Most cases of sporadic clear cell RCC are characterised by a defect in the tumour suppressor gene von Hippel-Lindau (VHL).

The VHL protein plays an important role in regulating the cellular response to hypoxia via its regulation of hypoxia-inducible factor (HIF), as a transcription factor.

Inactivation of the VHL gene mimics a hypoxic condition that causes accumulation of HIF, which increases the production of various growth factors including vascular endothelial growth factor (VEGF) platelet derived growth factor (PDGF) and transforming growth factor alpha (TGF-α), which stimulate cell growth as well as formation of new blood vessels. New blood vessel formation is also called angiogenesis, which plays an important role in the pathogenesis of RCC.1

Growth factors such as VEGF and PDGF-β bind to their respective receptors on endothelial cells and cancer cells, activating the tyrosine kinase at the intracellular part of the receptor, which in turn results in activation of intracellular signal transduction pathways, including the RAF/MEK/ERK and PI3K/AKT/mTOR pathways. These signalling pathways in turn influence cell behaviour including cell growth and angiogenesis. With the formation of new blood vessels, the tumour can obtain oxygen and nourishment in order to grow and spread.

VHL gene mutations cause overproduction of growth factors

• Mutation or inactivation of the VHL gene disrupts VHL gene function and HIF is not degraded^1,2
• HIFs move into the nucleus where they accumulate and cause transcription of hypoxia-inducible genes and overproduction of growth factors (e.g. VEGF, TGF-α and PDGF)^2,3
• Binding of growth factors to their receptors on the surface of endothelial and cancer cells promotes angiogenesis and cell growth^1,2

• Increased VEGF expression has been found in RCC, which correlates with microvessel density, a measure of the extent of angiogenesis¹
• After activation of HIF, VEGF and PDGF are upregulated and bind to their receptors on the surface of endothelial cells^2,3
• Promotes endothelial cell migration and proliferation, which is vital for the development of new tumour-induced blood vessels^1,2

VEGF and VEGFR are attractive molecular targets for the treatment of RCC because they play an important role in tumour angiogenesis.²

VHL inactivation also upregulates the tyrosine kinase receptor hepatocyte growth factor receptor (MET) and the arrest-specific protein 6-receptor (AXL). ^6,7

Increased expression of MET and AXL in RCC is associated with poor prognosis and resistance to VEGFR inhibitors.^6,8
AXL, anexelekto (Greek: uncontrolled); ccRCC, clear cell RCC; MET, hepatocyte growth factor receptor

FGF: fibroblast growth factor; HIF: hypoxia-inducible factor

In RCC, MET and AXL are thought to act as escape pathways potentially contributing to resistance to a more selective VEGFR-targeted therapy. ⁹

1. Rini BI, Campbell SC, Escudier B. Renal cell carcinoma. 2009;373(9669):1119–1132.
2. Linehan WM, Bratslavsky G, Pinto PA, et al. Molecular diagnosis and therapy of kidney cancer. Annu Rev Med. 2010;61:329-343.
3. Semenza GL. HIF-1 mediates metabolic responses to intratumoral hypoxia and oncogenic mutations. J Clin Invest. 2013;123(9):3664-3671.
4. Banumathy G, Cairns P. Signaling pathways in renal cell carcinoma. Cancer Biol Ther. 2010;10(7):658–664.
5. Pili R, Kauffman E, Rodriguez R. Cancer of the kidney. I: Niederhuber JE, Armitage JO, Doroshow JH, Kastan MB, Tepper JE, eds. Abeloff’s Clinical Oncology. 5th ed. Philadelphia, PA: Elsevier Saunders; 2014:1416–1444.
6. Choueiri TK, et al. N Engl J Med 2015;373:1814–23
7. Gibney GT, et al. Ann Oncol 2013;24:343–9
8. Rankin EB, et al. PNAS 2014;111:13373–8
9. Zhou L, et al. Oncogene 2016;35:2687–97