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Hypoxia Response Element VEGF Cascade Differentially Regulates Vascular Response and Growth Rate in Tumors1
Edwin L. Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital, and Harvard Medical School, Boston, Massachusetts 02114 [Y. T., D. F., C. K., R. K. J.], and Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, KU Leuven, B3000 Belgium [B. O., P. C.]
Although tumors can activate vascular endothelial growth factor (VEGF)
promoter in host stromal cells, the relative contribution to VEGF
production of host versus tumor cells and the resulting
vascular response have not been quantitated to date. To this end, we
implanted VEGF-/- and wild-type (WT) embryonic stem (ES)
cells in transparent dorsal skin windows in severe combined
immunodeficient mice. VEGF-/- ES cell-derived tumors
produced 
50% of VEGF compared with the WT tumors, suggesting
significant contribution of host stromal cells. To discern the
hypoxia-induced hypoxia inducible factor (HIF)-1
hypoxia
response element (HRE) VEGF signaling cascade, we also examined
tumors derived from HIF-1-/- and HRE-/-
ES cells. As expected, the VEGF protein level in
HIF-1-/- ES tumors was intermediate between
VEGF-/- and WT ES cell tumors. Surprisingly,
HRE-/- ES tumors produced the same level of VEGF as
the VEGF-/- ES tumors, suggesting a critical role of HRE
in tumor cell VEGF production. Angiogenesis in these tumors was
proportional to their VEGF levels (VEGF-/- 
HRE-/- < HIF-1-/- < WT). In contrast, vascular
permeability, leukocyte-endothelial adhesion, and tumor growth were
reduced in VEGF-/- and HRE-/- tumors but
were comparable in HIF-1-/- and WT tumors. This
discrepancy suggests that different intracellular signaling pathways
may be involved in each of these functions of VEGF. More importantly,
these data suggest that host cells are active players in tumor
angiogenesis and growth and need to be taken into account in the design
of any therapeutic strategy.
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