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Rescue of Hypoxia-inducible Factor-1-deficient Tumor Growth by Wild-Type Cells Is Independent of Vascular Endothelial Growth Factor¹

Institutes of Physiology, Veterinary Physiology [G. H., M. G., I. D.], Anatomy [U. Z.], and Section of Diagnostic Imaging, School of Veterinary Medicine [O. G., R. A., M. W., B. K-H.], University of Zürich, CH-8057 Zürich, Switzerland; Institute of Clinical Pathology, University Hospital Zürich, CH-8091 Zürich, Switzerland [T. S.]; Institute of Physiology, Medical University of Lübeck, D-23538 Lübeck, Germany [R. H. W.]; Department of Clinical Studies, Philadelphia, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104 [H. M. S.]; and School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester M20 4BX, United Kingdom [K. J. W., I. J. S.]

In tumors, rapid cell proliferation associated with deficient vascularization leads to areas of hypoxia.Tumor hypoxia has direct consequences on clinical and prognostic parameters and is a potential therapeutic target. The hypoxic response depends critically on hypoxia-inducible factor-1 (HIF-1) in pathological (e.g., tumorigenesis) as well as physiological (e.g., development and wound healing) processes. By s.c. injection of HIF-1^-/- embryonic stem (ES) cells in nude mice, we were able to demonstrate the role of HIF-1 in cell differentiation of teratocarcinomas. HIF-1^+/+ tumors grow fast and preferentially form neuronal tissue, whereas HIF-1^-/- tumors show delayed growth and favorably form mesenchyme-derived tissue. Mixing wild-type and HIF-1^-/- ES cells in the same tumor at a ratio as low as 1:100, we showed that HIF-1^+/+ cells can rescue the growth of mixed tumors although these tumors are not significantly different phenotypically or genotypically from the original HIF-1^-/- tumors. Interestingly, these results are not restricted to teratocarcinomas: they were confirmed with mixtures of Hepa1/Hepa1C4 cells (where HIF-1ß is mutated), demonstrating that growth changes are not related to differences in differentiation observed within teratocarcinomas. We also showed that despite lower mRNA expression, vascular endothelial growth factor protein status in HIF-1^-/- and mixed tumors does not significantly differ from the HIF-1^+/+ tumors. Moreover, we demonstrated that tumor vascularization remains proportional to vascular endothelial growth factor protein levels, but that hypoxic up-regulation of this growth factor is not the decisive factor influencing tumor growth. Differences in levels of apoptosis are not responsible for alteration in growth because poly(ADP-ribose) polymerase cleavage, a hallmark of the apoptotic process, was similar in HIF-1^+/+, HIF-1^-/-, and mixed tumors. Our data demonstrate that the HIF-1-dependent response of a few cells is capable of sustaining the growth of the whole tumor, probably through the secretion of factors up-regulated under low oxygen conditions.

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