The cause is unclear for most renal cell cancers (RCCs), although inactivation of the von Hippel-Lindau tumor-suppressor gene plays a key role for some clear-cell variants. The resulting elevation of hypoxia-inducible factor and subsequent dysregulation of cell growth is well documented. The role of inflammation as a cause or promoter of cancer cell growth has been appreciated better in the laboratory than in the clinic, but in recent years the spotlight has turned to inflammation, fueled primarily by two observations: (1) recognition of the neutrophil/lymphocyte ratio (NLR) as a marker of inflammation for many cancers, including renal cancer  and ; and (2) the extraordinarily rapid development of PD1/L1 inhibitors , , and , which has highlighted the importance of immune function in some cancers. The biological mechanisms for the interplay between inflammation and immune function are still unclear, but there is increasing evidence that perturbations to many parts of the immune and inflammation signaling pathways aid in the promotion of angiogenesis and immune surveillance tolerance.
In the clinic, evaluation of systemic inflammation is difficult and there is no gold standard test. Elevated C-reactive protein (CRP), elevated erythrocyte sedimentation rate, hypoalbuminemia, thrombocytosis, and leukocytosis are clues to a systemic inflammatory response. Others are combinations of clinical factors, including NLR, and clinical scores such as the modified Glasgow Prognostic score are perhaps more sensitive tests of clinical information. For RCC, it has been shown that all of these measurements are statistically significant prognostic factors in settings such as the preoperative scenario , , , and  and metastatic RCC , , and . Because NLR is cheap to measure and readily available, much evidence has emerged in the literature to support the hypothesis that inflammation is a key determinant of prognosis. Recent meta-analyses confirmed the prognostic value of NLR in RCC  and other solid tumors , as expected for a nonspecific driver of cancer cell fate. Presumably, NLR and other clinical markers of systemic inflammation represent nonspecific host responses to the presence of cancer.
However, whether there are specific inflammation-related gene products that drive the development or behavior of RCC is less clear; what data there are on this question appear to support the relationship. It was recently found that polymorphisms in MCP1 and its receptor CCR2, both major players in inflammation, were associated with RCC risk and prognosis . Similarly, it was found that polymorphisms of CXC12 and CXCR4 had a significant influence on both the risk of RCC development and prognosis . It has also been shown that intratumoral expression of P2X7, an ATP-gated plasma membrane ion channel, has prognostic significance for RCC patients .
However, not all potential markers of inflammation are necessarily related to RCC prognosis, nor are all cancers affected equally by the presence of inflammation. In a large population-based study, breast cancer prognosis appeared to be least influenced by systemic inflammation, whereas lung cancer was at the other extreme . In histopathology specimens, CRP, a downstream mediator of interleukin 6, was associated with clear-cell RCC stage or grade, whereas cyclooxygenase enzyme 2, an important component of the eicosanoid pathway for the production of inflammatory lipid mediators, was not .
In summary, while there are still many questions to be answered with regard to the role of inflammation and its relationship to immune function and RCC tumor heterogeneity in determining an individual's prognosis, particularly whether there are specific inflammatory genes driving RCC outcomes, there is already strong clinical evidence that host inflammatory biomarkers such as NLR and others play an important role.
Conflicts of interest
The authors have nothing to disclose.
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School of Medicine, University of Western Sydney, Penrith, Australia
Corresponding author. School of Medicine, University of Western Sydney, Penrith, NSW 2751, Australia. Tel. +61 2 97726836; Fax: +61 2 97726880.
© 2016 European Association of Urology, Published by Elsevier B.V.