Orthotopic inflammation-related pancreatic carcinogenesis in a wild-type mouse induced by combined application of caerulein and dimethylbenzanthracene.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal human malignancies, with a poor long-term prognosis, and effective therapeutic options are lacking. Observing the dynamics of the pathogenesis of pancreatic intraepithelial neoplasia (PanIN) and PDAC in tumor models can facilitate understanding of the molecular mechanisms involved in early PDAC. Furthermore, it can compensate for the research limitations associated with analyzing clinical specimens of late-stage PDAC. In this study, we orthotopically treated the pancreas with dimethylbenzanthracene (DMBA) combined with caerulein in wild-type C57BL/6 J mice to induce inflammation-related pancreatic carcinogenesis. We observed that DMBA and caerulein treatment induced a chronic consumptive disease, which caused a decrease in the relative body and pancreas weights, diminishing the health status of the mice and enhancing the inflammation-related histological changes. Moreover, mid-dose and high-frequency treatment with caerulein caused prolonged inflammatory damage to the pancreas and contributed to a permissive environment for the development of PDAC. CXCL12/CXCR4, CCL2/CCR2, and several cytokines, such as interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α were upregulated in the tumor tissue of DMBA and caerulein-induced PDAC mice. This orthotopic mouse pancreatic carcinogenesis model mimic human disease because it reproduces a spectrum of pathological changes observed in human PDAC, ranging from inflammatory lesions to pancreatic intraepithelial neoplasia. Thus, this mouse model may improve the understanding of molecular mechanisms underlying the injury-inflammation-cancer pathway in the early stages of pancreatic carcinogenesis.

• Authors: Chen Liang, Zhen Wang, Li Wu, Chen Wang, Bao-Hua Yu, Xiu-Zhong Yao, Xiao-Lin Wang, Ying-Yi Li
• Journal: Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine (Tumour Biol) Vol. 36 Issue 10 Pg. 7557-68 (Sep 2015) ISSN: 1423-0380 [Electronic] Netherlands
• PMID: 25916208 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Interleukin-1beta
• Interleukin-6
• Tumor Necrosis Factor-alpha
• 9,10-Dimethyl-1,2-benzanthracene
• Ceruletide

Topics

• 9,10-Dimethyl-1,2-benzanthracene (pharmacology)
• Animals
• Carcinogenesis (drug effects, metabolism)
• Carcinoma, Pancreatic Ductal (chemically induced, metabolism, pathology)
• Ceruletide (pharmacology)
• Female
• Inflammation (chemically induced, metabolism, pathology)
• Interleukin-1beta (metabolism)
• Interleukin-6 (metabolism)
• Mice
• Mice, Inbred C57BL
• Pancreatic Neoplasms (chemically induced, metabolism, pathology)
• Tumor Necrosis Factor-alpha (metabolism)
• Up-Regulation (drug effects)