RESUMO
Over the past two decades, 33 cases of colonic adenocarcinomas have been diagnosed in rhesus macaques (Macaca mulatta) at the nonhuman primate colony of the Keeling Center for Comparative Medicine and Research at The University of Texas MD Anderson Cancer Center. The distinctive feature in these cases, based on PET/computed tomography (CT) imaging, was the presence of two or three tumor lesions in different locations, including proximal to the ileocecal juncture, proximal to the hepatic flexure, and/or in the sigmoid colon. These colon carcinoma lesions selectively accumulated [18F]fluorodeoxyglucose ([18F]FDG) and [18F]fluoroacetate ([18F]FACE) at high levels, reflecting elevated carbohydrate and fatty acid metabolism in these tumors. In contrast, the accumulation of [18F]fluorothymidine ([18F]FLT) was less significant, reflecting slow proliferative activity in these tumors. The diagnoses of colon carcinomas were confirmed by endoscopy. The expression of MLH1, MSH2, and MSH6 proteins and the degree of microsatellite instability (MSI) was assessed in colon carcinomas. The loss of MLH1 protein expression was observed in all tumors and was associated with a deletion mutation in the MLH1 promoter region and/or multiple single-nucleotide polymorphism (SNP) mutations in the MLH1 gene. All tumors exhibited various degrees of MSI. The pedigree analysis of this rhesus macaque population revealed several clusters of affected animals related to each other over several generations, suggesting an autosomal dominant transmission of susceptibility for colon cancer. The newly discovered hereditary nonpolyposis colorectal cancer syndrome in rhesus macaques, termed MLH1-rheMac, may serve as a model for development of novel approaches to diagnosis and therapy of Lynch syndrome in humans.
Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/veterinária , Macaca mulatta , Proteína 1 Homóloga a MutL/metabolismo , Doenças dos Primatas/metabolismo , Animais , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico por imagem , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais Hereditárias sem Polipose/metabolismo , Feminino , Macaca mulatta/genética , Macaca mulatta/metabolismo , Masculino , Instabilidade de Microssatélites , Proteína 1 Homóloga a MutL/genética , Polimorfismo de Nucleotídeo Único , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Doenças dos Primatas/diagnóstico por imagem , Doenças dos Primatas/genética , Doenças dos Primatas/patologiaRESUMO
The role of Msh2 in chromosome stability has been investigated in a targeted mouse model for HNPCC, Msh2Delta7N. Chromosome aberration frequencies were similar in bone marrow of Msh2(+/+), Msh2(+/-)and Msh2(-/-)mice and no differential effects of in vivo X-irradiation were noted. By contrast, the induction of sister-chromatid exchanges (SCEs) by methyl nitrosourea (MNU) was reduced in Msh2(-/-)and Msh2(+/-)cells to approximately 20% and approximately 45% wild-type levels respectively indicating a phenotypic effect of haploinsufficiency of the mouse Msh2 gene.
