Abstract
The evolution of gastric carcinogenesis remains largely unknown. We established two gastric carcinogenesis models in New-World nonhuman primates. In the first model, ACP03 gastric cancer cell line was inoculated in 18 animals. In the second model, we treated 6 animals with N-methyl-nitrosourea (MNU). Animals with gastric cancer were also treated with Canova immunomodulator. Clinical, hematologic, and biochemical, including C-reactive protein, folic acid, and homocysteine, analyses were performed in this study. MYC expression and copy number was also evaluated. We observed that all animals inoculated with ACP03 developed gastric cancer on the 9th day though on the 14th day presented total tumor remission. In the second model, all animals developed pre-neoplastic lesions and five died of drug intoxication before the development of cancer. The last surviving MNU-treated animal developed intestinal-type gastric adenocarcinoma observed by endoscopy on the 940th day. The level of C-reactive protein level and homocysteine concentration increased while the level of folic acid decreased with the presence of tumors in ACP03-inoculated animals and MNU treatment. ACP03 inoculation also led to anemia and leukocytosis. The hematologic and biochemical results corroborate those observed in patients with gastric cancer, supporting that our in vivo models are potentially useful to study this neoplasia. In cell line inoculated animals, we detected MYC immunoreactivity, mRNA overexpression, and amplification, as previously observed in vitro. In MNU-treated animals, mRNA expression and MYC copy number increased during the sequential steps of intestinal-type gastric carcinogenesis and immunoreactivity was only observed in intestinal metaplasia and gastric cancer. Thus, MYC deregulation supports the gastric carcinogenesis process. Canova immunomodulator restored several hematologic measurements and therefore, can be applied during/after chemotherapy to increase the tolerability and duration of anticancer treatments.
Highlights
Gastric cancer is the fourth most frequent cancer type and the second highest cause of cancer mortality worldwide
4.1 C. apella gastric carcinogenesis Spontaneous tumors have been reported in nonhuman primates, usually due to the aging process [3]
Nonhuman primates offer a useful model for cancer research and other basic research into genetic and immunopathogenesis mechanisms as well as for the development and validation of new therapies for several diseases
Summary
Gastric cancer is the fourth most frequent cancer type and the second highest cause of cancer mortality worldwide. Gastric cancer prevalence is influenced by geographic, ethnic, and cultural factors [1]. Nonhuman primates present close phylogenic relationship to humans and greater similarities with regard to anatomy, physiology, biochemistry, and organ systems, as compared to rodents. They present a relatively large organ size which enables repeated diagnostic procedures, such as endoscopic examination, blood sample collection and biopsy, on the same animal over a long period of time [3]. Nonhuman primate models are not common and are expensive compared to rodent models, the long life span observed in nonhuman primates allows for long-term carcinogenic studies
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