Rescue of hypoxia-inducible factor-1α-deficient tumor growth by wild-type cells is independent of vascular endothelial growth factor

G Höpfl, RH Wenger, U Ziegler, T Stallmach… - Cancer research, 2002 - AACR
G Höpfl, RH Wenger, U Ziegler, T Stallmach, O Gardelle, R Achermann, M Wergin…
Cancer research, 2002AACR
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-1α (HIF-1α) in pathological (eg, tumorigenesis) as well as physiological (eg,
development and wound healing) processes. By sc injection of HIF-1α−/− embryonic stem
(ES) cells in nude mice, we were able to demonstrate the role of HIF-1α in cell differentiation …
Abstract
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-1α (HIF-1α) in pathological (e.g., tumorigenesis) as well as physiological (e.g., development and wound healing) processes. By s.c. injection of HIF-1α−/− embryonic stem (ES) cells in nude mice, we were able to demonstrate the role of HIF-1α in cell differentiation of teratocarcinomas. HIF-1α+/+ tumors grow fast and preferentially form neuronal tissue, whereas HIF-1α−/− tumors show delayed growth and favorably form mesenchyme-derived tissue. Mixing wild-type and HIF-1α−/− ES cells in the same tumor at a ratio as low as 1:100, we showed that HIF-1α+/+ cells can rescue the growth of mixed tumors although these tumors are not significantly different phenotypically or genotypically from the original HIF-1α−/− tumors. Interestingly, these results are not restricted to teratocarcinomas: they were confirmed with mixtures of Hepa1/Hepa1C4 cells (where HIF-1β 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-1α−/− and mixed tumors does not significantly differ from the HIF-1α+/+ 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-1α+/+, HIF-1α−/−, and mixed tumors. Our data demonstrate that the HIF-1α-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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