Transgenic expression of Helicobacter pylori CagA induces gastrointestinal and hematopoietic neoplasms in mouse

Abstract

Infection with cagA-positive Helicobacter pylori is associated with gastric adenocarcinoma and gastric mucosa-associated lymphoid tissue (MALT) lymphoma of B cell origin. The cagA-encoded CagA protein is delivered into gastric epithelial cells via the bacterial type IV secretion system and, upon tyrosine phosphorylation by Src family kinases, specifically binds to and aberrantly activates SHP-2 tyrosine phosphatase, a bona fide oncoprotein in human malignancies. CagA also elicits junctional and polarity defects in epithelial cells by interacting with and inhibiting partitioning-defective 1 (PAR1)/microtubule affinity-regulating kinase (MARK) independently of CagA tyrosine phosphorylation. Despite these CagA activities that contribute to neoplastic transformation, a causal link between CagA and in vivo oncogenesis remains unknown. Here, we generated transgenic mice expressing wild-type or phosphorylation-resistant CagA throughout the body or predominantly in the stomach. Wild-type CagA transgenic mice showed gastric epithelial hyperplasia and some of the mice developed gastric polyps and adenocarcinomas of the stomach and small intestine. Systemic expression of wild-type CagA further induced leukocytosis with IL-3/GM-CSF hypersensitivity and some mice developed myeloid leukemias and B cell lymphomas, the hematological malignancies also caused by gain-of-function SHP-2 mutations. Such pathological abnormalities were not observed in transgenic mice expressing phosphorylation-resistant CagA. These results provide first direct evidence for the role of CagA as a bacterium-derived oncoprotein (bacterial oncoprotein) that acts in mammals and further indicate the importance of CagA tyrosine phosphorylation, which enables CagA to deregulate SHP-2, in the development of H. pyloriassociated neoplasms.bacterial oncoprotein ͉ transgenic mouse

Linking epithelial polarity and carcinogenesis by multitasking Helicobacter pylori virulence factor CagA

“…The recent establishment of transgenic mice that systemically express CagA has provided convincing evidence for the in vivo function of CagA as a bacterial oncoprotein (Ohnishi et al, 2008). The cagA-transgenic mice developed gastric epithelial hyperplasia, gastric hyperplastic polyps and gastrointestinal carcinomas without showing any signs of inflammation, indicating that the oncogenic potential of CagA is cell autonomous.…”

“…The study of cagA-transgenic mice indicates that CagAmediated tumorigenesis is cell autonomous in that it neither requires additional bacterial factors nor elicits host responses such as inflammation (Ohnishi et al, 2008). Why does CagA have an oncogenic potential?…”

The C-Terminally Encoded, MHC Class II-Restricted T Cell Antigenicity of the Helicobacter pylori Virulence Factor CagA Promotes Gastric Preneoplasia

“…Experimental infection of Mongolian gerbils (23) and C57BL/6 mice (24) with wild type, but not CagA translocation-deficient H. pylori results in the rapid development of gastric cancer precursor lesions. Transgenic expression of CagA in the gastric mucosa further revealed that CagA is in itself sufficient to cause gastric hyperplasia, gastric polyps, and adenocarcinomas (22). In addition to the direct effects that the ectopic expression or natural delivery of CagA have on the cell biology of host cells, we demonstrate in this article that CagA has strong T cell antigenic properties.…”

“…CagA delivery to the host cell further disrupts cell polarity (20) and allows the bacteria to colonize the apical surface of cultured cells (21). In vivo, transgenic expression of CagA under a stomach-specific promoter is by itself sufficient to induce epithelial hyperplasia and, in a subset of mice, gastric polyps and adenocarcinoma (22), implying that CagA can function as a bacterial oncoprotein. In a Mongolian gerbil model of CagA + H. pylori infection, the bacteria induce gastric cancer precursor lesions that resemble H. pylori-associated lesions in humans (23).…”

Clonaje y expresión de un fragmento recombinante del gen cagA de Helicobacter pylori y su evaluación preliminar en el serodiagnóstico

“…Several studies in cell culture and animal models indicate the likely role of CagA in human cancer associated with H. pylori infection (3). Transgenic expression of CagA in mice led to the development of gastric epithelial hyperplasia and adenocarcinoma of the stomach and the small intestine, providing the first direct evidence of the potential oncogenicity of CagA in vivo (9). Thus, CagA is the first bacterial oncoprotein to be identified in relation to human cancer.…”