Gradual Telomere Shortening and Increasing Chromosomal Instability among PanIN Grades and Normal Ductal Epithelia with and without Cancer in the Pancreas

Abstract

A large body of evidence supports a key role for telomere dysfunction in carcinogenesis due to the induction of chromosomal instability. To study telomere shortening in precancerous pancreatic lesions, we measured telomere lengths using quantitative fluorescence in situ hybridization in the normal pancreatic duct epithelium, pancreatic intraepithelial neoplasias (PanINs), and cancers. The materials employed included surgically resected pancreatic specimens without cancer (n = 33) and with invasive ductal carcinoma (n = 36), as well as control autopsy cases (n = 150). In comparison with normal ducts, telomere length was decreased in PanIN-1, −2 and −3 and cancer. Furthermore, telomeres were shorter in cancer than in PanIN-1 and −2. Telomere length in cancer was not associated with histological type, lesion location, or cancer stage. PanINs with or without cancer showed similar telomere lengths. The incidences of atypical mitosis and anaphase bridges, which are morphological characteristics of chromosomal instability, were negatively correlated with telomere length. The telomeres in normal duct epithelium became shorter with aging, and those in PanINs or cancers were shorter than in age-matched controls, suggesting that telomere shortening occurs even when histological changes are absent. Our data strongly suggest that telomere shortening occurs in the early stages of pancreatic carcinogenesis and progresses with precancerous development. Telomere shortening and chromosomal instability in the duct epithelium might be associated with carcinogenesis of the pancreas. Determination of telomere length in pancreatic ductal lesions may be valuable for accurate detection and risk assessment of pancreatic cancer.

Telomere attrition in beta and alpha cells with age

“…Intriguingly, the difference between young and middle age was statistically significant, but the difference between middle age and elderly was not significant. Most recently, we have analyzed the telomere dynamics of human pancreatic ductal epithelial cell by tissue Q-FISH (same method of present study) and found that the profile of the telomere attrition was essentially similar to that obtained by previous Southern blotting analysis (Matsuda et al, 2015).…”

Morphological Markers of Chromosomal Instability

“…Cells in mitosis are often seen in normal tissues exhibiting rapid turnover, such as the epithelium of the gut, but the most important morphologic features of malignancy are atypical and bizarre mitotic igures. In our analysis, 30% of mitosis in pancreatic cancer cells was atypical mitosis, while normal epithelium did not show atypical mitosis and precancerous lesions showed only a few instances of atypical mitosis [9,18].…”

“…Telomeres protect each end of the chromosome from fusion; therefore, telomere dysfunction can be observed as an anaphase bridge [15,17]. A lot of evidence has shown that telomere dysfunction plays a key role in carcinogenesis via induction of CIN [9,27]; thus, detection of an anaphase bridge has been considered a useful method of indirectly evaluating telomere dysfunction and CIN. Multipolar mitosis is metaphase with an abnormal coniguration of the equatorial plate and the chromosomes are located along several radial axes.…”

“…Inlammation, alcohol drinking, and diabetes mellitus also accelerate telomere atrition [35][36][37]. Furthermore, telomere shortening initiates the early phase of carcinogenesis even when there are no histopathological changes [9,17]. Telomere dysfunction can be seen as nuclear atypia including the presence of micronuclei, nuclear buds, and anaphase bridges [38].…”

“…Previously, we showed that age-related shortening of telomere length in various tissues is correlated to aging-related diseases, such as cancers, diabetes mellitus, and cognitive disorders [7]. Telomere shortening often occurs in cancers, as well as in precancerous lesions [8][9][10]. Telomere shortening induces fusion of chromatids and chromosome missegregation and this phenomenon can be observed as abnormal mitotic igures and micronuclei.…”