Maria T. Abreu, M.D.
Professor of Medicine
Description of Research
The relationship of the human host to the intestinal microbiota may underlie common human illness from colon cancer to inflammatory bowel diesease. Dr. Abreu became interested in the role of toll-like receptors (TLRs) in the intestine in health and iflammation, and hypothesized that TLR4 (which recognizes lipopolysaccharide derived from the wall of Gram-negative bacteria) is essential for the development of colon cancer in the setting of chronic intestinal inflammation. TLR4 and its co-receptor MD-2 are normally expressed in low amounts in the epithelial cells lining the colon. Dr. Abreu's research determined that IFN-gamma increases expression of TLR4 and MD-2 through transcriptional activation of their promoters, and patients with ulcerative colitis and cancer have increased expression of TLR4 in their tumors, which supports a role for TLR4 in human disease. The absence of TLR4 leads to defective epithelial proliferation following injury. Dr. Abreu's laboratory was the first to describe that TLR4-deficient mice are protected from colitis-associated neoplasia. The clinical revelance is reflected in their finding that TLR4 expression is seen in colitis-associated cancer in patients with ulcerative colitis and in sporadic colorectal cancer. To further this observation, Dr. Abreu's laboratory developed a mouse model with constitutive TLR4 signaling specifically in intestinal epithelial cells. Currently they are testing the hypothesis that TLR4 activates intestinal epithelial cells to proliferate through the Wnt/beta-catenin pathway promoting colitis-associated cancer, and how TLRs regulate colon stem cells in health and in cancer. Dr. Abreu has also embarked studies looking at TLR signaling in obesity-linked colorectal cancer. The recent development of a gnotobiotic (germ-free) facility will permit the elucidation of microbial signals leading to inflammation and cancer. Dr. Abreu's hope is to target the TLR4 pathway for treatment of patients with TLR4-positive tumors.
Dr. Abreu’s research on host-bacterial interactions and, in particular, the role of toll-like receptor signaling in intestinal inflammation has shown that defective innate immune response may result in diminished bacterial clearance and ultimately dysregulated response to normal flora.
- The intestine normally has low expression of TLRs to protect against exuberant inflammation in response to the normal intestinal flora. Inflammatory bowel disease results in an increase in TLR expression.
- Colorectal cancers in patients with ulcerative colitis have high expression of TLR4
- Animals with deficient TLR4 expression (TLR4-/-) have defective ability to repair intestinal injury and are protected against inflammation-associated neoplasia.
- Dr. Abreu and her team have developed a unique animal model that over-expresses TLR4 in the intestinal epithelium and these animals have increased intestinal epithelial cell proliferation and increased susceptibility to colorectal cancer.
- TLR4 appears to activate the b-catenin pathway and may therefore lead to an increased risk of APC-dependent sporadic tumors.
Selected Cancer-Related Publications
- Sandborn WJ, Abreu MT, D'Haens G, Colombel JF, Vermeire S, Mitchev K, Jamoul C, Fedorak RN, Spehlmann ME, Wolf DC, Lee S, Rutgeerts P. Certolizumab Pegol in Patients With Moderate to Severe Crohn's Disease and Secondary Failure to Infliximab. Clin Gastroenterol Hepatol 8:688-695.e2, 2010 Read more »
- Fukata M, Abreu MT. Microflora in colorectal cancer: a friend to fear. Nat Med 16:639-41, 2010 Read more »
- Abreu MT. Toll-like receptor signalling in the intestinal epithelium: how bacterial recognition shapes intestinal function. Nat Rev Immunol 10:131-44, 2010 Read more »
- Hsu D, Fukata M, Hernandez YG, Sotolongo JP, Goo T, Maki J, Hayes LA, Ungaro RC, Chen A, Breglio KJ, Xu R, Abreu MT. Toll-like receptor 4 differentially regulates epidermal growth factor-related growth factors in response to intestinal mucosal injury. Lab Invest 90:1295-305, 2010 Read more »
- Mendoza JL, Abreu MT."Biological markers in inflammatory bowel disease: Practical consideration for clinicians." Gastroenterol Clin Biol 33 Suppl 3 (2009): S158-73 Read more »
Collaborating in the Multidisciplinary Research Program(s):