Functional significance of erythropoietin in renal cell carcinoma

Abstract

One of the molecules regulated by the transcription factor, hypoxia inducible factor (HIF), is the hypoxia-responsive hematopoietic factor, erythropoietin (EPO). This may have relevance to the development of renal cell carcinoma (RCC), where mutations of the von Hippel-Lindau (VHL) gene are major risk factors for the development of familial and sporadic RCC. VHL mutations up-regulate and stabilize HIF, which in turn activates many downstream molecules, including EPO, that are known to promote angiogenesis, drug resistance, proliferation and progression of solid tumours. HIFs typically respond to hypoxic cellular environment. While the hypoxic microenvironment plays a critical role in the development and progression of tumours in general, it is of special significance in the case of RCC because of the link between VHL, HIF and EPO. EPO and its receptor, EPOR, are expressed in many cancers, including RCC. This limits the use of recombinant human EPO (rhEPO) to treat anaemia in cancer patients, because the rhEPO may be stimulatory to the cancer. EPO may also stimulate epithelial-mesenchymal transition (EMT) in RCC, and pathological EMT has a key role in cancer progression. In this mini review, we summarize the current knowledge of the role of EPO in RCC. The available data, either for or against the use of EPO in RCC patients, are equivocal and insufficient to draw a definitive conclusion.

Figure 1

The putative role of VHL-HIF-EPO pathway in RCC progression. A functional VHL gene produces pVHL, which forms a pVHL-E3 ligase complex and mediates the poly ubiquitination (Ub) and proteasomal degradation (PD) of HIF. As a result, the translocation (TR) of HIF to the nucleus and the subsequent transactivation of HIF regulated molecules, including EPO is prevented. When the VHL gene is mutated, the production of pVHL and the formation of the pVHL-E3 ligase complex are either impaired or prevented. Subsequently, HIF is stabilized and up-regulated, and translocated to the nucleus, where it dimerizes with other HIF subunits and transactivates HIF responsive genes including EPO. EPO binds to its receptor EPOR and mediates some of the biological aspects of cancer progression such as increase in angiogenesis and inflammation and decrease in intrinsic and drug-induced apoptosis. Apart from VHL mutations, hypoxia is the single major factor that regulates the production of EPO. In normoxic conditions, the HIF is degraded, whereas in hypoxia, HIF is stabilized and lead leads to the activation of EPO.