We evaluated whether MYC, TP53, and chromosome 17 copy-number alterations occur in ACP02, ACP03, and AGP01 gastric cancer cell lines and in their tumor counterpart. Fluorescence in situ hybridization for MYC and TP53 genes and for chromosome 17 was applied in the 6th, 12th, 60th, and 85th passages of the cell lines and in their parental primary tumors. We observed that three and four MYC signals were the most common alterations in gastric cell lines and tumors. ACP02 presented cells with two copies of chr17 and loss of one copy of TP53 more frequently than ACP03 and AGP01. Only ACP03 and AGP01 presented clonal chr17 trisomy with three or two TP53 copies. The frequency of MYC gain, TP53 loss, and chromosome 17 trisomy seems to increase in gastric cell lines compared to their parental tumors. Our findings reveal that these cell lines retain, in vitro, the genetic alterations presented in their parental primary tumors.

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.

Background/Aim: The evolution of gastric carcinogenesis remains largely unknown, as the regulatory mechanisms involved in the aggressiveness of gastric cancer are still poorly understood. Kinases are downstream modulators and effectors of various cell signaling cascades and play key roles in the development of neoplastic diseases. The objective of this study was to evaluate the expression of genes and proteins of the SRC family, including FYN, YES, BLK, FGR, LYN and SRC, in a model of intestinal gastric carcinogenesis generated by treating Cebus apella, a New World non-human primate, with N-methyl nitrosourea (MNU). Materials and Methods: mRNA expression of genes was measured by real-time reverse transcription quantitative PCR (RT-qPCR) and protein expression was measured by western blotting in six Cebus apella treated with N-methylnitrosourea (MNU) for about 2.5 years. Results: Elevated mRNA and protein expression mainly of the SRC and LYN kinases was observed. Their expression was gradually increasing as non-atrophic gastritis was evolving to gastric cancer. Conclusion: SRC family kinases play a key role in tumor progression and metastasis and may be a promising target for the treatment of gastric cancer. Gastric cancer (GC) is the leading cause of cancer-related mortality worldwide and its incidence continues to increase in both developed and developing countries (1). Currently, the mechanisms underlying GC initiation, progression and metastasis are not fully understood (2). Most GC patients are diagnosed with advanced diseases, resulting in poor prognosis, thus highlighting the importance of identifying useful biomarkers (3). c-SRC was the first oncogene discovered in the group of kinases, and its protein product belongs to the family of non-receptor tyrosine kinases (SFKs), which are among the most studied proteins (4-6). SFKs are pleiotropic kinases involved in several cellular events, and their overexpression may contribute to different aspects of tumor development (6). Increased expression of c-Src has been observed in a variety of tumors, including GC (7-9). Of all the kinases of the SRC family-which also include FYN, YES, BLK, YRK, FGR, HCK, LCK and LYN, c-SRC is the prototype member and the one most frequently involved in cancer (6). Compared to rodents, non-human primates (PSN) are more similar to humans in regard to their genetic evolution, anatomy, physiology, biochemistry and organic systems (10), and, thus, provide a useful model for studies on carcinogenesis (11, 12). The aim of this study was to evaluate the mRNA and protein expression of SCR, LYN, BLK, Yes, FYN and FGR 6317

We observed that Canova actives macrophages in vivo and ex vitro. The lymphocytes cultured in a supplemented medium with macrophages activated by Canova treatment presented a higher number of proliferation cells than lymphocytes not exposed to macrophages activated by Canova. The Interferon gamma and Interleukin-5 cytokines were only observed in the medium of lymphocytes exposed to macrophages activated by Canova. Thus, Canova has potential as a new adjuvant therapy.