itic CD11b+ cells expressed higher levels of IL-12p40 and lower levels of arginase-1 in mice treated with MyD88 or IL1R deficient macrophages than control groups. Together, we conclude 20685848 that IL-1/IL-1R signal in macrophages induces, if not all, M2-type polarization through activation of IKKb/NF-kB pathway. Angiogenic VEGF-A and lymphangiogenic VEGF-C and VEGF-D were up-regulated in the tumor stromal macrophages of highly metastatic tumors expressing IL-1a and/or IL-1b. VEGF-C promotes lymphangiogenesis and metastasis, including that to lymph nodes, and its IPI 145 site expression together with that of its receptor is closely associated with lymph node metastasis and tumor progression in lung cancer cells. The expression of VEGF-C is highly sensitive to IL-1 and other inflammatory stimuli, while VEGF-D expression is stimulated by cell-cell contacts through a mechanism involving cadherin family proteins. Consistent with these studies, VEGF-D expression was similarly augmented in macrophages co-cultured with lower and highly metastatic cancer cells, could not be induced by indirect co-culture of macrophages and cancer cells, and was not inhibited by the IL-1R antagonist anakinra. As indicated earlier, IL-1a is mainly non-secretory, while IL-1b is secretory. The importance of non-secreted IL-1a, and thus of cell-cell contacts, for VEGF-A 22441874 and VEGF-C expression was also demonstrated, because the levels of these factors were much higher in direct, rather than indirect, cocultures of macrophages and tumor cells. In conclusion, our study suggests that inflammatory stimuli contribute to the establishment of a tumor microenvironment that, through macrophage activation, enables the growth, invasion, and metastasis of cancer cells. Specifically, IL-1-driven inflammatory stimuli in cancer cells enhance lymphangiogenesis and angiogenesis through up-regulation of CXC chemokines, VEGF-A, and VEGF-C, and inducing the transition of macrophages into the lymphangiogenic M2 type. Blocking of these inflammatory stimuli with the IL-1R antagonist anakinra consequently suppresses lymph node metastasis and tumor growth by highly aggressive cancer cells. In fact, clinical studies with anakinra have been now applied to treat with breast cancer, metastatic colorectal cancer, pancreatic cancer, and multiple myeloma. A number of previous studies have reported that high levels of IL-1 in lung cancer patients were correlated with poor prognosis and metastasis. However, clinical trials with anakinra in lung cancer have never been made so far. We further expect its clinical trial for patients with metastatic lung cancer. Supporting Information 14 IL-1-Driven Lymphangiogenesis by Cancer Cell Since the first commercialization in 1996, safety issues regarding the introduction of GM crops into food and feed have been debated. Among the globally available GM crops, Bt-maize is the only GM maize event authorized and cultivated in the EU and is mainly used in animal feeds. MON810 expresses Cry1Ab protein, which confers maize resistance to the European corn borer, Ostrinia nubilalis. The Cry proteins are a group of endotoxins produced by different strains of soil bacterium Bacillus thuringiensis and have putative species-specific toxicity for insects. The Cry toxins 
are considered non-toxic to higher animals and the Bt-crops have been suggested to be as safe and nutritious as their conventional/commercial counterparts for various animals in some, but not all studies. Among the latter, Cry1A to