Novel Stat3 Targeted Mouse Model of Colitis Mimics Tumor Progression in Human Ulcerative Colitis.
Kenneth Friedman, Elaine Y Lin, Joseph Albanese, Elaine Liu, Kathryn Tanaka, Aaron Leifer, Qiang Liu. Montefiore Medical Center of Albert Einstein College of Medicine, New York, NY
Background: To determine the link between inflammation and tumorigenesis in intestine, we have recently established a novel mouse model of colitis-induced colorectal cancer (Stat3-IKO mice), by targeting Stat3 specifically in hematopoietic cells including macrophages and certain populations of lymphocytes. Inflammation was initiated in the colon of the mutant mice at early age that was followed by the development of malignancies including invasive adenocarcinoma in the inflamed region of the intestine. We have previously demonstrated that this model shares several characteristics with human ulcerative colitis (UC)-associated colorectal cancers including the involvement of intestinal microflora, activation of oncogenic pathways in colonic epithelial cells and disrupted epithelial homeostasis.
Design: To characterize tumor progression in Stat3-IKO mice, tissue was collected in 60 Stat3-IKO and control mice at 5, 10-14, 26-27, and greater than 30 wks of ages to assess for inflammation, low and high grade dysplasia, and invasive adenocarcinoma. Furthermore, immunostaining was used to identify the potential tumor-promoting factors produced in the inflammatory microenvironment in both human UC and mouse colon.
Results: We found that inflammation in the colon was initiated at early age (5 wks) in Stat3-IKO mice. At 10-14 wks, low grade dysplasia was present in 60% of the Stat3-IKO mice. Older Stat3-IKO mice (26-27 wks) showed more severe inflammation and the lesion had progressed to high grade dysplasia (44%) and invasive carcinoma (22%). Finally, all three Stat3-IKO mice examined at greater than 30 wks have developed invasive adenocarcinoma. As seen in human UC-associated carcinoma, pathways involved in inflammation-induced neoplastic transformation including Toll-like receptors (TLRs), chemokines and their receptors as well as S100A9 are found to be upregulated in the inflamed colon and tumor lesions in Stat3-IKO mice.
Conclusions: Tumor progression in Stat3-IKO mice shares many morphologic features with human UC-associated adenocarcinoma. The histopathological development in the model follows the sequence of inflammation, dysplasia and then carcinoma suggesting that inflammation plays a critical role in tumorigenesis, which is compatible with that observed in human UC. Our study demonstrated that Stat3-IKO mice is a valuable pre-clinical model for illustrating the mechanism of inflammation-induced neoplastic transformation in colon, and may be useful for the development of therapeutic strategy for human UC.
Category: Special Category - Pan-genomic/Pan-proteomic approaches to Cancer
Monday, February 28, 2011 9:30 AM
Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 240, Monday Morning