Activation of Src and STAT3 in Intraductal Papillary Mucinous Neoplasm of the Pancreas (IPMN)
Jessica L Wang, Daniel Shvetz, Klaus Sahora, Carlos Fernandez-del Castillo, Martha Pitman, Mari Mino-Kenudson. Massachusetts General Hospital and Harvard Medical School, Boston, MA
Background: The STAT3 transcription factor is an important regulator of stem cell self-renewal, cancer cell survival, and inflammation, and the majority of pancreatic ductal adenocarcinomas (PDACs) show constitutive activation of STAT3, classically mediated by the JAK family of tyrosine kinases. Intraductal papillary mucinous neoplasm (IPMN) is a precursor to PDAC and is being increasingly diagnosed due to advances in imaging modalities. Recent studies have shown that somatic GNAS activating mutations are present in two thirds of IPMNs, and a fraction of benign and malignant hepatocellular tumors with an inflammatory phenotype. In the latter, the weak activation of STAT3 via Src has been reported. Thus, the aims of this study are: 1) to evaluate Src activation in IPMNs; 2) to correlate it with STAT3 activation and histomorphologic features.
Design: The study cohort consists of 86 IPMN lesions from 53 pancreatectomies. Of those, 42 were of the gastric type (IPMN-G), 33 the intestinal type (IPMN-I), 3 the pancreatobiliary type (IPMN-PB), and 8 the oncocytic type (IPMN-O). The grade of dysplasia was low (LGD) in 17, intermediate (IGD) in 31, and high (HGD) in 29, and 9 were invasive carcinoma (INV, 4 tubular and 5 colloid). The protein expressions of phosphorylated Src (pSrc) and STAT3 (pSTAT3) were evaluated using the H-scores (maximum score 300). The cut-offs for positive expression were set at 50.
Results: pSrc expression was seen in 49% of IPMN lesions and was correlated with that of pSTAT3 (Pearson r = 0.3648, P=0.0006). pSrc expression was significantly more prevalent in IPMN-G (67%) than IPMN-I (33%), IPMN-PB (33%) and IPMN-O (25%) (IPMN-G vs. others, P=0.0023). Similarly, Src was more frequently activated in LGD (76%) and IGD (55%) compared to HGD (34%) and INV (22%) (LGD + IGD vs. HGD + INV, P=0.0052). pSTAT3 expression was positive in 28% of IPMNs and there was no difference in the expression between epithelial types or grade.
Conclusions: Src is frequently activated in IPMNs and Src activation is related to STAT3 activation. Given the more prevalent Src activation seen in LGD and IGD, it may be involved in the initiation and/or development of IPMN.
Tuesday, March 5, 2013 1:00 PM
Poster Session IV # 170, Tuesday Afternoon