The epithelial IL4 receptor signaling axis mediates enhanced breast and colon tumor growth and metastasis

Abstract

Epithelial cancers of the lung, colon, breast, and pancreas comprise the top four most deadly cancers. Progress has been made in treating primary epithelial tumors, however metastatic tumors remain largely incurable and account for the majority of cancer-related deaths. Interleukin-4 (IL4), a Th2 cytokine, promotes the proliferation and survival of activated lymphocytes through the type I IL4 receptor (IL4R) in part by the downstream activation of Stat6, Akt, and mTor. The proliferation and survival phenotypes are supported by increased glucose and glutamine metabolism. Interestingly, many epithelial cancer types including breast and colon cancer overexpress a second type of IL4R, the type II IL4R, composed of the IL4R? and IL13R?1 subunits. The goal of this dissertation was to determine whether the epithelial IL4/IL4R signaling axis could drive metastatic tumor growth, and to elucidate IL4-induced mechanisms that regulate this growth using murine models of breast and colon cancer.

We demonstrated that IL4R? mediates enhanced proliferation and survival to promote the growth of mammary cancer metastases in the lung and liver, and that host IL4 promotes the growth of mammary and colon metastases. This enhanced metastatic ability was associated with IL4/IL4R?-activated Akt, Erk, mTor, and Stat6 in mammary cancer. We also found that IL4R? promoted mammary tumor growth at primary sites. In B lymphocytes, IL4-induced survival is dependent upon glucose metabolism. We demonstrated that IL4 enhances glucose uptake and metabolism in mammary and colon cancer cells, likely via the IL4-induced expression of glucose transporter 1. However, our results indicated that IL4/IL4R?-enhanced glucose uptake and metabolism does not help to sustain mammary cancer growth in vitro or metastatic colon cancer growth in vivo. Instead, IL4-induced breast cancer growth was dependent upon glutamine metabolism, and IL4 upregulated the expression of the main glutamine transporter, ASCT2, concomitantly with increased glutamine uptake in murine and human breast cancer cells. Collectively, our data indicates that targeting the IL4/IL4R signaling axis could limit epithelial cancer metastasis. Fortunately, therapies targeting this axis have already cleared phase I and II clinical trials for other diseases, and a therapy specific for the type II IL4R is in preclinical development.