Helicobactor pylori infection and the associated chronic gastric inflammation often progresses to adenocarcinoma. Bone-marrow-derived cells (BMDCs) are recruited to sites of inflammation and JeanMarie Houghton et al. now report that these cells actually contribute to Helicobactor-induced gastric tumours — challenging the widely held view of the epithelial origin of gastric cancer.

The authors investigated the role of BMDCs in gastric carcinogenesis using a mouse model in which gastric cancer is induced by Helicobactor felis infection. Female mice were lethally irradiated and then transplanted with male bone marrow tagged with β-galactosidase (β-gal) or green fluorescent protein (GFP). Three weeks of H. felis infection led to intense bone-marrow-derived inflammation. After 20 weeks of infection, apoptosis levels increased in the gastric mucosa and β-gal- or GFP-positive glands appeared. By 52 weeks, 90% of the proximal mucosa had been replaced with BMDCs that were β-gal or GFP positive and also positive for trefoil factor 2, which is expressed in metaplastic mucosal cells and is often overexpressed in cancer. At this stage the tissues showed histological signs of metaplasia and dysplasia, and 1 year after infection intramucosal carcinoma or high-grade gastrointestinal intraepithelial neoplasia (GIN) was evident. The GIN lesions comprised of BMDCs, which were not only β-gal or GFP positive but also contained the Y-chromosome, were actively proliferating and stained positive for standard epithelial markers such as cytokeratins but negative for the haematopoietic cell marker CD45. The authors concluded that the BMDCs had differentiated into a gastric epithelial phenotype.

Helicobactor infection seems to be necessary for this phenotype because uninfected mice did not show any BMDC engraftment, and other types of tissue injury such as acute gastric ulceration or depletion of one of the main types of gastric epithelial cells did not induce BMDC recruitment either. Importantly, fusion between BMDCs and gastric epithelial cells was ruled out as a possible origin of the cancer cells.

So, what population of bone-marrow cells is responsible for Helicobactor-induced gastric cancer? Houghton et al. cultured haematopoietic stem cells or mesenchymal stem cells with soluble factors from primary gastric epithelial cell cultures. Only the mesenchymal stem cells showed upregulation of gastric mucosal cell gene expression pattern, including trefoil factor 2.

These data offer a new model for development of epithelial cancer from chronic inflammation, which has implications for our general understanding of cancer initiation and progression.