Inferior vena cava filters are commonly encountered devices on diagnostic imaging that were highlighted in a 2010 Food and Drug Administration safety advisory regarding their complications from long-term implantation. The Predicting the Safety and Effectiveness of Inferior Vena Cava Filters (PRESERVE) trial is an ongoing after-market study investigating the safety and utility of commonly utilized filters in practice today. While most of these filters are safe, prompt recognition and management of any filter-associated complication is imperative to prevent or reduce the morbidity and mortality associated with them. This review is aimed at discussing the appropriate utilization and placement of inferior vena cava filters in addition to the recognition of filter-associated complications on cross-sectional imaging. An overview of the PRESRVE trial filters is also provided to understand each filter's propensity for specific complications.
Recently, our group has elucidated that metformin, the commonly used medication for type 2 diabetes, has anti-ovarian cancer (OvCa) effects in preclinical models and use of the drug is associated with improved OvCa survival in retrospective epidemiological studies. While the cytotoxic effects of metformin in ovarian cancer cell lines is well demonstrated, the impact of metformin on tumor-stromal interactions in the tumor microenvironment is not well defined. Currently, our work has focused on the impact of metformin on the tumor microenvironment and cancer cell behavior in physiologic models of tumor metastasis. Using a 3D organotypic model, we demonstrate that OvCa cell invasion is inhibited by metformin. In evaluating the molecular mechanism mediating this effect we show that OvCa cells co-cultured with stromal cells or stimulated with TGFβ1 upregulate the production of the extracellular matrix (ECM) proteins fibronectin and collagen 1 and that this effect is attenuated by metformin. Interestingly, metformin’s inhibition of ECM production was not dependent on AMP-activated kinase (AMPK), a common metformin target. To expand on this finding we performed label-free shotgun proteomics and identified collagens, fibronectin and TGFBR2 to be among the proteins most highly repressed in response to metformin exposure in OvCa cells. Finally, we identified that this repression of ECM remodeling by metformin was associated with an overall reduction in TGFBR2 expression and consequent SMAD/STAT3 activity. Taken together, our data indicate that metformin may have novel targets in the tumor microenvironment where it targets pro-tumorigenic effects of the stromal compartment by repressing TGFβ-dependent stromal cell ECM secretion, thereby inhibiting ovarian cancer invasion and metastasis.
Citation Format: Peter C. Hart, Shermeen Sheikh, Ernst Lengyel, Iris Romero. Metformin inhibits TGFβ-induced stromal ECM remodeling to impede invasion in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3062. doi:10.1158/1538-7445.AM2017-3062
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