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

Campbell, Lee, Jasani, Bharat, Edwards, K., Gumbleton, Mark ORCID: https://orcid.org/0000-0002-7386-311X and Griffiths, David Francis Rees 2008. Combined expression of caveolin-1 and an activated AKT/mTOR pathway predicts reduced disease-free survival in clinically confined renal cell carcinoma. British Journal of Cancer 98 (5) , pp. 931-940. 10.1038/sj.bjc.6604243

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine Pharmacy
Subjects:	R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer) R Medicine > RM Therapeutics. Pharmacology
Uncontrolled Keywords:	renal cell carcinoma; caveolin-1; AKT/mTOR pathway; vascular invasion; metastasis; rapamycin; prognosis
Publisher:	Nature Publishing Group
ISSN:	0007-0920
Last Modified:	18 Mar 2023 02:08
URI:	https://orca.cardiff.ac.uk/id/eprint/6468

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