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Renal cell carcinoma (RCC) comprises 2‑3% of all malignant tumors in adults. Many studies have established the key roles of smoking, hypertension and other components of metabolic syndrome in the occurrence of RCC. Diabetes mellitus (DM), one of the main consequences of metabolic syndrome, appears much more often in patients with RCC. The prognosis for patients suffering from both diabetes and RCC is worse than for those with kidney cancer only. Diabetes is linked to higher rate of recurrence and a greater number of distant metastases. These factors contribute to a reduction in overall survival (OS) and cause‑specific survival (CSS). Diabetes can also occur as a paraneoplastic syndrome. Tyrosine kinase inhibitors (TKIs), which are agents used in the therapy of metastatic RCC, may have unexpected effects when administered to patients with diabetes. Studies and case reports have shown that they influence blood glucose levels (BGLs) in diabetic patients, sometimes causing dangerous episodes of hypoglycemia. Hyperinsulinemia and hyperglycemia can be considered independent carcinogenic factors, as they increase the amount of pro‑inflammatory cytokines, reactive oxygen species and lipid peroxidation. TKIs have yet to be re‑evaluated as to their safety of use in patients with diabetes.

The cancer stem cell (CSC) model has recently been approached also in renal cell carcinoma (RCC). A few populations of putative renal tumor-initiating cells (TICs) were identified, but they are indifferently understood; however, the first and most thoroughly investigated are CD105-positive CSCs. The article presents a detailed comparison of all renal CSC-like populations identified by now as well as their presumable origin. Hypoxic activation of hypoxia-inducible factors (HIFs) contributes to tumor aggressiveness by multiple molecular pathways, including the governance of immature stem cell-like phenotype and related epithelial-to-mesenchymal transition (EMT)/de-differentiation, and, as a result, poor prognosis. Due to intrinsic von Hippel-Lindau protein (pVHL) loss of function, clear-cell RCC (ccRCC) develops unique pathological intra-cellular pseudo-hypoxic phenotype with a constant HIF activation, regardless of oxygen level. Despite satisfactory evidence concerning pseudo-hypoxia importance in RCC biology, its influence on putative renal CSC-like largely remains unknown. Thus, the article discusses a current knowledge of HIF-1α/2α signaling pathways in the promotion of undifferentiated tumor phenotype in general, including some experimental findings specific for pseudo-hypoxic ccRCC, mostly dependent from HIF-2α oncogenic functions. Existing gaps in understanding both putative renal CSCs and their potential connection with hypoxia need to be filled in order to propose breakthrough strategies for RCC treatment.

The natural history of clear cell renal cell cancer is highly unpredictable with various progressors and with populations where small renal masses may be accompanied by metastatic disease. Currently, there is a critical need to determine patient risk and optimize treatment regimes. For these patients, molecular markers may offer significant information in terms of prognostic and predictive values, as well as determination of valid therapeutic targets. Until now, only a few of the many identified clear cell renal cell cancer biomarkers have been clinically validated in large cohorts. And only several biomarkers are integrated in predictive or prognostic models. Therefore, a large cohesive effort is required to advance the field of clear cell renal cell cancer prognostic biomarkers through systematic discovery, verification, validation and clinical implementation.

The last few years have brought advances in the understanding of the molecular biology of metastatic clear cell renal cell carcinoma (RCC). Both preclinical research and clinical trials brought together results from the latest advancements in RCC diagnostic and staging. Understanding of the complex molecular alterations involved in the development and progression of RCC enables development of immunohistochemical and genetic diagnostic tools and is also opening the doors for experimental targeted therapies. At the same time, improvements of medical and molecular imaging improves the sensitivity and specificity of metastatic disease diagnosis. Moreover, independent validation of molecular profiles across high-throughput platforms, methods, laboratories and cancer populations has recently been successfully performed in RCC. Generation of informative, clinical diagnostic tools is likely to contribute to development of novel personalized diagnostic and treatment protocols and ensure prolonged survival of RCC patient in the near future.