Experimental Gastric Carcinogenesis in Cebus apella Nonhuman Primates

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.

hTERT, MYC and TP53 deregulation in gastric preneoplastic lesions

“…The detection of MYC immunoreactivity in intestinal metaplasia of individuals from three Northern Brazil populations corroborates previous studies of our group that demonstrated the presence of MYC protein overexpression only in intestinal metaplasia and neoplastic tissue from all patients with intestinal type gastric cancer, which is preceded by preneoplastic lesions [21-23], as well as in intestinal metaplasia of non-human primates treated with N-methyl-nitrosourea (MNU) [24]. On the other hand, MYC immunoreactivity was described in gastritis samples, as well as intestinal metaplasia, in Asian populations [15,25-27].…”

“…To our knowledge, this is the first study to sensitively quantify MYC mRNA expression in precancerous gastric lesions. The increased MYC expression in intestinal metaplasia supports a previous study of our group in non-human primates, in which we demonstrated a continuous increase of MYC mRNA expression during the sequential steps of gastric carcinogenesis in MNU-treated animals [24]. In these animals, the mRNA expression increased about 3-fold in intestinal metaplasia compared to normal gastric mucosa.…”

Prognostic and Predictive Significance of MYC and KRAS Alterations in Breast Cancer from Women Treated with Neoadjuvant Chemotherapy

“…Universal peroxidase-conjugated secondary antibody kit (DakoCytomation, USA) was used for the detection system and 3,30-diamino-benzidine/H 2 O 2 (Dakocytomation, Denmark) was used as the chromogen. Positive ER, PR or MYC expression was defined as clear nuclear immunostaining in more than 10% of tumor cells [18], [19], [20], [21]. HER2 protein staining was scored as 0 (negative), 1+(weakly positive), 2+ (moderately positive) and 3+ (strongly positive) [2].…”

Evaluation of the Biochemical, Hematological and Genotoxic Parameters of Cebus Apella Treated with N-Methyl-Nitrosurea (NMU) Followed by Treatment with a Complex Homeopathic Compound (Canova)

“…Experiments in vivo and in vitro point out that treatment with CA can cause tumor size reduction and regression in animals, and can also recover cells viability after they were damaged [2] . NMU was successfully used as an inductor of gastric carcinogenesis in Cebus apella and the treatment with CA was able to restore several hematologic measurements in those animals, suggesting that CA can be used during/after chemotherapy to increase the tolerability and duration of anticancer treatments [3] . Thus, the aim of the present study was to evaluate possible protective effects mediated by CA against the genotoxicity caused by oral MNU ingestion in non-human primates of the specie Cebus apella.…”