Abstract 1415: Telomere shortening in centroacinar-acinar region of the pancreas: relationships with aging, cancers and tissue stem cells

Abstract Background: Telomeres play a key role in preventing chromosomal instability. There is a striking link between advanced age and increased incidence of pancreatic cancer, suggesting a combined effect of mutation load, epigenetic regulation, telomere(definition) dysfunction, and an altered stromal milieu. Pancreatic intraepithelial neoplasia (PanIN) is a major precursor lesion of human pancreatic cancers. However, in genetically engineered mice, there is evidence that pancreatic cancer might arise in the centroacinar-acinar region, possibly through a process of acinar-to-ductal metaplasia (ADM). Determining whether ADM is a precursor lesion of human pancreatic cancers is not clear yet. In this study, we analyzed telomere length in the centroacinar-acinar region of the human pancreas with and without cancer. Methods: We used surgically resected and autopsied pancreatic specimens without cancer (n = 27) and with invasive ductal carcinoma (n = 11). We selected areas without inflammation. Immunohistochemical staining was performed for acinar, ductal, and stem cell markers. Using our quantitative fluorescence in situ hybridization (Q-FISH) technique (Takubo, et al. J Pathol, 2010), we estimated the telomere lengths of acinar and centroacinar cells. Results: Immunohistochemical staining revealed centroacinar cells with cytokeratin (CK) 19 (+)/CK7 (+)/trypsin (-)/CD133 (focal +) and acinar cells with CK19 (-)/CK7 (-)/ trypsin (+)/ CD133 (-). Telomeres in the centroacinar cells was significantly longer than in the acinar cells. In addition, telomere length in centroacinar and acinar cells decreased with age. The rate of decline in telomere length due to age was greater in centroacinar cells than in acinar cells. However, in elderly people at least 60 years of age, telomere length in the centroacinar cells did not decrease, while those in acinar cells continued to decrease after 60 years. The length of telomeres in the centroacinar and acinar cells of pancreatic cancer cases (minimum age, 60 years) was shorter than that in the cells of the cases without cancers. Discussion: Centroacinar cells expressed the stem cell marker, CD133, and had longer telomeres, suggesting that the centroacinar compartments are frequently included among cell types proposed as candidate pancreatic stem. The fact that the maximum regression of telomeres was found in centroacinar cells suggests that the number of stem cells and cells with the longest telomeres decreases with age, as previously described (Aida, et al. Exp Gerontol, 2008). Furthermore, in pancreatic cancer cases, telomere shortening in centroacinar and acinar cells occurs in the early stages of pancreatic carcinogenesis without histological changes. In conclusion, critical telomere dysfunction in the centroacinar-acinar region is possibly due to high annual telomere attrition, which leads to chromosomal instability and carcinogenesis in the pancreas. Citation Format: Yoko Matsuda, Naotaka Izumiyama-Shimomura, Toshiyuki Ishiwata, Mutsunori Fujiwara, Ken-ichiro Tomita, Naoki Hiraishi, Hideki Hamayasu, Ken-ichi Nakamura, Naoshi Ishikawa, Steven Poon, Junko Aida, Kaiyo Takubo, Tomio Arai. Telomere shortening in centroacinar-acinar region of the pancreas: relationships with aging, cancers and tissue stem cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1415. doi:10.1158/1538-7445.AM2015-1415