Heterogeneity of Platelet Derived Growth Factor Pathway Gene Expression Profile Defines Three Distinct Subgroups of Renal Cell Carcinomas

Abstract

Background/Aim: We previously described four different vascular patterns (reticular, diffuse, fasciculate, and trabecular) in renal cell carcinoma (RCC) suggesting an early and heterogeneous acquisition of perivascular cells most probably due to a particular PDGF pathway gene expression profile. The aim of the study was to study PDGF pathway gene expression profiles, separately for each vascular pattern. Materials and Methods: TaqMan assay for the PDGF pathway was performed on twelve cases of ccRCC previously evaluated by histopathology, immunohistochemistry, and RNAscope. Gene expression profile was correlated with grade, invasion, vascular patterns, and VEGF. Results: PIK3C3 and SLC9A3 genes were overexpressed in all vascular patterns, but they were significantly correlated with high VEGF mRNA in the reticular and diffuse pattern. STAT1, JAK2, SHC2, SRF and CHUK (IKK) were exclusively overexpressed in cases with diffuse vascular pattern. SLC9A3, CHUK and STAT3 were overexpressed in G2 tumors. Conclusion: Three ccRCC subgroups were defined: 1) PIK3C3 (VSP34)/SLC9A3 which may be proper for anti PIK3C3 inhibitors; 2) VEGF high subgroup where association of anti VEGF may be a benefit and 3) JAK2/STAT1 subgroup, potentially being eligible for anti JAK/STAT therapy associated with IKK inhibitors.Renal cell carcinoma (RCC) represents about 2.2% of total diagnosed cancers worldwide with an estimated number of newly diagnosed patients of 400,000 approximately (1, 2). Fifteen percent of newly diagnosed cancers are diagnosed in the primary metastatic RCC (mRCC) stage of disease but more than 30% of cases which had no metastases at the time of diagnosis become metastatic in a variable period of time of 4 to 8 years from the primary diagnosis despite application of novel and targeted therapies (3). Renal cell carcinoma clear cell type (ccRCC) arises from the proximal tubules of the kidney parenchyma and is the most common subtype of RCC, representing 80% of RCCs (4). ccRCC is a complex disease with a silent development and an unexpected behavior having a highly heterogeneous response to therapy (5). Normal kidney and malignant tissue arising from it have a special and unique microenvironment (6) and this, may be influence the resistance to therapy which appear 477

Proinflammatory activity of VEGF-targeted treatment through reversal of tumor endothelial cell anergy

“…There are multiple other possible scenarios behind the increased inflammatory microenvironment boost post antiangiogenic therapy. A recently published study by Ferician et al suggests the role of JAK/STAT pathway in defining a special subgroup of ccRCC with moderate and high VEGF expression [58]. Chang et al described the role of JAK/STAT pathway in cancer associated inflammatory microenvironment [59].…”

Derivative Chromosome 3 Loss from t(3;6)(q12;q14) Followed by DifferentialVHLMutations Underlie Multifocal ccRCC

“…HIFs up-regulate transcription of hypoxia-responsive genes promoting tumor growth (26). Therefore, targeting the pathways of hypoxia-responsive genes using tyrosine kinase inhibitors in combination with HIF inhibitors could be a promising treatment strategy (26,27). 3) and der (6).…”

Therapeutic potential of vasculogenic mimicry in urological tumors

“…Therefore, targeting non-cancer cells and molecules in the tumor microenvironment has become a strategy for treating tumor angiogenesis. Among them, drugs targeting fibroblasts and macrophages, such as Imatinib and Dasatinib.Studies have shown that dasatinib can effectively inhibit the growth of fibroblasts by inhibiting PDGF receptor signaling at biologically relevant concentrations ( 145 , 146 ). PDGF is normally expressed in a variety of cell types, including fibroblasts, neuronal cells, macrophages, smooth muscle cells, platelets, and preosteoclastic cells.…”