Renal cell carcinoma (RCC) accounts for 2 percent of all cancers [1]. In Europe, 40,000 patients are diagnosed with RCC each year, leading to 20,000 deaths [2].

One-third of patients are initially diagnosed with locally invasive or stage IV disease [3]. Recurrence occurs in 25 percent of patients having surgical resection for localized disease with a curative intent [4]. The prognosis for patients with distant disease is poor, with a five-year survival rate of 10 percent or less [5].

A major breakthrough has recently occurred in the knowledge of the genetics and transduction pathways involved in RCC [6]. Novel targeted therapies directed against angiogenesis and mammalian target of rapamycin (mTOR) pathway are revolutionizing the treatment of metastatic RCC (mRCC).

This review covers the key molecular pathways and provides the latest data likely to modify current practice [6].

KEY MOLECULAR PATHWAYS FOR THERAPEUTIC TARGETING

A major breakthrough was obtained with recognition of the importance of the hypoxia-driven pathway involving hypoxia-inducible factor (HIF) and related knowledge on angiogenesis with vascular endothelial growth factor (VEGF). Furthermore, new insights on mechanisms of disease resistance in the HIF/VEGF pathway have led to the consideration of alternative pathways. The mTOR pathway seems to be an important primary or alternative pathway in RCC.

Hypoxia-Induced Pathway

Similar to other deprivation factors, hypoxia may affect cell growth. In normoxia, the subunit alpha of HIF (HIFα) is hydroxylated by a Von Hippel–Lindau protein (pVHL) complex unit and degraded through the proteasome [7].