Senescence in intraductal papillary mucinous neoplasm of the pancreas

Intraductal papillary mucinous neoplasm of the pancreas is attracting attention as a precursor lesion of the invasive ductal adenocarcinoma, whereas it has been reported that some intraductal papillary mucinous neoplasms do not display progression to malignancy and remain almost unchanged in size and morphology. Recent studies have reported that oncogene-induced senescence has been observed in neoplasms, especially in premalignant lesions, and that it can play an important role in preventing malignant progression. To clarify the presence of senescence in intraductal papillary mucinous neoplasms, we analyzed the expression of several markers of senescence. The intraductal papillary mucinous neoplasms evaluated in this study were classified into 4 groups according to the degree of dysplasia. Senescence-associated β-galactosidase activity and senescence-associated heterochromatin foci formation were investigated in 33 cases of intraductal papillary mucinous neoplasms and 6 normal controls. Immunohistochemical analysis of p16 ^INK4a and p15 ^INK4b was performed in 158 cases of intraductal papillary mucinous neoplasms and 10 normal controls. In the normal controls, neither senescence-associated β-galactosidase activity nor senescence-associated heterochromatin foci formation was observed. Most of the normal epithelia were negative for either p16 ^INK4a or p15 ^INK4b. For all 4 markers, the percentages of positive cases reached a peak in intraductal papillary mucinous neoplasm with low-grade dysplasia and showed significant decreasing trends in the transition from intraductal papillary mucinous neoplasm with low-grade dysplasia to intraductal papillary mucinous neoplasm with an associated invasive carcinoma. Our results indicate that senescence is induced in the early stage of intraductal papillary mucinous neoplasm and gradually attenuated according to the progression. It is suggested that senescence plays a role in preventing malignant progression of intraductal papillary mucinous neoplasm.