Possible Prognostic and Therapeutic Significance of c-Kit Expression, Mast Cell Count and Microvessel Density in Renal Cell Carcinoma

Abstract

Renal cell carcinoma (RCC) is the most frequent renal tumor and its incidence is increasing worldwide. Tumor angiogenesis is known to play a crucial role in the etiopathogenesis of RCC and over the last few years an even deeper knowledge of its contribution in metastatic RCC development has led to the development of numerous molecular targeting agents (such as sunitinib, sorafenib, pazopanib, axitinib, tivozanib, and dovitinib). The above agents are principally directed against vascular endothelial growth factor receptor (VEGFR) members and also against c-Kit receptor (c-KitR). The role of c-kitR inhibition on clear cell RCC (ccRCC), the main RCC subtype, is less well established. Whether c-kitR activation through its ligand, stem cell factor (SCF) contributes significantly to the effects of tyrosine kinase inhibitors (TKIs) treatment remains to be established. It is important to underscore that the c-KitR is expressed on mast cells (MCs) and cancer cells. After an examination of the c-KitR/SCF pathway, we review here the principal studies that have evaluated c-Kit expression in RCC. Moreover, we summarize some investigations that have observed the distribution of MCs in primary renal cancer and in adjacent normal tissue with appropriate histological immunohistochemical techniques. We also focus on few studies that have evaluated the correlation between RCC proliferation, MC count and microvessel density (MVD), as hallmarks of tumor angiogenesis. Thus, the aim of this review of the literature is to clarify if c-KitR expression, MC count and MVD could have prognostic significance and the possible predictive therapeutic implications in RCC.

The Human Kinome Targeted by FDA Approved Multi-Target Drugs and Combination Products: A Comparative Study from the Drug-Target Interaction Network Perspective

“…VEGF and its receptor VEGFR2 were extensively tested primary therapeutic targets currently in clinical for renal cell carcinoma (RCC), and the development of RCC was proved to be relied on VEGF signaling and its receptor [42]. Similar to VEGFR2, c-Kit was proposed essential in the occurrence and development of the metastatic RCC, and its overexpression was well demonstrated in the chromophobe variety of RCC [43]. Thus, VEGFR2 and c-Kit were identified as the most popular therapeutic targets of approved multi-target drugs, and the binding of which could provide substantial influence on the pathogenesis of the RCC.…”

A Phase I/II Trial of BNC105P with Everolimus in Metastatic Renal Cell Carcinoma

“…(22) Several studies have shown a correlation between clinical outcome and SCF, and mutations in the substrate binding pocket of SCF have been implicated in conferring resistance to TKIs. (23, 24) Less is known about the mechanistic role of the remaining two biomarkers, SAP and SHBG, in the pathogenesis of RCC, although some studies have suggested a prognostic role of SAP in the disease. (25) In an exploratory analysis, the four biomarkers noted herein were assessed in combination to generate a potential signature for response.…”

Sodium butyrate enhances the growth inhibitory effect of sunitinib in human renal cell carcinoma cells

“…PDGFR signaling is also a promising target for RCC (23). Activation of the c-Kit receptor has been known to induce transduction signaling, including induction of the mitogen-activated protein kinase and phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathways in RCC, which in turn leads to mast cell activation (24).…”