New insights into the biology of renal cell carcinoma

Abstract

Ninety percent or more of kidney cancers are believed to be of epithelial cell origin, and are referred to as renal cell carcinoma (RCC), which are further subdivided based on histology into clear-cell RCC (75%), papillary RCC (15%), chromophobe tumor (5%), and oncocytoma (5%). Some genes confer an increased risk of these various histologic RCC subtypes. In practice, there is some overlap among the histologic subtypes, and there are some shared molecular features among these tumor types. This review focuses primarily on the most common form of RCC, clear-cell renal carcinoma, noting some recent advances in the other histologic subtypes.

Fig. 1

Regulation of hypoxia-inducible factor (HIF) by von Hippel-Landau tumor suppressor protein (pVHL). Under normoxic conditions, HIFα is hydroxylated by EglN prolyl hydroxylases. In addition to O₂, this reaction also requires α-ketoglutarate, which is converted to succinate, and reduced iron. Succinate dehydrogenase (SDH) converts succinate to fumarate, which is further converted to malate by fumarate hydratase (FH). Accumulation of succinate and fumarate can inhibit HIFα hydroxylation. Hydroxylated HIFα is recognized by pVHL, the substrate recognition subunit of an E3 ubiquitin ligase complex, polyubiquitinated, and degraded by the proteasome. Under hypoxic conditions, HIFα is stabilized, dimerizes with HIFβ, and activates target gene transcription. GLUT1, glucose transporter 1; HRE, hypoxia response element; TGFα, transforming growth factor α; VEGF, vascular endothelial growth factor.

Fig. 2

HIF-independent functions of VHL. See text for details. NF-κB, nuclear factor κB; RTK, receptor tyrosine kinase.

Fig. 3

Angiogenesis and targeted therapies in RCC. Inactivation of VHL in RCC cells lead to increased HIF activity. As a result, RCC cells secrete increased levels of vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF), which activate VEGF receptors and PDGF receptors to promote angiogenesis. Bevacizumab is a neutralizing antibody for VEGF. Sunitinib, sorafenib, and pazopanib act to block VEGF receptor and PDGF receptor activation. HIF protein levels are also influenced by mTOR kinase activity. Temsirolimus and everolimus block mTOR and thereby inhibit HIFα production. HIF, hypoxia-inducible factor; MAPK, mitogen-activated protein kinase; MEK, mitogen-activated protein kinase kinase; mTOR, mammalian target of rapamycin; NO, nitric oxide; PI3K, phosphatidylinositol 3-kinase; PKC, protein kinase C; PLCgg, phospholipase-C gamma.