Vascular endothelial growth factor (VEGF) modulation by targeting hypoxia-inducible factor-1 alpha -> hypoxia response element -> VEGF cascade differentially regulates vascular response and growth rate in tumors

Although tumors can activate vascular endothelial growth factor (VEGF) prom oter 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 com bined immunodeficient mice. VEGF(-/-) ES cell-derived tumors produced simil ar to 50% of VEGF compared with the WT tumors, suggesting significant contr ibution of host stromal cells. To discern the hypoxia-induced hypoxia induc ible factor (HIF)-1 alpha --> hypoxia response element (HRE) --> VEGF signa ling cascade, we also examined tumors derived from HIF-1 alpha (-/-) and HR E-/- ES cells, As expected, the VEGF protein level in HIF-1 alpha (-/-) 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 tumo rs, suggesting a critical rot of HRE in tumor cell VEGF production, Angioge nesis in these tumors war proportional to their VEGF levels (VEGF(-/-) appr oximate to HRE-/- HIF-1 alpha (-/-) < WT). In contrast, vascular permeabili ty, leukocyte-endothelial adhesion, and tumor growth were reduced in VEGF(- /-) and HRE-/- tumors but were comparable in HIF-1<alpha>(-/-) and WT tumor s, This discrepancy suggests that different intracellular signaling pathway s may be involved in each of these functions of VEGF, More importantly, the se data suggest that host cells are active players in tumor angiogenesis an d growth and need to be taken into account in the design of any therapeutic strategy.