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Overexpression of HER2 in the pancreas promotes development of intraductal papillary mucinous neoplasms in mice.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDA) has a 5-year survival rate of less than 5% and is the sixth leading cause of cancer death. Although KRAS mutations are one of the major driver mutations in PDA, KRAS mutation alone is not sufficient to induce invasive pancreatic cancer in mice model. HER2, also known as ERBB2, is a receptor tyrosine kinase, and overexpression of HER2 is associated with poor clinical outcomes in pancreatic cancer. However, no report has shown whether HER2 and its downstream signaling contributes to the pancreatic cancer development. By immunohistochemical analysis in human cases, HER2 protein expression was detected in 40% of PDAs and 29% of intraductal papillary mucinous carcinomas, another type of pancreatic cancer. In a mouse model, we showed overexpression of activated HER2 (HER2 NT ) in the pancreas, in which cystic neoplastic lesions resembling intraductal papillary mucinous neoplasm-like lesions in humans had developed. We also found that HER2 NT cooperated with oncogenic Kras to accelerate the development of pancreatic intraepithelial neoplasms. In addition, using pancreatic organoids in 3D cultures, we found that organoids cultured from HER2 NT /Kras double transgenic mice showed proliferative potential and tumorigenic ability cooperatively. HER2-signaling inhibition was suggested to be an new therapeutic target in some types of PDAs.

SUBMITTER: Shibata W

PROVIDER: S-EPMC5906617 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Overexpression of HER2 in the pancreas promotes development of intraductal papillary mucinous neoplasms in mice.

Shibata Wataru W Kinoshita Hiroto H Hikiba Yohko Y Sato Takeshi T Ishii Yasuaki Y Sue Soichiro S Sugimori Makoto M Suzuki Nobumi N Sakitani Kosuke K Ijichi Hideaki H Mori Ryutaro R Endo Itaru I Maeda Shin S

Scientific reports 20180418 1

Pancreatic ductal adenocarcinoma (PDA) has a 5-year survival rate of less than 5% and is the sixth leading cause of cancer death. Although KRAS mutations are one of the major driver mutations in PDA, KRAS mutation alone is not sufficient to induce invasive pancreatic cancer in mice model. HER2, also known as ERBB2, is a receptor tyrosine kinase, and overexpression of HER2 is associated with poor clinical outcomes in pancreatic cancer. However, no report has shown whether HER2 and its downstream ...[more]

PMID: 29670173

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Project description:BackgroundThe international consensus guidelines for intraductal papillary mucinous neoplasm of the pancreas (IPMN) presented clinical features as indications for surgery. Whereas surveillance for recurrence, including de novo lesions, is essential, optimal surveillance protocols have not been established.Aim and methodsThis study aimed to assess the clinical features of recurrence at the remnant pancreas (Rem-Panc) and extra-pancreas (Ex-Panc) after surgery for IPMN. Ninety-one patients of IPMN that underwent detailed preoperative assessment and pancreatectomy were retrospectively analyzed, focusing especially on the type of recurrence.ResultsThe IPMNs were finally diagnosed as low-grade dysplasia (LDA, n = 42), high-grade dysplasia (HAD, n = 19), and invasive carcinoma (IPMC, n = 30). Recurrence was observed in 26 patients (29%), of which recurrence was seen at Rem-Panc in 19 patients (21%) and Ex-Panc in 7 patients (8%). The frequency of Rem-Panc recurrence was 10% in LDA, 21% in HDA, and 37% in IPMC. On the other hand, Ex-Panc recurrence was observed only in IPMC (23%). Ex-Panc recurrence showed shorter median recurrence-free survival (RFS) and overall survival (OS) than Rem-Panc recurrence (median RFS 8 months vs. 35 months, p < 0.001; median OS 25 months vs. 72 months, p < 0.001). Regarding treatment for Rem-Panc recurrence, repeat pancreatectomy resulted in better OS than no repeat pancreatectomy (MST 36 months vs. 15.5 months, p = 0.033). On multivariate analysis, main duct stenosis or disruption as a preoperative feature (hazard ratio [HR] 10.6, p = 0.002) and positive surgical margin (HR 4.4, p = 0.018) were identified as risk factors for Rem-Panc recurrence.ConclusionsThe risk factors for Rem-Panc and Ex-Panc recurrence differ. Therefore, optimal surveillance on these features is desirable to ensure that repeat pancreatectomy for Rem-Panc recurrence can be an appropriate surgical intervention.

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Overexpression of HER2 in the pancreas promotes development of intraductal papillary mucinous neoplasms in mice.

Publications

Overexpression of HER2 in the pancreas promotes development of intraductal papillary mucinous neoplasms in mice.

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