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Alpha-v Beta-3

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David A. Cheresh – 1st expert on this subject based on the ideXlab platform

  • Involvement of integrins alpha v beta 3 and alpha v beta 5 in ocular neovascular diseases.
    Proceedings of the National Academy of Sciences of the United States of America, 1996
    Co-Authors: Martin Friedlander, Chandra L. Theesfeld, Miyuki Sugita, Marcus Fruttiger, Matthew A. Thomas, Stanley Chang, David A. Cheresh

    Abstract:

    Angiogenesis underlies the majority of eye diseases that result in catastrophic loss of vision. Recent evidence has implicated the integrins alpha v beta 3 and alpha v beta 5 in the angiogenic process. We examined the expression of alpha v beta 3 and alpha v beta 5 in neovascular ocular tissue from patients with subretinal neovascularization from age-related macular degeneration or the presumed ocular histoplasmosis syndrome or retinal neovascularization from proliferative diabetic retinopathy (PDR). Only alpha v beta 3 was observed on blood vessels in ocular tissues with active neovascularization from patients with age-related macular degeneration or presumed ocular histoplasmosis, whereas both alpha v beta 3 and alpha v beta 5 were present on vascular cells in tissues from patients with PDR. Since we observed both integrins on vascular cells from tissues of patients with retinal neovascularization from PDR, we examined the effects of a systemically administered cyclic peptide antagonist of alpha v beta 3 and alpha v beta 5 on retinal angiogenesis in a murine model. This antagonist specifically blocked new blood vessel formation with no effect on established vessels. These results not only reinforce the concept that retinal and subretinal neovascular diseases are distinct pathological processes, but that antagonists of alpha v beta 3 and/or alpha v beta 5 may be effective in treating individuals with blinding eye disease associated with angiogenesis.

  • Human neural cell adhesion molecule L1 and rat homologue NILE are ligands for integrin alpha v beta 3.
    Journal of Cell Biology, 1996
    Co-Authors: Anthony M.p. Montgomery, David A. Cheresh, Jürgen C. Becker, Vance Lemmon, James D. Pancook, Xiaoning Zhao, Ralph A. Reisfeld

    Abstract:

    Integrin alpha v beta 3 is distinct in its capacity to recognize the sequence Arg-Gly-Asp (RGD) in many extra-cellular matrix (ECM) components. Here, we demonstrate that in addition to the recognition of ECM components, alpha v beta 3 can interact with the neural cell adhesion molecule L1-CAM; a member of the immunoglobulin superfamily (IgSF). M21 melanoma cells displayed significant Ca(++)-dependent adhesion and spreading on immunopurified rat L1 (NILE). This adhesion was found to be dependent on the expression of the alpha v-integrin subunit and could be significantly inhibited by an antibody to the alpha v beta 3 heterodimer. M21 cells also displayed some alpha v beta 3-dependent adhesion and spreading on immunopurified human L1. Ligation between this ligand and alpha v beta 3 was also observed to promote significant haptotactic cell migration. To map the site of alpha v beta 3 ligation we used recombinant L1 fragments comprising the entire extracellular domain of human L1. Significant alpha v beta 3-dependent adhesion and spreading was evident on a L1 fragment containing Ig-like domains 4, 5, and 6. Importantly, mutation of an RGD sequence present in the sixth Ig-like domain of L1 abrogated M21 cell adhesion. We conclude that alpha v beta 3-dependent recognition of human L1 is dependent on ligation of this RGD site. Despite high levels of L1 expression the M21 melanoma cells did not display significant adhesion via a homophilic L1-L1 interaction. These data suggest that M21 melanoma cells recognize and adhere to L1 through a mechanism that is primarily heterophilic and integrin dependent. Finally, we present evidence that melanoma cells can shed and deposit L1 in occluding ECM. In this regard, alpha v beta 3 may recognize L1 in a cell-cell or cell-substrate interaction.

  • Antiintegrin alpha v beta 3 blocks human breast cancer growth and angiogenesis in human skin.
    Journal of Clinical Investigation, 1995
    Co-Authors: Peter C. Brooks, Staffan Strömblad, Richard L. Klemke, Daniel W Visscher, F. H. Sarkar, David A. Cheresh

    Abstract:

    Abstract
    Angiogenesis plays a fundamental role in human breast tumor progression. In fact, recent findings indicate that vascular density is a prognostic indicator of breast cancer disease status. Evidence is presented that the integrin alpha v beta 3 is not only a marker of human breast tumor-associated blood vessels, but that it plays a significant role in human angiogenesis and breast tumor growth. To assess the role of alpha v beta 3-dependent angiogenesis in the progression of human breast cancer, we examined a SCID mouse/human chimeric model with transplanted full thickness human skin containing alpha v beta 3-negative human breast tumor cells. This tumor induced a human angiogenic response as measured by vascular cell immunoreactivity with monoclonal antibodies LM609 and P2B1 directed to human alpha v beta 3 and CD31, respectively. Intravenous administration of LM609 either prevented tumor growth or markedly reduced tumor cell proliferation within the microenvironment of the human skin. These LM609-treated tumors not only contained significantly fewer human blood vessels but also appeared considerably less invasive than tumors in control animals. These findings demonstrate that alpha v beta 3 antagonists may provide an effective antiangiogenic approach for the treatment of human breast cancer.

