In agreement with these reports, www.selleckchem.com/products/chir-99021-ct99021-hcl.html we show that in vitro IL 4 stimulation enhanced IGF 1 production by primary BAL macrophages. Tumor educated BAL macrophages produced significantly more IGF 1 than na ve macrophages, both basally and in response to IL 4 stimulation. We previously found that lung tumors recruit increasing numbers of macrophages to the alveolar space. Therefore, the lung tumor media and 40 times higher than what is detected in BAL fluid, Erk1/2 activity was not significantly Inhibitors,Modulators,Libraries elevated and Akt levels were unaffected. EGF may partially stimulate Erk1/2 activity at supra physiological levels, but this was not sufficient to stimulate cellular growth. When administered at cell and tissue relevant levels, IGF Inhibitors,Modulators,Libraries 1 sti mulated both Erk1/2 and Akt activation, elevated cellular cyclin D1 content, and induced neoplastic proliferation.
environment Inhibitors,Modulators,Libraries contains not only more macrophages, but macrophages with heightened IGF 1 production. Consis tent with this conclusion, BALF IGF 1 levels were 3 fold higher in lung tumor bearing mice compared to na ve littermates. While the role of primary lung macrophages in med iating lung cancer proliferation has not been previously examined, the effects of co cultured stromal cell types on a Kras mutant mouse lung AC cell line was recently reported. When cultured with media conditioned by MH S cells, proliferation of AC cells increased significantly, in agreement with our observa tions. This study focused on the migration resulting from the increased CXCL1 and IL 18 observed under co culture conditions, and did not determine if exogenous KC or IL 18 stimulated neoplastic prolifera tion.
They also found that MH S conditioned Inhibitors,Modulators,Libraries media had no effect on neoplastic colony formation in soft agar, while we describe the potent stimulation of anchorage independent growth of two Kras mutant lung tumor derived cell lines, using two independent assays. By fractionating M CM, we demonstrate that the factors responsible for stimulating neoplastic proliferation are 7 11 kDa, making IL 18 an unlikely candidate. KC, on the other hand, is a potent 8 kDa chemokine. Based on molecular weight alone, we cannot rule out KC as contri buting to the increased growth caused by M CM. how ever, several lines of evidence make this unlikely.
First, both MH S and primary na ve BAL macrophages stimu Inhibitors,Modulators,Libraries late neoplastic proliferation, but KC was undetectable in media conditioned by MH S macrophages or primary BAL macrophages isolated from na ve or lung tumor bear ing animals. Second, unlike IGF 1, KC expression does not increase in alternatively activated macrophages . alternative activation increases IGF 1 production, and this stimulates neoplastic proliferation. Lastly, although Zhong, et. al. examined inhibitor Trichostatin A an exhaustive array of cytokines, they did not measure IGF 1 . thus, they did not evaluate the role of IGF 1 in mediating the effects observed in their co culture model.