Objectives-We have previously reported that vascular injury or treatment of cultured vascular smooth muscle cells with platelet-derived growth factor-BB (PDGF-BB) or fibroblast growth factor-2 (FGF2) increases the levels of protein tyrosine phosphatase (PTP)1B. The current study was designed to test the hypothesis that PTP1B attenuates PDGF-or FGF-induced motility and proliferation of cultured cells, as well as neointima formation in injured rat carotid arteries. Methods and Results-Treatment of cultured cells with adenovirus expressing PTP1B decreased PDGF-BB-or FGF2-induced cell motility and blocked PDGF-BB-or FGF2-induced proliferation, whereas expression of dominant negative PTP1B (C215S-PTP1B) uncovered the motogenic effect of subthreshold levels of PDGF-BB or FGF2, increased neointimal and medial cell proliferation, and induced neointimal enlargement after balloon injury. The inhibitory effect of PTP1B directed against PDGF in cultured cells was associated with dephosphorylation of the PDGF␤ receptor. Conclusions-PTP1B suppresses cell proliferation and motility in cultured smooth muscle cells treated with PDGF-BB or FGF2, and the phosphatase plays a counter-regulatory role in vascular injury-induced cell proliferation and neointima formation. Taken together with previous studies indicating increased PTP1B levels in cells treated with growth factors, the current findings are the first to report the existence of an inhibitory feedback loop involving PDGF or FGF, and PTP1B in blood vessels. Key Words: PTP1B Ⅲ growth factors Ⅲ neointima formation Ⅲ cell motility Ⅲ cell proliferation M igration and proliferation of smooth muscle cells are of critical importance in neointima formation and remodeling occurring in response to vascular injury. 1 Increased release of platelet-derived growth factor (PDGF) and/or fibroblast growth factor-2 (FGF2), followed by activation of PDGF and/or FGF2 receptor tyrosine kinase activities, are thought to be major events contributing to vascular remodeling. 2 Several reports indicate that injury-induced movement of smooth muscle cells from media to intima and the proliferation of smooth muscle cells in intima are significantly reduced by pharmacological antagonists of the function or availability of PDGF or FGF2. [3][4][5][6][7] Conversely, administration of PDGF-BB or FGF2 has been reported to enhance smooth muscle cell movement from media to intima, followed by cell proliferation in vessels with minimal endothelial damage. 7,8 These studies indicate that PDGF and FGF are important mediators of neointima formation in models of vascular injury. Tyrosyl phosphorylation of growth factor receptors via their intrinsic tyrosine kinase activities is a pivotal event for activation of downstream signaling that mediates increased motility and proliferation in cultured cells. Furthermore, balloon injury or treatment in vivo with PDGF also induces PDGF receptor tyrosyl phosphorylation in vascular smooth muscle, 6,9 a finding consistent with experiments in vitro.Protein tyrosine phosphatases ...

Objective: Type 2 diabetes mellitus (T2DM) affects 10% of Americans and is associated with an increased incidence of cancer. Statins are first-line cholesterol-lowering medications in the treatment of hyperlipidemia. Several studies have demonstrated a relationship between statin use and reduced cancer incidence. We examined the cancer benefits of statin subtypes, with specific attention to disease-free survival (DFS) and overall survival (OS). Methods: This retrospective review included adults with T2DM diagnosed with solid tumors at Roswell Park Cancer Institute in Buffalo, NY, USA (2003–2010). Individuals with gestational diabetes, incomplete records, or diagnosed with rare solid tumors were excluded. Follow-up began at the date of diagnosis and ended with the first confirmed recurrence, death, or loss of contact. Demographics were assessed by Chi-square, Kaplan–Meier survival analyses, and Cox proportional hazards regression. Findings: Overall, 1102 patients met inclusion criteria, 52.1% of the study participants were female, and 578 participants (52.5%) died during the follow-up period which ranged from 0 to 156 months. Hydrophilic statin use was associated with improved DFS at 5-year follow-up (41.0% vs. 36.9%, P = 0.0077) compared to lipophilic statin use. Multivariate regression revealed that hydrophilic statins were associated with improved DFS (hazard ratio [HR]: 0.706, 95% confidence interval [CI]: 0.526–0.947) and OS (HR: 0.685, 95% CI: 0.503–0.934). Pravastatin was associated with improved OS (HR: 0.674, 95% CI: 0.471–0.964). Conclusion: In patients with T2DM and cancer, hydrophilic statins, and pravastatin in particular, are associated with improved DFS as well as OS. Further research examining the cancer-specific effects of hydrophilic and lipophilic statins is needed to better understand their beneficial effects.

Background: Low-density lipoproteins levels are significant predictors of clinical outcomes in ovarian cancer (OvCa) patients. Despite American Diabetes Association (ADA) guidelines, suboptimal hyperlipidemia management is reported in women diagnosed with both OvCa and diabetes mellitus (DM). This study evaluated the impact of cholesterol drugs utilization and importance of following ADA guidelines on OvCa recurrence and survival. Methods: All DM patients newly diagnosed with OvCa between 2003 and 2010 at Roswell Park Cancer Institute were retrospectively reviewed (n=482). A total of 60 newly diagnosed OvCa patients having a form of diabetes at the time of cancer diagnosis were identified. Out of these, 14 patients were excluded due to presence of type 1 diabetes (n=6) or prior cancer history (n=8). The remaining 46 patients were included in the final analyses. Tumor pathology, outcomes, baseline co-morbidities and self-reported drug therapy were documented. Follow-up began at cancer diagnosis and ended with first confirmed recurrence and/or death. Cases lost to follow-up were censored at the date of last contact. To analyze categorical outcomes across different treatment groups, Fisher's exact test was used. All multivariate analyses were done using Cox proportional hazards models while accounting for age, weight, stage, histology, and cumulative comorbidity. A nominal significance level of 0.05 was used in all testing. Results: Average age at diagnosis and body mass index in this data set was 70±10 years and 34.76±7.07 kg/m2, respectively. Over three quarters of this population was diagnosed with advanced stage OvCa and 96% had a tumor grade of 2 or higher. Roughly two thirds of the tumors evaluated had a serous histology. Out of the cases reviewed, 52% did not receive any form of cholesterol management and 46% received a statin alone or in combination. After a median follow-up of 26.9 months, patients receiving statin monotherapy for cholesterol management were found to have improved recurrence (HR=0.17, 95% CI: 0.04 to 0.73, P=0.02); however, no impact on overall mortality was noted as compared to patients not receiving any cholesterol management medication. Conclusions: This study explored for the first time the association between statin utilization and prognosis in OvCa patients with DM. Given the identified benefit, reinforcing compliance with DM guidelines for hyperlipidemia management in OvCa patients deserves further attention. Our findings seed the beginning of a novel approach in personalized OvCa care. Citation Format: Michelle E. Amsler, Kristina A. Chmiel, Olesya Yaremko, Clare Carroll, Jingjing Yin, Terry Mashtare, Anthony Miliotto, Rachel Brightwell, Kunle Odunsi, Alice C. Ceacareanu. Statins use prevents ovarian cancer recurrence in women with diabetes mellitus. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-18. doi:10.1158/1538-7445.AM2013-LB-18