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

Abstract

We previously reported that tumour-associated caveolin-1 is a potential biomarker in renal cell carcinoma (RCC), whose overexpression predicts metastasis following surgical resection for clinically confined disease. Much attention has recently focused on the AKT/mTOR pathway in a number of malignancies, including RCC. Since caveolin-1 and the AKT/mTOR signalling cascade are independently shown to be important regulators of tumour angiogenesis, we hypothesised that caveolin-1 interacts with the AKT/mTOR pathway to drive disease progression and metastasis in RCC. The aims of this study were to determine (i) the expression status of the activated AKT/mTOR pathway components (phosphorylated forms) in RCC and (ii) their prognostic value when combined with caveolin-1. Immunohistochemistry for caveolin-1, pAKT, pmTOR, pS6 and p4E-BP1 was performed on tissue microarrays from 174 clinically confined RCCs. Significantly decreased mean disease-free survival was observed when caveolin-1 was coexpressed with either pAKT (2.95 vs 6.14 years), pmTOR (3.17 vs 6.28 years), pS6 (1.45 vs 6.62 years) or p4E-BP1 (2.07 vs 6.09 years) than when neither or any one single biomarker was expressed alone. On multivariate analysis, the covariate of 'caveolin-1/AKT' (neither alone were influential covariates) was a significant influential indicator of poor disease-free survival with a hazard ratio of 2.13 (95% CI: 1.15-3.92), higher than that for vascular invasion. Tumours that coexpressed caveolin-1 and activated mTOR components were more likely to be larger, higher grade and to show vascular invasion. Our results provide the first clinical evidence that caveolin-1 cooperates with an activated AKT/mTOR pathway in cancer and may play an important role in disease progression. We conclude that evaluation of the 'caveolin-1/AKT/mTOR axis' in primary kidney tumours will identify subsets of RCC patients who require greater postoperative surveillance and more intensive treatment.

Figure 1

Representative TMA of clinically confined RCC showing the immunohistochemical expression intensity and pattern of (A) caveolin-1, (B) pAKT, (C) pmTOR, (D) pS6 and (E) p4E-BP1 for tumours that were typically stratified as either ‘Positive’ or ‘Negative’ (see Materials and Methods).

Figure 2

Kaplan–Meier metastasis-free overall survival estimates of RCC patients with clinically confined disease stratified by ‘Positive’ vs ‘Negative’ expression of (A) caveolin-1, (B) pAKT, (C) pmTOR, (D) pS6 and (E) p4E-BP1.

Figure 3

Kaplan–Meier metastasis-free overall survival estimates of RCC patients with clinically confined disease according coexpression of caveolin-1 with (A) pAKT, (B) pmTOR, (C) pS6 and (D) p4E-BP1. Patients who coexpressed caveolin-1 and activated components of the AKT/mTOR pathway had significantly worse prognosis compared with patients whose tumours were negative for either biomarker and/or had single biomarker-positive expression.

Figure 4

Schematic of the putative caveolin-1/AKT/mTOR axis in RCC.