Activation and function of receptor tyrosine kinases in human clear cell renal cell carcinomas
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 RTK...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2019-11-01
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| Series: | BMC Cancer |
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| Online Access: | http://link.springer.com/article/10.1186/s12885-019-6159-2 |
| _version_ | 1818210626581823488 |
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| author | Qing Zhang Jian-He Liu Jing-Li Liu Chun-Ting Qi Lei Yan Yu Chen Qiang Yu |
| author_facet | Qing Zhang Jian-He Liu Jing-Li Liu Chun-Ting Qi Lei Yan Yu Chen Qiang Yu |
| author_sort | Qing Zhang |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-12T05:19:36Z |
| format | Article |
| id | doaj.art-aca52a090fb1443ca718b3bdc5facee3 |
| institution | Directory Open Access Journal |
| issn | 1471-2407 |
| language | English |
| last_indexed | 2024-12-12T05:19:36Z |
| publishDate | 2019-11-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Cancer |
| spelling | doaj.art-aca52a090fb1443ca718b3bdc5facee32022-12-22T00:36:39ZengBMCBMC Cancer1471-24072019-11-0119111310.1186/s12885-019-6159-2Activation and function of receptor tyrosine kinases in human clear cell renal cell carcinomasQing Zhang0Jian-He Liu1Jing-Li Liu2Chun-Ting Qi3Lei Yan4Yu Chen5Qiang Yu6Shanghai Institute of Materia Medica, Chinese Academy of SciencesThe Department of Urology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai Institute of Materia Medica, Chinese Academy of SciencesShanghai Institute of Materia Medica, Chinese Academy of SciencesShanghai Institute of Materia Medica, Chinese Academy of SciencesShanghai Institute of Materia Medica, Chinese Academy of SciencesShanghai Institute of Materia Medica, Chinese Academy of SciencesAbstract 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.http://link.springer.com/article/10.1186/s12885-019-6159-2Receptor tyrosine kinases (RTKs)Activation and functionClear cell renal cell carcinomas (ccRCCs)Targeted therapyPDGFRβStroma cells |
| spellingShingle | Qing Zhang Jian-He Liu Jing-Li Liu Chun-Ting Qi Lei Yan Yu Chen Qiang Yu Activation and function of receptor tyrosine kinases in human clear cell renal cell carcinomas BMC Cancer Receptor tyrosine kinases (RTKs) Activation and function Clear cell renal cell carcinomas (ccRCCs) Targeted therapy PDGFRβ Stroma cells |
| title | Activation and function of receptor tyrosine kinases in human clear cell renal cell carcinomas |
| title_full | Activation and function of receptor tyrosine kinases in human clear cell renal cell carcinomas |
| title_fullStr | Activation and function of receptor tyrosine kinases in human clear cell renal cell carcinomas |
| title_full_unstemmed | Activation and function of receptor tyrosine kinases in human clear cell renal cell carcinomas |
| title_short | Activation and function of receptor tyrosine kinases in human clear cell renal cell carcinomas |
| title_sort | activation and function of receptor tyrosine kinases in human clear cell renal cell carcinomas |
| topic | Receptor tyrosine kinases (RTKs) Activation and function Clear cell renal cell carcinomas (ccRCCs) Targeted therapy PDGFRβ Stroma cells |
| url | http://link.springer.com/article/10.1186/s12885-019-6159-2 |
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