Search

Introduction: Recent evidence suggests that tumour lymphangiogenesis promotes lymph node metastasis, a major prognostic factor for survival of breast cancer patients. However, signaling mechanisms involved in tumour-induced lymphangiogenesis remain poorly understood. The expression of ezrin, a membrane cytoskeletal crosslinker and Src substrate, correlates with poor outcome in a diversity of cancers including breast. Furthermore, ezrin is essential in experimental invasion and metastasis models of breast cancer. Ezrin acts cooperatively with Src in the regulation of the Src-induced malignant phenotype and metastasis. However, it remains unclear if ezrin plays a role in Src-induced tumour angio/lymphangiogenesis., Methods: The effects of ezrin knockdown and mutation on angio/lymphangiogenic potential of human MDA-MB-231 and mouse AC2M2 mammary carcinoma cell lines were examined in the presence of constitutively active or wild-type (WT) Src. In vitro assays using primary human lymphatic endothelial cells (hLEC), an ex vivo aortic ring assay, and in vivo tumour engraftment were utilized to assess angio/lymphangiogenic activity of cancer cells., Results: Ezrin-deficient cells expressing activated Src displayed significant reduction in endothelial cell branching in the aortic ring assay in addition to reduced hLEC migration, tube formation, and permeability compared to the controls. Intravital imaging and microvessel density (MVD) analysis of tumour xenografts revealed significant reductions in tumour-induced angio/lymphangiogenesis in ezrin-deficient cells when compared to the WT or activated Src-expressing cells. Moreover, syngeneic tumours derived from ezrin-deficient or Y477F ezrin-expressing (non-phosphorylatable by Src) AC2M2 cells further confirmed the xenograft results. Immunoblotting analysis provided a link between ezrin expression and a key angio/lymphangiogenesis signaling pathway by revealing that ezrin regulates Stat3 activation, VEGF-A/-C and IL-6 expression in breast cancer cell lines. Furthermore, high expression of ezrin in human breast tumours significantly correlated with elevated Src expression and the presence of lymphovascular invasion., Conclusions: The results describe a novel function for ezrin in the regulation of tumour-induced angio/lymphangiogenesis promoted by Src in breast cancer. The combination of Src/ezrin might prove to be a beneficial prognostic/predictive biomarker for early-stage metastatic breast cancer.

Background: Although use of the internal thoracic artery has been shown to improve outcomes after coronary artery bypass grafting, the same cannot be said of alternative arterial conduits. To determine the benefit of radial artery (RA) grafting, a case-matched review was undertaken., Methods: Between March 1994 and March 1999, 2,847 patients underwent isolated coronary artery bypass grafting with a left internal thoracic artery graft, plus saphenous vein grafts (SVGs). Of these patients, 478 also received an RA graft (RA group). The RA patients were matched at a ratio of 1:2 with patients receiving only SVGs and a left internal thoracic artery graft (SVG group; n = 956) using six prognostic risk factors: age, sex, Canadian Cardiovascular Society class, left ventricular grade, number of diseased vessels, and timing of operation. Target vessels were graded according to quality and graftability and were similar between groups. Outcomes were evaluated by univariate and multivariate analyses., Results: There was a significantly higher prevalence of diabetes, hypertension, and peripheral vascular disease in the RA group (p < 0.05). Although stay in the intensive care unit was shorter in the RA group (RA, 30 +/- 2 hours, and SVG, 37 +/- 2 hours; p = 0.0002), total hospital stay was similar between groups. The incidence of perioperative myocardial infarction was higher in the SVG group (SVG, 31 of 956 or 3.2%, and RA, 6 of 478 or 1.3%; p = 0.02). Multivariate analysis revealed RA grafting to be protective against early mortality and morbidity (odds ratio = 0.58; 95% confidence interval, 0.37 to 0.90; p = 0.015) and late mortality and morbidity including late reintervention (risk ratio = 0.60; 95% confidence interval, 0.37 to 0.93; p = 0.02). Actuarial freedom from events at 36 months postoperatively was greater in the RA group (RA, 95% +/- 2%, and SVG, 86% +/- 4%; p = 0.01)., Conclusions: Despite a higher prevalence of preoperative comorbidity, patients in the RA group demonstrated improved outcomes after coronary artery bypass grafting. The RA is a viable and beneficial conduit for this operation.