title: Expression of angiogenesis-related gene profiles and development of resistance to tyrosine-kinase inhibitor in advanced renal cell carcinoma: characterization of sorafenib-resistant cells derived from a cutaneous metastasis.
abstract: OBJECTIVE
  To investigate the potential mechanism of development of resistance to tyrosine kinase inhibitor in renal cell carcinoma.
  
  
  METHODS
  A primary culture of renal cell carcinoma cells (KMRM-S2) was established from an advanced renal cell carcinoma patient with cutaneous metastasis, who had not responded to sorafenib. A total of 84 human angiogenesis-related genes were compared between cutaneous metastasis and the primary tumor by real time polymerase chain reaction. Spectral karyotyping and cell proliferation assay were carried out to determine the biological features of the cells.
  
  
  RESULTS
  Primary tumor was histopathologically diagnosed as high-grade clear cell carcinoma with sarcomatoid change and rhabdoid features. The cutaneous metastasis also consisted of sarcomatoid components. Expression levels of many angiogenesis-related genes in the cutaneous metastasis were relatively higher than those of primary tumor. Chromosomal analysis of the KMRM-S2 showed cytogenetic abnormalities with hypertriploidy and translocation. In vitro proliferation assay showed the relatively higher resistance of KMRM-S2 against sorafenib.
  
  
  CONCLUSIONS
  The sarcomatoid change and rhabdoid features of renal cell carcinoma with cytogenetic hyperploidy might be associated with elevated expression of angiogenesis-related genes, which leads to resistance against tyrosine kinase inhibitor. The present study might contribute to discovering novel therapeutic targets for the treatment of patients with advanced renal cell carcinoma resistant to tyrosine kinase inhibitor.
authors: Department of Urology, Kochi University, Nankoku City, Japan. karasima@kochi-u.ac.jp
authors: Takashi
authors: T
authors: Karashima
authors: Hideo
authors: H
authors: Fukuhara
authors: Kenji
authors: K
authors: Tamura
authors: Shingo
authors: S
authors: Ashida
authors: Masayuki
authors: M
authors: Kamada
authors: Keiji
authors: K
authors: Inoue
authors: Takahiro
authors: T
authors: Taguchi
authors: Naoto
authors: N
authors: Kuroda
authors: Taro
authors: T
authors: Shuin
mesh_terms: D000782:Aneuploidy; D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000235:genetics*; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology*; D061251:Primary Cell Culture; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D012878:Skin Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000556:secondary; D000077157:Sorafenib; D059467:Transcriptome; D014407:Tumor Cells, Cultured
chemical_list: D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D009536:Niacinamide; D000077157:Sorafenib
keywords: angiogenesis-related genes; renal cell carcinoma; resistance; tyrosine-kinase inhibitor