| Literature DB >> 31043488 |
Masaya Baba1,2, Mitsuko Furuya3, Takanobu Motoshima4, Martin Lang2, Shintaro Funasaki5, Wenjuan Ma5, Hong-Wei Sun6, Hisashi Hasumi2,7, Ying Huang2, Ikuma Kato3, Tsuyoshi Kadomatsu8, Yorifumi Satou9, Nicole Morris10, Baktiar O Karim11, Lilia Ileva12, Joseph D Kalen12, Luh Ade Wilan Krisna5, Yukiko Hasumi2, Aiko Sugiyama13, Ryoma Kurahashi4,8, Koshiro Nishimoto14, Masafumi Oyama14, Yoji Nagashima15, Naoto Kuroda16, Kimi Araki17, Masatoshi Eto18, Masahiro Yao7, Tomomi Kamba4, Toshio Suda19,20, Yuichi Oike8, Laura S Schmidt21,22, W Marston Linehan21.
Abstract
Renal cell carcinoma (RCC) associated with Xp11.2 translocation (TFE3-RCC) has been recently defined as a distinct subset of RCC classified by characteristic morphology and clinical presentation. The Xp11 translocations involve the TFE3 transcription factor and produce chimeric TFE3 proteins retaining the basic helix-loop-helix leucine zipper structure for dimerization and DNA binding suggesting that chimeric TFE3 proteins function as oncogenic transcription factors. Diagnostic biomarkers and effective forms of therapy for advanced cases of TFE3-RCC are as yet unavailable. To facilitate the development of molecular based diagnostic tools and targeted therapies for this aggressive kidney cancer, we generated a translocation RCC mouse model, in which the PRCC-TFE3 transgene is expressed specifically in kidneys leading to the development of RCC with characteristic histology. Expression of the receptor tyrosine kinase Ret was elevated in the kidneys of the TFE3-RCC mice, and treatment with RET inhibitor, vandetanib, significantly suppressed RCC growth. Moreover, we found that Gpnmb (Glycoprotein nonmetastatic B) expression was notably elevated in the TFE3-RCC mouse kidneys as seen in human TFE3-RCC tumors, and confirmed that GPNMB is the direct transcriptional target of TFE3 fusions. While GPNMB IHC staining was positive in 9/9 cases of TFE3-RCC, Cathepsin K, a conventional marker for TFE3-RCC, was positive in only 67% of cases. These data support RET as a potential target and GPNMB as a diagnostic marker for TFE3-RCC. The TFE3-RCC mouse provides a preclinical in vivo model for the development of new biomarkers and targeted therapeutics for patients affected with this aggressive form of RCC. IMPLICATIONS: Key findings from studies with this preclinical mouse model of TFE3-RCC underscore the potential for RET as a therapeutic target for treatment of patients with TFE3-RCC, and suggest that GPNMB may serve as diagnostic biomarker for TFE3 fusion RCC. ©2019 American Association for Cancer Research.Entities:
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Year: 2019 PMID： 31043488 PMCID： PMC6679785 DOI： 10.1158/1541-7786.MCR-18-1235
Source DB: PubMed Journal: Mol Cancer Res ISSN： 1541-7786 Impact factor: 5.852