title: Caveolin-1 in renal cell carcinoma promotes tumour cell invasion, and in co-operation with pERK predicts metastases in patients with clinically confined disease.
abstract: BACKGROUND
  Up to 40% of patients initially diagnosed with clinically-confined renal cell carcinoma (RCC) and who undergo curative surgery will nevertheless relapse with metastatic disease (mRCC) associated with poor long term survival. The discovery of novel prognostic/predictive biomarkers and drug targets is needed and in this context the aim of the current study was to investigate a putative caveolin-1/ERK signalling axis in clinically confined RCC, and to examine in a panel of RCC cell lines the effects of caveolin-1 (Cav-1) on pathological processes (invasion and growth) and select signalling pathways.
  
  
  METHODS
  Using immunohistochemistry we assessed the expression of both Cav-1 and phosphorylated-ERK (pERK) in 176 patients with clinically confined RCC, their correlation with histological parameters and their impact upon disease-free survival. Using a panel of RCC cell lines we explored the functional effects of Cav-1 knockdown upon cell growth, cell invasion and VEGF-A secretion, as well Cav-1 regulation by cognate cell signalling pathways.
  
  
  RESULTS
  We found a significant correlation (P = 0.03) between Cav-1 and pERK in a cohort of patients with clinically confined disease which represented a prognostic biomarker combination (HR = 4.2) that effectively stratified patients into low, intermediate and high risk groups with respect to relapse, even if the patients' tumours displayed low grade and/or low stage disease. In RCC cell lines Cav-1 knockdown unequivocally reduced cell invasive capacity while also displaying both pro-and anti-proliferative effects; targeted knockdown of Cav-1 also partially suppressed VEGF-A secretion in VHL-negative RCC cells. The actions of Cav-1 in the RCC cell lines appeared independent of both ERK and AKT/mTOR signalling pathways.
  
  
  CONCLUSIONS
  The combined expression of Cav-1 and pERK serves as an independent biomarker signature with potential merit in RCC surveillance strategies able to predict those patients with clinically confined disease who will eventually relapse. In a panel of in-vitro RCC cells Cav-1 promotes cell invasion with variable effects on cell growth and VEGF-A secretion. Cav-1 has potential as a therapeutic target for the prevention and treatment of mRCC.
authors.affiliation: Cardiff School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff CF10 3XF, UK. gumbleton@cf.ac.uk.
authors.forename: Lee
authors.initials: L
authors.lastname: Campbell
authors.forename: Ghaith
authors.initials: G
authors.lastname: Al-Jayyoussi
authors.forename: Robert
authors.initials: R
authors.lastname: Gutteridge
authors.forename: Nigel
authors.initials: N
authors.lastname: Gumbleton
authors.forename: Rosie
authors.initials: R
authors.lastname: Griffiths
authors.forename: Simon
authors.initials: S
authors.lastname: Gumbleton
authors.forename: Mathew W
authors.initials: MW
authors.lastname: Smith
authors.forename: David F R
authors.initials: DF
authors.lastname: Griffiths
authors.forename: Mark
authors.initials: M
authors.lastname: Gumbleton
mesh_terms: D002292:Carcinoma, Renal Cell / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D051242:Caveolin 1 / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D006801:Humans; D007680:Kidney Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D015999:Multivariate Analysis; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D010766:Phosphorylation / Q000187:drug effects; D011379:Prognosis; D016016:Proportional Hazards Models; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D053245:RANK Ligand / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000378:metabolism
chemical_list: D051242:Caveolin 1; D053245:RANK Ligand; D042461:Vascular Endothelial Growth Factor A; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; C497446:VHL protein, human