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

Campbell L, Jasani B, Edwards K, Gumbleton M, Griffiths DF - Br. J. Cancer (2008)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Experimental Cancer Therapeutics, School Of Pharmacy, Department of Pathology, Cardiff University, Cardiff CF10 3XF, UK.

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.

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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.
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fig3: 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.

Mentions: We next evaluated by Kaplan–Meier analysis the ability of the combined expression of caveolin-1 and each of the other individual downstream-activated components of the AKT/mTOR pathway to predict relapse using the composite covariates previously described. Within the combined caveolin-1/pAKT data set (n=160), 23/26 (88%) of the caveolin-1-positive tumours also coexpressed pAKT, while within the combined data sets of caveolin-1/pmTOR (n=96), caveolin-1/pS6 (n=106) and caveolin-1/p4E-BP1 (n=143) the number of caveolin-1-positive tumours that coexpressed the selected individual AKT/mTOR pathway marker was 43, 35 and 52%, respectively (Figure 3).


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

Campbell L, Jasani B, Edwards K, Gumbleton M, Griffiths DF - Br. J. Cancer (2008)

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.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2266860&req=5

fig3: 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.
Mentions: We next evaluated by Kaplan–Meier analysis the ability of the combined expression of caveolin-1 and each of the other individual downstream-activated components of the AKT/mTOR pathway to predict relapse using the composite covariates previously described. Within the combined caveolin-1/pAKT data set (n=160), 23/26 (88%) of the caveolin-1-positive tumours also coexpressed pAKT, while within the combined data sets of caveolin-1/pmTOR (n=96), caveolin-1/pS6 (n=106) and caveolin-1/p4E-BP1 (n=143) the number of caveolin-1-positive tumours that coexpressed the selected individual AKT/mTOR pathway marker was 43, 35 and 52%, respectively (Figure 3).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Experimental Cancer Therapeutics, School Of Pharmacy, Department of Pathology, Cardiff University, Cardiff CF10 3XF, UK.

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.

Show MeSH
Related in: MedlinePlus