Abstract
BackgroundUp to 40% of patients initially diagnosed with clinically-confined renal cell carcinoma (RCC) and who undergo curative surgery will nevertheless relapse with metastatic disease (mRCC) associated with poor long term survival. The discovery of novel prognostic/predictive biomarkers and drug targets is needed and in this context the aim of the current study was to investigate a putative caveolin-1/ERK signalling axis in clinically confined RCC, and to examine in a panel of RCC cell lines the effects of caveolin-1 (Cav-1) on pathological processes (invasion and growth) and select signalling pathways.MethodsUsing immunohistochemistry we assessed the expression of both Cav-1 and phosphorylated-ERK (pERK) in 176 patients with clinically confined RCC, their correlation with histological parameters and their impact upon disease-free survival. Using a panel of RCC cell lines we explored the functional effects of Cav-1 knockdown upon cell growth, cell invasion and VEGF-A secretion, as well Cav-1 regulation by cognate cell signalling pathways.ResultsWe found a significant correlation (P = 0.03) between Cav-1 and pERK in a cohort of patients with clinically confined disease which represented a prognostic biomarker combination (HR = 4.2) that effectively stratified patients into low, intermediate and high risk groups with respect to relapse, even if the patients’ tumours displayed low grade and/or low stage disease. In RCC cell lines Cav-1 knockdown unequivocally reduced cell invasive capacity while also displaying both pro-and anti-proliferative effects; targeted knockdown of Cav-1 also partially suppressed VEGF-A secretion in VHL-negative RCC cells. The actions of Cav-1 in the RCC cell lines appeared independent of both ERK and AKT/mTOR signalling pathways.ConclusionThe combined expression of Cav-1 and pERK serves as an independent biomarker signature with potential merit in RCC surveillance strategies able to predict those patients with clinically confined disease who will eventually relapse. In a panel of in-vitro RCC cells Cav-1 promotes cell invasion with variable effects on cell growth and VEGF-A secretion. Cav-1 has potential as a therapeutic target for the prevention and treatment of mRCC.
Highlights
Caveolin-1 (Cav-1) is a regulator of signal transduction events and cytoskeletal dynamics [1,2]
We have shown pERK-1/2 to be a significant predictor of poor disease-free survival (DFS) in renal cell carcinoma (RCC) and shown it to serve as an independent prognostic biomarker [27]
Consistent with pro-aggressive features of Cav-1 in the clinical data we show in a panel of RCC cell lines of varying genetic background that Cav-1 levels directly influence RCC cell growth and cell invasion, and its expression is associated with pro-angiogenic potential in VHL-negative RCC cells
Summary
Caveolin-1 (Cav-1) is a regulator of signal transduction events and cytoskeletal dynamics [1,2]. Cav-1 has been shown to facilitate both ERK and AKT signalling in cancer cells derived from colon [6], prostate [7], epidermis [8] and smooth muscle [9], and is associated with promoting cell invasion, proliferation, angiogenesis and multi-drug resistance. The elevated levels of Cav-1 in clinical tumour tissue from prostate [10], bladder [11] and multiple myeloma [12] is unequivocally linked with metastasis and poor prognosis. The discovery of novel prognostic/predictive biomarkers and drug targets is needed and in this context the aim of the current study was to investigate a putative caveolin-1/ERK signalling axis in clinically confined RCC, and to examine in a panel of RCC cell lines the effects of caveolin-1 (Cav-1) on pathological processes (invasion and growth) and select signalling pathways
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