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Hypoxia-Inducible Factor-1 Target Genes as Indicators of Tumor Vessel Response to Vascular Endothelial Growth Factor Inhibition

¹ Division of Gastroenterology, ² Division of Hematology/Oncology, Department of Internal Medicine, The University of Michigan Medical Center, ³ University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan; ⁴ Nevada Cancer Institute, Las Vegas, Nevada; ⁵ Prostate Cancer Research Laboratory, Department of Urology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; ⁶ Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, Michigan; ⁷ The University of Puerto Rico Cancer Center, San Juan, Puerto Rico; and ⁸ National Cancer Institute, Frederick, Maryland

Requests for reprints: Long H. Dang, The University of Michigan Medical Center, 1150 West Medical Center Drive, MSRB I, 6514 Ann Arbor, MI 48109. Phone: 734-647-2964; Fax: 734-763-2535; E-mail: lhdang{at}umich.edu.

Key Words: HIF-1 • VEGF • pericytes • hypoxia • SMA • NG2 • DPP4 • angiogenic inhibition

Antiangiogenic therapy improves survival in patients with advanced stage cancers. Currently, there are no reliable predictors or markers for tumor vessel response to antiangiogenic therapy. To model effective antiangiogenic therapy, we disrupted the VEGF gene in three representative cancer cell lines. HCT116 xenografts had low proportions of endothelial tubes covered by pericytes that stained with -smooth muscle actin (SMA) antibody. Upon disruption of VEGF, HCT116^VEGF–/– xenografts had significantly decreased tumor microvessel perfusion compared with their parental counterparts. Furthermore, HCT116^VEGF–/– xenografts mounted a tumor-reactive response to hypoxia, characterized by the induction of hypoxia-inducible factor-1 (HIF-1) target genes. One highly induced protein was DPP4, a measurable serum protein that has well-described roles in cancer progression. In contrast, LS174T and MKN45 tumor xenografts had high proportion of endothelial tubes that were covered by SMA+ pericytes. Upon disruption of VEGF, LS174T^VEGF–/– and MKN45^VEGF–/– xenografts maintained tumor microvessel perfusion. As such, there were no changes in intratumoral hypoxia or HIF-1 induction. Together, these data show that the extent of tumor vessel response to angiogenic inhibition could be correlated with (a) the preexisting coverage of tumor endothelial tubes with SMA+ pericytes and (b) differential tumor induction of HIF-1 target genes. The data further show that DPP4 is a novel marker of HIF-1 induction. Altogether, these preclinical findings suggest novel clinical trials for predicting and monitoring tumor vessel responses to antiangiogenic therapy. [Cancer Res 2008;68(6):1872–80]