Loss of Integrin?9?1 on Tumor Keratinocytes Enhances the Stromal Vasculature and Growth of Cutaneous Tumors

Angiogenesis is critical to tumor progression, and the function of integrins in tumor angiogenesis is complex. In this study, we report that loss of integrin rx9131 expression from epidermal tumor cells is critical to maintaining persistent stromal vessel density. Forced expression of rx9 in transformed mouse keratinocytes dramatically reduces vessel density in allograft tumors in vivo compared with that in the same cells lacking rx9131. Moreover, a9 mRNA expression is dramatically reduced in mouse and human epidermal tumors as is rx9131-dependent gene regulation. Loss of tumor cell rx9131 occurs through at least two mechanisms: (i) ITGA9 gene copy number loss in human tumors and (ii) epigenetic silencing in mouse and human tumors. Importantly, we show that reversal of epigenetic silencing of Itga9 restores rx9 expression in mouse keratinocytes and that human tumors without ITGA9 copy number loss have increased promoter methylation. Our data suggest that for epidermal tumorigenesis to occur, tumor cells must avoid the tumor and angiogenic suppressive effects of rx9131 by repressing its expression through deletion and/or epigenetic silencing, thereby promoting stromal development and tumor growth.