Telomeres are shortened in acinar-to-ductal metaplasia lesions associated with pancreatic intraepithelial neoplasia but not in isolated acinar-to-ductal metaplasias

Abstract

Telomeres protect against chromosomal breakage, fusion, and interchromosome bridges during cell division. Shortened telomeres have been observed in the lowest grade of pancreatic intraepithelial neoplasia. Genetically engineered mouse models of pancreatic neoplasia develop acinar-to-ductal metaplasia prior to the development of pancreatic intraepithelial neoplasia suggesting that acinar-to-ductal metaplasias can be an early precursor lesion to pancreatic cancer. Some human pancreatic intraepithelial neoplasias are associated with acinar-to-ductal metaplasias, and it has been suggested that these acinar-to-ductal metaplasias arise as a consequence of growth of adjacent pancreatic intraepithelial neoplasias. Since the earliest known genetic lesions of pancreatic intraepithelial neoplasias is shortened telomeres we compared the telomere lengths of acinar-to-ductal metaplasia lesions, pancreatic intraepithelial neoplasias and adjacent normal cells of human pancreata to determine if acinar-to-ductal metaplasias could be precursors to pancreatic intraepithelial neoplasia. We used quantitative fluorescent in situ hybridization to measure the telomere length of cells from pancreatic lesions and adjacent normal pancreata from 22 patients, including 20 isolated acinar-to-ductal metaplasias, 13 pancreatic intraepithelial neoplasias associated with acinar-to-ductal metaplasias, and 12 pancreatic intraepithelial neoplasias. Normalized mean telomere fluorescence was significantly different among the cell types analyzed; 12.6±10.2 units in normal acinar cells, 10.2±6.4 in ductal cells, 8.4±5.9 in fibroblasts, 9.4±7.3 in isolated acinar-to-ductal metaplasias, 4.1±2.9 in pancreatic intraepithelial neoplasia-associated acinar-to-ductal metaplasias, and 1.6±1.9 in pancreatic intraepithelial neoplasias, respectively (p<0.001, ANOVA with randomized block design). Telomeres were significantly shorter in pancreatic intraepithelial neoplasia-associated acinar-to-ductal metaplasias (p<0.05, post-hoc Duncan test) and in pancreatic intraepithelial neoplasias (p<0.05), than in normal cells, or isolated acinar-to-ductal metaplasias. Thus, shortened telomeres are found in pancreatic intraepithelial neoplasia-associated acinar-to-ductal metaplasias, but not in isolated acinar-to-ductal metaplasia lesions. These results indicate that isolated acinar-to-ductal metaplasias are not a precursor to pancreatic intraepithelial neoplasia, and support the hypothesis that pancreatic intraepithelial neoplasia-associated acinar-to-ductal metaplasias arise secondary to pancreatic intraepithelial neoplasia lesions.

Sirtuin-1 Regulates Acinar-to-Ductal Metaplasia and Supports Cancer Cell Viability in Pancreatic Cancer

“…The ADM in our in vivo models corresponds to what has been described by Strobel and colleagues (19), that is, tubular complexes and mucinous metaplastic lesions (MML) and occurs isolated in the absence of pancreatic intraepithelial neoplasias (PanIN; ref. 20). The transient ADM is characterized by cytoplasmic retention of acinar enzymes, such as carboxypeptidase A1 (CpA1; Fig.…”

Disruption of Cell Cycle Machinery in Pancreatic Cancer

“…It results in greatly enhanced genomic instability that causes global genome rearrangements and facilitates accumulation of subsequent point mutations. Telomerase appears to be re-activated if these lesions progress and become ductal adenocarcinomas, perhaps to reduce genome rearrangements that threaten cancer cell viability (Hong, et al, 2011). The early onset of telomere shortening in pancreatic cancer suggests that the affected cell may not be subject to limited replicative potential, further evidence supporting a stem cell origin for the disease.…”

“…As is always the case with cancer, enhanced genetic instability underlies accumulation of transforming mutations (Negrini, et al, 2010). One such genetic alteration occurring very early in pancreatic cancer is telomere abnormalities (Gisselsson, et al, 2001, Hong, et al, 2011, Kobitsu, et al, 1997, van Heek, et al, 2002.…”

“…In the case of pancreatic cancer, however, telomere shortening appears to be a very early event in the formation of PanIN precursor lesions (Bogenrieder & Herlyn, 2003, Hong, et al, 2011. It results in greatly enhanced genomic instability that causes global genome rearrangements and facilitates accumulation of subsequent point mutations.…”

“…The central role of cell cycle disruptions can be modeled by considering mutations in the context of the progression model. Greater than 90% of low-grade PanIN lesions show shortened telomeres, providing a mechanism for rapidly generating genetic alterations required for cell transformation (Hong, et al, 2011, van Heek, et al, 2002. K-ras mutation is one of the earliest abnormalities and is likely an initiating event, being present in 36% of PanIN-1A, 44% of PanIN-1B, and 87% of PanIN-2/3 precursor lesions (Caldas & Kern, 1995.…”