A Shift from pStat6 to pStat3 Predominance Is Associated with Inflammatory Bowel Disease-Associated Dysplasia.
Robert E LeBlanc, Elizabeth C Wick, Drew M Pardoll, Cynthia L Sears, Christine A Iacobuzzio-Donahue. Johns Hopkins University School of Medicine, Baltimore, MD
Background: Mucosal inflammatory response in ulcerative colitis(UC) and Crohn's disease(CD) is characterized by Th1, Th2 and Th17 effector cells. Th1 differentiation is dependent on activation of Stat1/4, Th2 on Stat6 and Th17 on Stat3. Activated Stat3 is an important mediator of oncogenesis. This study examined the distribution of activated Stat1(pStat1), Stat 6(pStat6) and Stat3(pStat3) in the continuum of inactive UC and CD to colitis-associated cancer(CAC). Such data may begin to define whether select Stat activation is an early initiator of neoplastic transformation leading to CAC.
Design: Tissue microarrays were constructed with biopsy and colectomy specimens from 67 patients(pts) with UC and CD(1983-2001) and 11 controls without clinical or pathologic diagnosis of colitis or cancer. Analysis of 136 samples included inactive (n=32) and active colitis(n=39), low grade(n=21) and high grade dysplasia(n=19), and CAC(n=25). 2-10 samples were analyzed per patient. Immunohistochemistry(IHC) was used to score pStat1, pStat6 and pStat3 in colonic epithelial(EC) and mucosal immune cells(IC) by two blinded observers(scale 0-3). IHC was correlated with clinical and pathologic data(tumor location, histologic type, grade and node involvement).
Results: pStat3 was more common in UC than CD (34/39 vs 10/18, p<0.02). In chronic colitis without dysplasia, pStat3 was limited to rare IC and EC. Colitis associated dysplasia had intense IC pStat3. In a CAC subset, EC pStat3 was prominent and always in association with intense pStat3 in surrounding IC. IC pStat3 in CAC was greater in low compared to high grade CAC, in lymph node positive compared to lymph node negative cancers, and in patients with underlying UC compared to CD. In contrast, IC pStat6 expression was more common in control patients compared to CAC (8/10 vs. 9/25, p<0.03). pStat1 was detected in only a small subset of pts with UC and CD colitis but not with CAC.
Conclusions: pStat3 is a marker for neoplastic transformation in a subset of pts with UC and CD. A shift from predominant IC pStat6 expression to pStat3 expression may be an early sign of neoplasia. Additional data are needed to define the signals promoting this change and to determine how pStat3 correlates with clinical course and prognosis.
Wednesday, March 2, 2011 9:30 AM
Poster Session V # 24, Wednesday Morning