Attenuation of MKP-1 levels by shRNA did not affect proliferation, whereas it significantly increased T-ALL cell death following drug treatment or serum starvation. Importantly, tumorigenesis of MKP-1 deficient T-ALL cells was markedly impaired compared to controls. Our results elucidate a novel mechanism downstream of Notch3 find more by

which the direct interplay between endothelial and tumor cells promotes survival of T-ALL cells. O24 Role of Foxm1 Transcription Factor in Tumor Microenvironment Tanya Kalin 1 , David Balli1, Fu-Sheng Chow1, Vladimir Kalinichenko1 1 Pulmonary Biology, Cincinnati Children’s Hospital, Cincinnati, OH, USA The Forkhead Box m1 (Foxm1) protein is induced in a majority of human cancers, including non-small cell lung cancers. Increased Foxm1 expression is associated with poor prognosis. However, specific requirements for the Foxm1 in each cell type of the cancer lesion during lung tumor formation

DihydrotestosteroneDHT remain unknown. In this study, we examined the role of Foxm1 in tumor microenvironment using conditional knockout mouse models with Foxm1 deficiency in macrophages (LysM-Cre Foxm1fl/fl mice; macFoxm1 −/−) or endothelial cells (Tie2-Cre Foxm1fl/fl mice; enFoxm1 −/−). Lung tumors in mice were induced using two experimental protocols: 3-methylcholanthrene (MCA) / butylated hydroxytoluene (BHT) or urethane. GNA12 Conditional deletion of Foxm1 from macrophages caused a significant decrease in lung inflammation during induction of lung tumors, leading to reduction in the number and size of lung adenomas. Decreased lung tumorigenesis in macFoxm1 −/− mice was associated with diminished proliferation of tumor cells, decreased numbers of tumor-associated macrophages and reduced expression of pro-inflammatory cytokines in the lung and bronchoalveolar lavage fluid. Furthermore,

we demonstrated that Foxm1 −/− mice displayed a dramatic decrease in proliferation and migration of macrophages in vivo and in vitro. In our studies, we also demonstrated that deletion of Foxm1 from endothelial cells resulted in accelerated lung tumorigenesis. The increased numbers and sizes of lung tumors in enFoxm1 −/− mice resulted from increased endothelial leakage and infiltration of inflammatory cells into lung tissue. The enFoxm1 −/− mice displayed increased tumor cell proliferation and increased mRNA levels of cell cycle regulator cMyc and cyclin D1. Deletion of Foxm1 from endothelial cells caused reduced expression of Foxf1 and Foxf2 transcription factors, both of which are critical regulators of endothelial cell functions and VEGF signaling. Altogether, our studies demonstrated that Foxm1 plays a dual role in tumor microenvironment: it controls cellular permeability in endothelial cells and induces inflammation and migration of macrophages into lung tumors.