HIF-dependent Signaling Pathways in Cancer

Sammanfattning: The cellular response to hypoxia, primarily orchestrated by hypoxia-inducible factors (HIFs; mainly HIF-1α and HIF-2α), is at the center of several signaling pathways conferring aggressive tumor behavior. HIFs may be crucially involved in tumor initiation, as seen in clear cell renal cell carcinoma, as well as maintenance of resistance cancer stem cell phenotypes, as observed in glioma. In the first part of this thesis we demonstrated increased expression of the Notch1 signaling pathway in ccRCC compared to normal kidney. To further evaluate the role of increased Notch1 signaling we conditionally deleted Vhl combined with NICD1 overexpression in the proximal tubules of the renal cortex. NICD was demonstrated to co-operate with Vhl loss to promote early signs of ccRCC tumorigenesis by inducing the presence of clusters of dysplastic cells with a clear cytoplasm. Next we demonstrated that hypoxia induced expression of the dopamine transporter SLC6A3 in normal renal epithelium but not in other tissues. We further demonstrated that ccRCC tumors uniquely harbor a functional uptake of dopamine though the SLC6A3 transporter, which constitute a possible target in the clinic. In the second part of this thesis we showed that CD44 signaling, through CD44-ICD, modulate hypoxic and stem-like phenotypes of glioma stem cells by interacting with HIF-2α. Pharmacological inhibition of CD44 was demonstrated to reduce the hypoxic and stem like phenotypes and by contrast induced expression of differentiation markers. We finally showed that glioma-associated astrocytes promote stem-like phenotypes of glioma cells both in response to hypoxia and after radiation therapy. Such phenotypes were mainly mediated by direct cell-cell interactions and by changes in the ECM. All together these data highlight some of the molecular mechanisms explaining how tumor hypoxia and hypoxic signaling confer aggressive tumor growth.