Edmond Sabo – 2nd expert on this subject based on the ideXlab platform

  • ‘Normalizing’ the malignant phenotype of luminal breast cancer cells via alpha(v)beta(3)-integrin
    Cell Death & Disease, 2016
    Co-Authors: Hanan Abu-tayeh, Geula Klorin, Keren Weidenfeld, Alisa Zhilin-roth, Sagi Schif-zuck, Sonja Thaler, Cristina Cotarelo, Jean P. Thiery, Jeffrey E Green, Edmond Sabo

    Abstract:

    Reestablishing tissue organization of breast cancer cells into acini was previously shown to override their malignant phenotype. In our study, we demonstrate that alpha(v)beta(3) integrin (Int- α v β 3), previously shown to play a role in cancer progression, promoted differentiation and growth arrest of organoids derived from luminal A breast cancer cells grown in their relevant three-dimensional microenvironment. These organoids differentiated into normal-like acini resembling a benign stage of breast tissue. Likewise, we demonstrate that Int- α v β 3 is selectively expressed in the epithelium of the benign stage of breast tissues, and is lost during the early stages of luminal A breast cancer progression. Notably, the organoids’ reversion into normal-like acini was mediated by cancer luminal progenitor-like cells expressing both EpCAM^highCD49f^lowCD24^+ and Int- α v β 3. Furthermore, downregulation of Notch4 expression and downstream signaling was shown to mediate Int- α v β 3-induced reversion. Intriguingly, when luminal A breast cancer cells expressing Int- α v β 3 were injected into a humanized mouse model, differentiated tumors developed when compared with that generated by control cells. Hence, our data suggest that promoting differentiation of luminal A breast cancer cells by signaling emanating from Int- α v β 3 can potentially promote ‘normalization’ of their malignant phenotype and may prevent the malignant cells from progressing.

Hanan Abu-tayeh – 3rd expert on this subject based on the ideXlab platform

  • ‘Normalizing’ the malignant phenotype of luminal breast cancer cells via alpha(v)beta(3)-integrin.
    Cell Death and Disease, 2016
    Co-Authors: Hanan Abu-tayeh, Keren Weidenfeld, Alisa Zhilin-roth, Sagi Schif-zuck, Sonja Thaler, Cristina Cotarelo, Jean P. Thiery, Jeffrey Green, Geula Klorin

    Abstract:

    ‘Normalizing’ the malignant phenotype of luminal breast cancer cells via alpha(v)beta(3)-integrin

  • ‘Normalizing’ the malignant phenotype of luminal breast cancer cells via alpha(v)beta(3)-integrin
    Cell Death & Disease, 2016
    Co-Authors: Hanan Abu-tayeh, Geula Klorin, Keren Weidenfeld, Alisa Zhilin-roth, Sagi Schif-zuck, Sonja Thaler, Cristina Cotarelo, Jean P. Thiery, Jeffrey E Green, Edmond Sabo

    Abstract:

    Reestablishing tissue organization of breast cancer cells into acini was previously shown to override their malignant phenotype. In our study, we demonstrate that alpha(v)beta(3) integrin (Int- α v β 3), previously shown to play a role in cancer progression, promoted differentiation and growth arrest of organoids derived from luminal A breast cancer cells grown in their relevant three-dimensional microenvironment. These organoids differentiated into normal-like acini resembling a benign stage of breast tissue. Likewise, we demonstrate that Int- α v β 3 is selectively expressed in the epithelium of the benign stage of breast tissues, and is lost during the early stages of luminal A breast cancer progression. Notably, the organoids’ reversion into normal-like acini was mediated by cancer luminal progenitor-like cells expressing both EpCAM^highCD49f^lowCD24^+ and Int- α v β 3. Furthermore, downregulation of Notch4 expression and downstream signaling was shown to mediate Int- α v β 3-induced reversion. Intriguingly, when luminal A breast cancer cells expressing Int- α v β 3 were injected into a humanized mouse model, differentiated tumors developed when compared with that generated by control cells. Hence, our data suggest that promoting differentiation of luminal A breast cancer cells by signaling emanating from Int- α v β 3 can potentially promote ‘normalization’ of their malignant phenotype and may prevent the malignant cells from progressing.