The process leading from inflammation to dysplasia to colon cancer in patients with inflammatory bowel disease or sporadic cancer remains poorly understood. Studying the link between inflammation, in particular, innate immune signaling, and colon cancer offers the possibility to identify novel ways to both prevent and treat cancer. Colonic bacteria have been suspected to contribute to the development of colon cancer. The contribution of bacteria and bacterial products to carcinogenesis in inflammatory bowel disease, however, has been difficult to ferret out. Part of the difficulty in understanding the contribution of bacterial signaling to colon carcinogenesis is that commensal bacteria are required for initiation of colitis. Therefore, the independent contribution of bacterial recognition and signaling in development of colitis- associated neoplasia could not adequately be explored. The current proposal emanates from work performed with the support of a NIDDK-sponsored R21 entitled: Role of TLR4 in development of acute and chronic murine colitis. In studying the role of TLR4 in acute and chronic colitis, we discovered that TLR4 is essential for the colon's ability to recover from mucosal injury. Animals deficient in TLR4 do not upregulate Cox-2 expression, have impaired production of PGE2, and have decreased intestinal epithelial cell (IEC) proliferation (Fukata, et al. 2006). Epithelial repair and cancer are the mirror image of the other. The current proposal explores the mechanism by which TLR4 may be important in the switch from repair to carcinogenesis in the colonic epithelium. We hypothesize that signaling through TLR4 is involved in the development of colitis-associated neoplasia. We have found that TLR4 is overexpressed in human CAC but not the surrounding mucosa supporting a role for TLR4 in human disease (Fukata, et al. 2007). Our data demonstrate that TLR4-/- mice are protected from development of dysplasia in a mouse model of colitis-associated neoplasia. We now show that over-expression of constitutively-active TLR4 in the intestinal epithelium (villin-TLR4) results in increased tumorgenicity. We believe the results of our studies will permit rational therapies to be developed that combine blockade of TLR4 and other signaling pathways, such as epidermal growth factor receptor (EGFR), in the prevention or treatment of colitis associated cancers.
Inflammation is important in the development of colon cancer. We have found that a certain receptor of the immune system that recognizes bacteria, TLR4, may be involved in causing colon cancer especially in patients with inflammatory bowel disease. With the support of this grant we can examine how TLR4 contributes to the development of colon cancer and try to prevent colon cancer by blocking TLR4.
|Dheer, Rishu; Santaolalla, Rebeca; Davies, Julie M et al. (2016) Intestinal Epithelial Toll-Like Receptor 4 Signaling Affects Epithelial Function and Colonic Microbiota and Promotes a Risk for Transmissible Colitis. Infect Immun 84:798-810|
|Davies, Julie M; Santaolalla, Rebeca; von Furstenberg, Richard J et al. (2015) The Viral Mimetic Polyinosinic:Polycytidylic Acid Alters the Growth Characteristics of Small Intestinal and Colonic Crypt Cultures. PLoS One 10:e0138531|
|Davies, Julie M; Abreu, Maria T (2015) The innate immune system and inflammatory bowel disease. Scand J Gastroenterol 50:24-33|
|Davies, Julie M; Abreu, Maria T (2015) Host-microbe interactions in the small bowel. Curr Opin Gastroenterol 31:118-23|
|Ramesh, Radha; Kozhaya, Lina; McKevitt, Kelly et al. (2014) Pro-inflammatory human Th17 cells selectively express P-glycoprotein and are refractory to glucocorticoids. J Exp Med 211:89-104|
|Davies, Julie M; Hua, Hong-Uyen; Dheer, Rishu et al. (2014) Stool phospholipid signature is altered by diet and tumors. PLoS One 9:e114352|
|Sussman, Daniel A; Santaolalla, Rebeca; Bejarano, Pablo A et al. (2014) In silico and Ex vivo approaches identify a role for toll-like receptor 4 in colorectal cancer. J Exp Clin Cancer Res 33:45|
|Abreu, Maria T; Peek Jr, Richard M (2014) Gastrointestinal malignancy and the microbiome. Gastroenterology 146:1534-1546.e3|
|Strobel, Sebastian; Abreu, Maria T (2013) Update on idiopathic colitides. Curr Opin Gastroenterol 29:60-5|
|Santaolalla, Rebeca; Sussman, Daniel A; Ruiz, Jose R et al. (2013) TLR4 activates the ?-catenin pathway to cause intestinal neoplasia. PLoS One 8:e63298|
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