Neoangiogenesis is essential for tumor development. Hypoxia inducible factor (HIF), a transcriptional factor composed of two subunits (α and β) plays a key role in this process, activating proangiogenic factors, such as VEGF. The HIF α subunits are critically regulated by oxygen but also modulated by growth factors. Kaposi Sarcoma (KS) is a highly vascular tumor which releases large amounts of VEGF and for which we have recently described an essential role for Insulin-like Growth Factor (IGF) system. We therefore investigated the expression of HIF αs subunits in biopsies from KS tumors and their modulation by IGF-I in KSIMM, a KS cell line.
Both HIF-1α and HIF-2α are expressed in KS biopsies in all tumoral stages. HIF-1α immunopositivity increases through the tumor development with highest expression in late nodular stages.
In KSIMM cells, IGF-I induces accumulation of both HIF α subunits (western blot). The induction suggests a translation mechanism as demonstrated by cycloheximide (CHX) chase experiment coupled with constant RNA levels as evaluated by qRT-PCR. IGF-I induced HIF αs accumulation is followed by increase of HIF function as documented by reporter gene assay and by induction of endogenous target genes as evaluated by qRT-PCR (VEGF-A and GLUT-1) and ELISA (VEGF-A). Blocking the IGF-IR with picropodophyllin (PPP), a specific IGF-IR tyrosine kinase inhibitor, diminishes the basal and IGF-I-dependent induction of both HIF α congeners and VEGF.
These novel findings shed lights on the coupling between the IGF system and HIF pathway in KS and suggest their contribution in the tumor characteristically vascular phenotype.
01 - 05 Apr 2006
European Society of Endocrinology