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A mosaic mouse model of astrocytoma identifies αvβ8 integrin as a negative regulator of tumor angiogenesis

Oncogene volume 29, pages 4460–4472 (2010)Cite this article

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Abstract

Angiogenesis involves a complex set of cell–cell and cell–extracellular matrix (ECM) interactions that coordinately promote and inhibit blood vessel growth and sprouting. Although many factors that promote angiogenesis have been characterized, the identities and mechanisms of action of endogenous inhibitors of angiogenesis remain unclear. Furthermore, little is known about how cancer cells selectively circumvent the actions of these inhibitors to promote pathological angiogenesis, a requisite event for tumor progression. Using mosaic mouse models of the malignant brain cancer, astrocytoma, we report that tumor cells induce pathological angiogenesis by suppressing expression of the ECM protein receptor αvβ8 integrin. Diminished integrin expression in astrocytoma cells leads to reduced activation of latent TGFβs, resulting in impaired TGFβ receptor signaling in tumor-associated endothelial cells. These data reveal that astrocytoma cells manipulate their angiogenic balance by selectively suppressing αvβ8 integrin expression and function. Finally, these results show that an adhesion and signaling axis normally involved in developmental brain angiogenesis is pathologically exploited in adult brain tumors.

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Acknowledgements

We thank Dr Nami McCarty for providing assistance with FACS analysis and Dr Russell Pieper for generously providing E6/E7 and G12VH-Ras plasmids. This research was supported by grants awarded to JHM from the National Institutes of Neurological Disease and Stroke (R01NS059876), the National Cancer Institute (P50CA127001) and the Ellison Medical Foundation (AG-NS-0324-06). This work was also supported in part by a National Cancer Institute core grant (CA-16672) awarded to The University of Texas MD Anderson Cancer Center.

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Authors and Affiliations

  1. Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX, USA

    J H Tchaicha, A K Mobley, M G Hossain & J H McCarty

  2. Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA

    K D Aldape

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  1. J H Tchaicha
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Correspondence to J H McCarty.

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Tchaicha, J., Mobley, A., Hossain, M. et al. A mosaic mouse model of astrocytoma identifies αvβ8 integrin as a negative regulator of tumor angiogenesis. Oncogene 29, 4460–4472 (2010). https://doi.org/10.1038/onc.2010.199

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