Endothelin axis expression is markedly different in the two main subtypes of renal cell carcinoma

Cancer. 2004 May 15;100(10):2118-24. doi: 10.1002/cncr.20222.


Background: The endothelin axis has been implicated in cancer growth, angiogenesis, and metastasis, but to the authors' knowledge the expression of endothelin genes has not been defined in renal cell carcinoma (RCC).

Methods: Tissue specimens were harvested from both normal and tumor-affected regions at the time of radical nephrectomy from 35 patients with RCC (22 with clear cell RCC [ccRCC] and 13 with papillary RCC [PRCC]). Real-time reverse transcriptase-polymerase chain reaction analysis determined the expression profile of the preproendothelins (PPET-1, PPET-2, and PPET-3), the endothelin receptors (ET(A) and ET(B)), and the endothelin-converting enzymes (ECE-1 and ECE-2).

Results: PPET-1 was found to be up-regulated in ccRCC tumor specimens and down-regulated in PRCC tumor specimens. ET(A) was significantly down-regulated in PRCC tumor specimens. ECE-1 was expressed in all tissue specimens at comparable levels, with moderate but significant elevation in normal tissue specimens associated with PRCC. Of the other genes, PPET-2 and ET(B) were expressed in all tissue specimens and no differences were observed between tumor subtypes or tumor-affected and normal tissue specimens, whereas PPET-3 and ECE-2 were present in all tissue specimens but were barely detectable.

Conclusions: The endothelin axis was expressed differently in the two main subtypes of RCC and appeared to match macroscopic features commonly observed in these tumors (i.e., high expression of PPET-1 in hypervascular ccRCC contrasted against low PPET-1 and ET(A) expression in hypovascular PRCC). The presence of ECE-1 mRNA in these tissue specimens suggested that active endothelin ligands were present, indicating endothelin axis activity was elevated in ccRCC compared with normal kidney, but impaired in PRCC. The current study provided further evidence that it is not appropriate to consider ccRCC and PRCC indiscriminately in regard to treatment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aspartic Acid Endopeptidases
  • Biomarkers, Tumor / genetics*
  • Carcinoma, Papillary / genetics*
  • Carcinoma, Papillary / surgery
  • Carcinoma, Renal Cell / genetics*
  • Carcinoma, Renal Cell / surgery
  • Endothelin-1 / genetics
  • Endothelin-Converting Enzymes
  • Endothelins / genetics*
  • Gene Expression Regulation, Neoplastic / genetics*
  • Humans
  • Kidney Neoplasms / genetics*
  • Kidney Neoplasms / surgery
  • Metalloendopeptidases / genetics
  • Nephrectomy
  • Protein Precursors / genetics
  • RNA, Messenger / metabolism
  • Receptor, Endothelin A / genetics
  • Receptor, Endothelin B / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transcription, Genetic


  • Biomarkers, Tumor
  • Endothelin-1
  • Endothelins
  • Protein Precursors
  • RNA, Messenger
  • Receptor, Endothelin A
  • Receptor, Endothelin B
  • preproendothelin 2
  • preproendothelin-3
  • Aspartic Acid Endopeptidases
  • Metalloendopeptidases
  • ECE1 protein, human
  • ECE2 protein, human
  • Endothelin-Converting Enzymes