Caveolin-1 overexpression predicts poor disease-free survival of patients with clinically confined renal cell carcinoma

Abstract

Renal cell carcinomas, although usually apparently fully resected at surgery, commonly recur as distant metastasis. New markers are needed to predict which patients may relapse especially as novel methods of treatment (e.g. laproscopic resection) may make it impossible to assess conventional pathological prognostic markers. The caveolins are a family of proteins that represent the major structural components of caveolae; recent work suggests that these may have influence on several signalling pathways and they are thus potential prognostic markers. Immunohistochemistry for caveolin-1 was performed on sections of peripheral tumour from 114 consecutative nonmetastatic RCCs. Cytoplasmic caveolin-1 immunohistochemical (ICC) reaction was scored on a semiquantative scale of 1 -3. Immunohistochemical score was tested for impact on disease-free survival by Kaplan -Meier and Cox regression methods. A total of 50 tumours had ICC score 1; 43 had score 2 and 21 score 3. Larger, higher grade and tumours with vascular invasion had significantly higher scores. On univariate survival analysis (Kaplan -Meier), patients with tumours scoring 1 had a mean disease-free survival of 6.61 years (95% CI 5.76 -7.46) compared with 5.4 years (4.53 -6.30) and 3.15 years (1.87 -4.44) for scores 2 and 3, respectively. This is a significant difference (P ¼ 0.0017 log rank test). On multivariate analysis with size, grade and caveolin ICC score as independent covariates, caveolin ICC score 3 was an influential predictor of poor disease-free survival with a hazard ratio of 2.6 (P ¼ 0.03). We conclude that cytoplasmic overexpression of caveolin-1 predicts a poor prognosis in RCC; that this is likely to be a useful prognostic marker and that it may have importance in tumour progression.

The Caveolin-1 Connection to Cell Death and Survival

“…Several reports suggest that Caveolin-1 participates as an important mediator of drug-resistance in cancer cells. In patients, up-regulation of Caveolin-1 levels is frequently observed in advanced stages of lung [51,131], prostate [42,44], breast [44], pancreas [132] and renal cancer [133]. In these cases, Caveolin-1 is associated with poor patient prognosis and reduced patient survival.…”

Caveolin-1 promotes pancreatic cancer cell differentiation and restores membranous E-cadherin via suppression of the epithelial-mesenchymal transition

“…As a consequence, many studies recognize Cav-1 as a modulator of cell transformation, proliferation and metastasis. 4,5 Depending on the tissue context, Cav-1 can act either as a tumor suppressor, for example in pulmonary, 6,7 mammary, 8,9 colon 10 and ovarian 11 cancers, or as a tumor promoter, for example in prostate, 12 bladder 13 and renal 14 cancers.…”

Combined expression of caveolin-1 and an activated AKT/mTOR pathway predicts reduced disease-free survival in clinically confined renal cell carcinoma

“…Complete clinical follow-up was carried out as previously described (Griffiths et al, 2002;Campbell et al, 2003), and the following information extracted from the patients notes date of birth, sex, date of surgery, date last seen, date of death, cause of death and the date on which recurrent or metastatic disease was first identified.…”

“…Immunohistochemical procedures examining for expression of caveolin-1, pAKT (Ser473), pmTOR (Ser2448), pS6 (Ser235/236) and p4E-BP1 (Ser65) were carried out using standard procedures as previously described (Campbell et al, 2003). Primary antibodies were obtained from New England Biolabs (Herts, UK).…”

“…In 2003, we were the first to reveal that overexpression of caveolin-1 in localised RCC predicts poor disease-free survival (Campbell et al, 2003). Subsequently, several laboratories have independently examined the expression of caveolin-1 (Horiguchi et al, 2004;Joo et al, 2004;Phuoc et al, 2007) or activated AKT/ mTOR/S6 (Lin et al, 2006;Pantuck et al, 2007;Robb et al, 2007) in RCC.…”