論文

査読有り 国際誌
2019年8月

TFE3 Xp11.2 Translocation Renal Cell Carcinoma Mouse Model Reveals Novel Therapeutic Targets and Identifies GPNMB as a Diagnostic Marker for Human Disease.

Molecular cancer research : MCR
  • Masaya Baba
  • ,
  • Mitsuko Furuya
  • ,
  • Takanobu Motoshima
  • ,
  • Martin Lang
  • ,
  • Shintaro Funasaki
  • ,
  • Wenjuan Ma
  • ,
  • Hong-Wei Sun
  • ,
  • Hisashi Hasumi
  • ,
  • Ying Huang
  • ,
  • Ikuma Kato
  • ,
  • Tsuyoshi Kadomatsu
  • ,
  • Yorifumi Satou
  • ,
  • Nicole Morris
  • ,
  • Baktiar O Karim
  • ,
  • Lilia Ileva
  • ,
  • Joseph D Kalen
  • ,
  • Luh Ade Wilan Krisna
  • ,
  • Yukiko Hasumi
  • ,
  • Aiko Sugiyama
  • ,
  • Ryoma Kurahashi
  • ,
  • Koshiro Nishimoto
  • ,
  • Masafumi Oyama
  • ,
  • Yoji Nagashima
  • ,
  • Naoto Kuroda
  • ,
  • Kimi Araki
  • ,
  • Masatoshi Eto
  • ,
  • Masahiro Yao
  • ,
  • Tomomi Kamba
  • ,
  • Toshio Suda
  • ,
  • Yuichi Oike
  • ,
  • Laura S Schmidt
  • ,
  • W Marston Linehan

17
8
開始ページ
1613
終了ページ
1626
記述言語
英語
掲載種別
DOI
10.1158/1541-7786.MCR-18-1235

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.

リンク情報
DOI
https://doi.org/10.1158/1541-7786.MCR-18-1235
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/31043488
PubMed Central
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6679785