Loss of Integrin α9β1 on Tumor Keratinocytes Enhances the Stromal Vasculature and Growth of Cutaneous Tumors

Abstract

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 α9β1 expression from epidermal tumor cells is critical to maintaining persistent stromal vessel density. Forced expression of α9 in transformed mouse keratinocytes dramatically reduces vessel density in allograft tumors in vivo compared with that in the same cells lacking α9β1. Moreover, α9 mRNA expression is dramatically reduced in mouse and human epidermal tumors as is α9β1-dependent gene regulation. Loss of tumor cell α9β1 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 α9 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 α9β1 by repressing its expression through deletion and/or epigenetic silencing, thereby promoting stromal development and tumor growth.