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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 stratified by ‘Positive' vs ‘Negative' expression of (A) caveolin-1, (B) pAKT, (C) pmTOR, (D) pS6 and (E) p4E-BP1.
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fig2: 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.

Mentions: Univariate survival analysis of our series showed that those patients having caveolin-1-positive tumours had significantly worse prognosis with mean disease-free survival of 3.44 years compared to 6.20 years in those with negative caveolin-1 tumours (P=0.0005); a finding consistent with our previous investigation (Campbell et al, 2003). Kaplan–Meier plots revealed that the expression of cytoplasmic pAKT, pmTOR and p4E-BP1 did not significantly influence disease-free survival. Cumulative survival curves for pAKT, pmTOR and p4E-BP1 are illustrated in Figure 2 and mean disease-free survival values shown in Table 2. In contrast, pS6 was the only component of the activated mTOR pathway that significantly predicted relapse (Figure 2) where the mean disease-free survival in patients whose primary tumours expressed pS6 was 3.77 vs 6.11 in those patients whose tumours did not (P=0.0096).


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 stratified by ‘Positive' vs ‘Negative' expression of (A) caveolin-1, (B) pAKT, (C) pmTOR, (D) pS6 and (E) p4E-BP1.
© Copyright Policy
Related In: Results  -  Collection

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

fig2: 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.
Mentions: Univariate survival analysis of our series showed that those patients having caveolin-1-positive tumours had significantly worse prognosis with mean disease-free survival of 3.44 years compared to 6.20 years in those with negative caveolin-1 tumours (P=0.0005); a finding consistent with our previous investigation (Campbell et al, 2003). Kaplan–Meier plots revealed that the expression of cytoplasmic pAKT, pmTOR and p4E-BP1 did not significantly influence disease-free survival. Cumulative survival curves for pAKT, pmTOR and p4E-BP1 are illustrated in Figure 2 and mean disease-free survival values shown in Table 2. In contrast, pS6 was the only component of the activated mTOR pathway that significantly predicted relapse (Figure 2) where the mean disease-free survival in patients whose primary tumours expressed pS6 was 3.77 vs 6.11 in those patients whose tumours did not (P=0.0096).

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