Abstract 2361: TGFβ signaling deficiency enhances tumor associated inflammation in colon cancer

Abstract

In early colon cancer development, there is considerable evidence suggesting that transforming growth factor-β (TGFβ) serves as a tumor suppressor due to its growth-inhibitory effects in the epithelium. This is in contrast to observations suggesting that in advanced disease, TGFβ promotes tumor progression by contributing to metastasis. Therefore, to better understand the effects of TGFβ signaling on colon cancer, we examined the effect of global or epithelial reduction in TGFβ signaling on tumor progression in the APC murine model of colon cancer. Initially, we examined the relationship between TGFβ signaling and inflammation in human colon cancer specimens. We found that loss of SMAD4 in epithelial cells correlates with increased inflammation in tissue from colon cancer patients. Moreover, APC mice with global TGFBR deficiency (ATG mice) demonstrated increased inflammation that was also associated with loss of SMAD4 in epithelial cells. In contrast, APC mice with epithelial loss of TGFBR signaling (ATC mice) do not demonstrate loss of SMAD4, but have even more pronounced inflammation concomitant with rectal bleeding and prolapse, significant weight loss, the presence of crypt abscesses and lymphoid aggregates, and increased mortality. Similarly, ATC mice, in contrast to the ATG and the APC mice, show markedly increased tumor infiltrating macrophages, splenic macrophages, and serum levels of the cancer-associated cytokines IL8, TGFβ1, and TNFα. Overall, these findings demonstrate that loss of TGFβ signaling, particularly in epithelial cells, dramatically worsens tumor progression. Yet, the attempt to reduce metastasis by treating colon cancer patients with TGFβ inhibitors may result in worse outcome by invoking a robust inflammatory response.

Citation Format: Daniel R. Principe, Brian DeCant, Riley J. Mangan, Elizabeth A. Wayne, Andrew M. Diaz, Dominic Vitello, Hidayatullah G. Munshi, Paul Grippo, Barbara Jung. TGFβ signaling deficiency enhances tumor associated inflammation in colon cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2361. doi:10.1158/1538-7445.AM2015-2361