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2012; 30:555C68

2012; 30:555C68. was present and phosphorylated in both WT PDXs and in the human samples from which they were derived. FAK inhibition decreased cellular survival, proliferation, and cell cycle progression in both PDXs but only significantly decreased migration, invasion, and attachment-independent growth in the primary WT PDX. Kinomic profiling revealed that platelet-derived growth factor receptor beta (PDGFR) may be affected by FAK inhibition in WT. Pharmacologic inhibition of FAK and PDGFR was synergistic in primary WT PDX cells. These findings broaden the knowledge of metastatic WT and support further investigations around the potential use of FAK and PDGFR inhibitors. [8]. In the same way FAK is involved in the invasive behavior of normal renal development, FAK signaling is usually thought to be required for the invasion of neoplastic cells [8]. Early studies of FAK in normal tissue compared to primary and metastatic colon carcinomas from individual patients exhibited a progressive increase in mRNA levels suggesting FAK confers metastatic potential [11]. Several studies have since exhibited overexpression of FAK in a variety of malignancy types and significant correlations with tumor size, higher disease stage, and poorer patient prognosis [12]. Migration, adhesion, and invasion are essential for the formation of metastases and inhibition of FAK activity has been shown to decrease these prerequisites for metastases in renal cell carcinoma both [13] and [14]. FAK inhibition has also decreased tumorigenicity in other adult cancers including non-small cell lung cancer, gastric cancer, hepatocellular carcinoma, and bladder cancer [15C18] and in pediatric malignancies including neuroblastoma and Ewing sarcoma [19, 20]. In pediatric renal tumors, FAK inhibition decreased cell viability, migration, and invasion and tumor volume in a malignant rhabdoid kidney tumor cell line [21]. While the specific mechanisms remain to be elucidated, evidence supports that FAK contributes to both tumor formation and malignant progression [22] and these findings formed the rationale for our investigation of FAK in WT. Kinomic profiling is usually a new, high-throughput method used to investigate kinase signaling to identify potential therapeutic targets. The PamGene PamChip? system allows direct recording of cellular kinase activity for comparison of phosphorylation of tyrosine or serine/threonine peptides as they are phosphorylated by cellular kinases [23]. This system has been used to Omeprazole profile a variety of malignancies including renal cell carcinoma [24]. Currently there are only a limited number of cell lines available for the study of metastatic WT, such as WiT49 and CCG-99-11 [25]. We established a Omeprazole novel patient-derived xenograft (PDX) model of a liver metastasis, COA 42, and a PDX of its matched isogenic primary renal WT, COA 25, to investigate the functions of FAK in WT. Because FAK is only one of many kinases involved in tumorigenesis, we also sought to explore kinases upstream and downstream of FAK. We hypothesized that FAK plays a role in the tumorigenicity of metastatic WT and that FAK inhibition would result in a less aggressive phenotype in metastatic Omeprazole WT. In the current study, we exhibited abrogation of FAK in PDX cell lines of primary and metastatic WT resulted in decreased tumorigenicity murine model of renal cell carcinoma [44]. Additionally, PDGFR expression has been shown to correlate with poor prognosis in renal cell carcinoma [32]. With regards to WT, while some information is known about PDGFR, little is known about the expression and role of PDGFR. An analysis of 62 pre-treated patient WTs exhibited that PDGFR was primarily Rabbit Polyclonal to HTR2C expressed in epithelial components and its expression correlated with a favorable prognosis [45]. Additionally, mutations in PDGFR have not been found to play a role in WT [46]. During embryogenic development of the kidney, PDGFR is usually expressed in undifferentiated metanephric blastema, vascular structures, and interstitial cells, and as the glomerular tuft forms, PDGFR is usually primarily expressed within mesangial cells [47]. Studies have shown that high expression of PDGFR is usually predictive of poorer prognosis in renal cell carcinoma [32] but no studies have examined its expression in WT. In the current study, immunohistochemical staining for PDGFR exhibited its presence in the cell cytoplasm and membrane of both PDXs. This staining Omeprazole pattern was previously shown in localized renal cell carcinoma where its expression Omeprazole correlated with the development of distant metastases. The authors of that study hypothesized that PDGFR expression in localized disease may be part of the early events leading to metastasis [32]. PDGFR has also been shown to be expressed on stromal cells that support neo-angiogenic vessels in solid tumors, such as small cell lung cancer and prostate cancer [48C50] and our study also exhibited PDGFR in the stroma of both PDXs. Complex interactions between tumor cells and their microenvironment, including the development of a rich vascular blood supply, are required for metastasis [51] and given its location,.