1. Activation and function of receptor tyrosine kinases in human clear cell renal cell carcinomas
- Author
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Lei Yan, Jian-He Liu, Qing Zhang, Chunting Qi, Yu Chen, Jingli Liu, and Qiang Yu
- Subjects
Male ,0301 basic medicine ,Cancer Research ,medicine.medical_treatment ,PDGFRβ ,Cell ,Kidney ,Receptor tyrosine kinase ,Targeted therapy ,0302 clinical medicine ,Surgical oncology ,Molecular Targeted Therapy ,Phosphorylation ,Mice, Inbred BALB C ,biology ,Middle Aged ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Kidney Neoplasms ,Activation and function ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Heterografts ,Female ,Research Article ,Stromal cell ,Mice, Nude ,Stroma cells ,Clear cell renal cell carcinomas (ccRCCs) ,lcsh:RC254-282 ,03 medical and health sciences ,Cell Line, Tumor ,Genetics ,medicine ,Animals ,Humans ,Receptor tyrosine kinases (RTKs) ,Carcinoma, Renal Cell ,Gene ,Aged ,Cell Proliferation ,Receptor Protein-Tyrosine Kinases ,medicine.disease ,Clear cell renal cell carcinoma ,030104 developmental biology ,biology.protein ,Cancer research ,Neoplasm Transplantation ,Clear cell - Abstract
Background The receptor tyrosine kinases (RTKs) play critical roles in the development of cancers. Clear cell renal cell carcinoma (ccRCC) accounts for 75% of the RCC. The previous studies on the RTKs in ccRCCs mainly focused on their gene expressions. The activation and function of the RTKs in ccRCC have not been fully investigated. Methods In the present study, we analyzed the phosphorylation patterns of RTKs in human ccRCC patient samples, human ccRCC and papillary RCC cell lines, and other kidney tumor samples using human phospho-RTK arrays. We further established ccRCC patient-derived xenograft models in nude mice and assessed the effects of RTKIs (RTK Inhibitors) on the growth of these cancer cells. Immunofluorescence staining was used to detect the localization of keratin, vimentin and PDGFRβ in ccRCCs. Results We found that the RTK phosphorylation patterns of the ccRCC samples were all very similar, but different from that of the cell lines, other kidney tumor samples, as well as the adjacent normal tissues. 9 RTKs, EGFR1–3, Insulin R, PDGFRβ, VEGFR1, VEGFR2, HGFR and M-CSFR were found to be phosphorylated in the ccRCC samples. The adjacent normal tissues, on the other hand, had predominantly only two of the 4 EGFR family members, EGFR and ErbB4, phosphorylated. What’s more, the RTK phosphorylation pattern of the xenograft, however, was different from that of the primary tissue samples. Treatment of the xenograft nude mice with corresponding RTK inhibitors effectively inhibited the Erk1/2 signaling pathway as well as the growth of the tumors. In addition, histological staining of the cancer samples revealed that most of the PDGFRβ expressing cells were localized in the vimentin-positive periepithelial stroma. Conclusions Overall, we have identified a set of RTKs that are characteristically phosphorylated in ccRCCs. The phosphorylation of RTKs in ccRCCs were determined by the growing environments. These phosphorylated/activated RTKs will guide targeting drugs development of more effective therapies in ccRCCs. The synergistical inhibition of RTKIs combination on the ccRCC suggest a novel strategy to use a combination of RTKIs to treat ccRCCs.
- Published
- 2019