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The VHL/HIF pathway is how cells sense oxygen (the 2019 Nobel Prize). VHL destroys HIF when oxygen is present. Kidney cancers lose VHL, so HIF-2α is permanently on and drives blood vessel growth and proliferation.
In normoxia, prolyl hydroxylases (PHD) hydroxylate HIF-α, allowing the VHL E3 ligase to ubiquitinate it for proteasomal degradation. In hypoxia (or with VHL loss in ~90% of clear-cell RCC), HIF-α accumulates, dimerises with HIF-1β (ARNT), and transcribes VEGF, PDGF, GLUT1, CAIX, cyclin D1, and EPO. HIF-2α is the oncogenic paralogue in RCC; belzutifan blocks its dimerisation. CAIX is a PET and radioligand target (89Zr-girentuximab).
VHL is the shredder that destroys the 'we are suffocating' memo whenever there is oxygen around. Kidney cancer breaks the shredder, so the memo piles up and the cell keeps ordering new blood vessels and sugar.
Shares Hallmark: reprogramming cellular metabolism, Warburg effect, Nutrient competition & metabolic immunosuppression, Metabolic theory of cancer: from Warburg to oncometabolites.
Shares Hallmark: inducing or accessing vasculature, Angiogenesis, Renal cell carcinoma (KEGG map), HIF-2α.
Shares HIF-1α (HIF1A), Choline metabolism in cancer, Temsirolimus, Renal cell carcinoma (KEGG map).
Shares VHL, Pheochromocytoma and paraganglioma (PPGL), Belzutifan.
Shares Nutrient competition & metabolic immunosuppression, HIF-2α, The angiogenic switch & tumour vessels.
Shares CAIX PET (89Zr-girentuximab), HIF-2α, Renal cell carcinoma.
Shares The pre-metastatic niche, Nutrient competition & metabolic immunosuppression, VEGF / VEGFR.
Shares CAIX PET (89Zr-girentuximab), Belzutifan, Renal cell carcinoma.