1996) . "
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    ABSTRACT: Aims: To study the expression of integrins αvβ3 and αvβ5 and their ligands in tumour, stroma and endothelial cells from human glioblastoma and CNS metastases from breast, lung and skin tumours. Methods and results: Integrin and integrin ligand expression was quantified in frozen tumour surgical specimens (15 glioblastomas and breast carcinoma metastases as well as 16 lung carcinoma and melanoma metastases) using immunohistochemistry. Gene expression profiles were evaluated in glioblastomas (n=424) and in normal brain (n=11). Overall, αvβ3 expression was more common than αvβ5 except in tumours derived from lung. αvβ3 expression was most frequent in glioblastomas and melanoma metastases. Most lung-derived tumours expressed αvβ5 but expression was less frequent in other tumours; about 20% of breast-derived tumours strongly expressed αvβ5. Melanoma-derived tumours did not express αvβ5. Expression of integrin ligands vitronectin, fibrinogen, fibronectin and osteopontin was variable between tumours, although most tumours expressed the ligands to some extent. Marked αvβ3, but not αvβ5, expression was common in stroma of CNS metastases. In blood vessels, αvβ3 expression was more frequent than αvβ5 and more pronounced in CNS metastases than in glioblastomas. Integrin ligand expression occurred in blood vessels in most tumours. In glioblastomas, mRNA expression of αvβ3, αvβ5, osteopontin and fibronectin were significantly upregulated over normal brain. Conclusions: Overall, we report distinct and heterogeneous patterns of integrin expression in primary and secondary brain tumours that may be relevant to the future development of integrin-targeting therapeutic approaches to brain tumours.
    Preview · Article · Dec 2012 · Histology and histopathology
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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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    ABSTRACT: The development of multicellular organisms, as well as maintenance of organ architecture and function, requires robust regulation of cell fates. This is in part achieved by conserved signaling pathways through which cells process extracellular information and translate this information into changes in proliferation, differentiation, migration, and cell shape. Gene deletion studies in higher eukaryotes have assigned critical roles for components of the extracellular matrix (ECM) and their cellular receptors in a vast number of developmental processes, indicating that a large proportion of this signaling is regulated by cell-ECM interactions. In addition, genetic alterations in components of this signaling axis play causative roles in several human diseases. This review will discuss what genetic analyses in mice and lower organisms have taught us about adhesion signaling in development and disease.
    Full-text · Article · Feb 2011 · Cold Spring Harbor perspectives in biology
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