α2β1 integrin expression in the tumor microenvironment enhances tumor angiogenesis in a tumor cell-specific manner

To define the role of the alpha 2 beta 1 integrin in pathologic angiogenesis, we investigated tumor-associated growth and angiogenesis in wild-type and alpha 2-null mice. Our findings reveal that the alpha 2 beta 1 integrin plays an important role in angiogenesis via regulation of VEGFR1 expression. When challenged with B16F10 melanoma cells, mice lacking alpha 2 beta 1 integrin expression exhibit increased tumor angiogenesis associated with up-regulated VEGFR1 expression. In contrast, there was no alpha 2 beta 1 integrin-dependent difference in the angiogenic response to Lewis lung carcinoma (LLC) cells. Interestingly, whereas B16F10 cells secrete high levels of placental growth factor (PLGF), LLC cells produce high levels of VEGF, but low levels of PLGF: The alpha 2 beta 1 integrindependent difference in angiogenesis was restored to LLC cells by expression of PLGF, strongly suggesting that the angiogenic phenotype and tumor growth in the alpha 2-null host is dependent on specific interactions between the tumor cell and the genetically defined integrin repertoire of the host microenvironment. Thus integrin alpha 2-null mice represent an example of genetic alterations of "the soil" determining response to the "seed."