H pylori recruit bone marrow-derived cells to the gastric mucosa that contribute to tumor development, according to the February issue of Gastroenterology.
H pylori infection promotes gastric carcinogenesis through many mechanisms, such as causing inflammation and producing virulence factors that alter gastric cell activity. Over time, these lead to metaplasia, dysplasia, and finally adenocarcinoma.
Cancer stem cells are also involved in gastric tumor formation. Christine Varon et al. investigated whether H pylori infection might somehow support a cancer stem cell population in the stomachs of mice.
Cancer stem cells, which generate tumors through unlimited self-renewal, could originate from de-differentiated epithelial cells or local progenitors of the gastric mucosa, but there are also theories that they develop from stem cells in bone marrow.
To find out if bone marrow-derived cells (BMDCs) contribute to tumors that develop in mice following H pylori infection, Varon et al. transplanted fluorescently labeled bone marrow cells from male mice into female mice. This approach gave them 2 ways to track the cells—via the fluorescent label and the Y chromosome. They then infected the female mice with different strains of H pylori and followed the carcinogenic process.
Not surpisingly, the bacterial infection promoted various levels of inflammation. The infected mice developed a thicker gastric mucosa, atrophy, metaplasia and dysplasia, over a period of 15 to 75 weeks. In tracking the fluorescently labeled BMDCs, the authors observed that these localized to the epithelial glands of the gastric mucosa in mice with H pylori infection.
The fluorescence of the gastric epithelial glands increased over time, and by 75 weeks after infection 50% to 90% of the mice had fluorescent epithelial glands. About 20% of the glands in each mouse contained the BMDCs.
The glands that contained the BMDCs were more frequently associated with histopathologic lesions than the glands without BMDCs, and the severity of these lesions increased over time. One year after infection, the presence of BMDCs in epithelial glands was significantly associated with increases in mucosal atrophy and pseudointestinal metaplasia and dysplasia.
How might the BMDCs contribute to gastric cancer development? Varon et al. observed that BMDCs were in close contact with other epithelial cells forming the glands and displayed a polarized, epithelial morphology. They expressed epithelial cytokeratins but did not express CD45, indicating that they had lost their hematopoietic markers, and instead acquired epithelial markers and phenotype. However, Y-chromosome−positive cells outside the epithelial glands remained cytokeratin-negative and CD45-positive, indicating that they had maintained features of leukocytes.
Varon et al. propose that the premaligant gastric epithelial gland undergoes a conversion; BMDCs in these glands might become cancer stem cells that mediate growth of adenocarcinoma. The low percentage of dysplastic glands that contained BMDCs in the mice indicated that the conversion occurred at a low frequency.
How and why do the BMDC localize to the gastric mucosa, specifically during H pylori infections? The authors propose that chemokines secreted by infected gastric cells during chronic infection might recruit bone marrow stem cells. They showed that the more inflammatory the strain of bacteria, the more BMDC were recruited, and the more significant the BMDC-positive dysplasia.
Varon et al. state that the origin of gastric carcinoma cannot be restricted to stem cells recruited from the bone marrow—that multiple, diverse local stem and progenitor cells could also contribute to gastric carcinogenesis. However, BMDC might also be considered as a source of cancer stem cells for certain tumor types.
They propose that BMDC engraftment is a late feature of lesion development. Because only about a quarter of dysplastic lesions contained BMDCs, this is not the most frequent origin of gastric dysplasia. However, these findings challenge the model in which cancer stem cells arise from local transformation of epithelial or progenitor cells.
Read the article online.
Varon C, Dubus P, Mazurier F, et al. Helicobacter pylori infection recruits bone marrow-derived cells that participate in gastric preneoplasia in mice. Gastroenterology 2012;281–291.