Resumen de Immunohistochemical evidence for an impairment of autophagy in tumorigenesis of gastric carcinoids and adenocarcinomas in rodent models and patients

Reidar Alexander Vigen, Yosuke Kodama, Trond Viset, Reidar Fossmark, Mark Kidd, Timothy C Wang, Irvin M. Modlin, Duan Chen, Chun Mei Zhao

• Background/Aim: Autophagy has dual roles in tumorigenesis: tumor-promoting or tumor-suppressing. The aim of the present study was to examine autophagy-related markers by immunohisto-chemistry in gastric carcinoids and adenocarcinomas in rodent models and patients.

  Methods: Gastric carcinoids in Mastomys were induced by loxtidine treatment. Spontaneously developed gastric adenocarcinomas in Japanese cotton rats and INS-GAS transgenic mice were included. Patient tissue samples of gastric carcinoids or adenocarcinomas were collected. Immunohistochemistry was performed against autophagy-related gene protein-6 (ATG-6, also called beclin-1), ATG-5 and ATG-16.

  Results: In tumor-free Mastomys, ATG-5, ATG-16 and beclin-1 were immunepositive in the gastric mucosa. In tumor-bearing Mastomys, ATG-5 and ATG-16 were negative in the tumors, whereas beclin-1 was positive in four of five animals. In carcinoid patients, ATG-5 was negative in six of ten, ATG-16 negative in nine of ten, and beclin-1 negative in three of ten patients. In cotton rats, ATG-5 and ATG-16 were negative in all tumors. Beclin-1 was negative in three of five rats. In INS-GAS mice, ATG-5 and beclin-1 were positive in the tumor area, but the numbers of immunopositive cells per gland were reduced by about 50% in comparison with wild-type mice. In adenocarcinoma patients, ATG-5 and ATG-16 were negative in eight of ten, and beclin-1 positive in all ten patients.

  Conclusions: An impaired autophagy took place at the stage of formation of ATG-5-ATG-12-ATG-16 complex in both gastric carcinoids and adenocarcinoma of both rodent models and patients. ATG-5 and ATG-16 might be better markers than beclin-1 in assessing autophagy in these lesions