**3. Is gastric cancer a stem cell disease?**

Gastric carcinoma is a multifactorial disease, involving a chronic *Helicobacter pylori* infection as the main cause as well as the Epstein-Barr Virus to a small extent, diet (low vitamins, nitrosamines, chemicals, etc.), smoking, and genetic susceptibility of the host [23, 24]. At the histological level, the WHO described more than five different histological subtypes, divided into two main groups in the Lauren classification of gastric tumors, i.e., the intestinal type and the diffuse type [25]. At the molecular level, gastric carcinomas are classified in four main groups based on their mutational profile [26, 27]. These classifications are not currently used in clinical practice to orientate toward a specific targeted therapy.

More than 93% of distal gastric carcinoma cases are associated with a chronic *H. pylori* infection of the gastric mucosa [28]. Most of these cases represent the intestinal histological subtype. *H. pylori* infection induces a chronic inflammation of the gastric mucosa, i.e., gastritis. In 5–10% of cases, gastritis evolves into gastric or duodenal ulcer, and in 1% of cases, gastritis leads to stomach cancers. In this last case, the loss of specialized epithelial cells results in a chronic atrophic gastritis and to the compensatory cellular hyperproliferation and aberrant differentiation at the origin of the intestinal metaplasia (firstly appearing in the pylorus) and/or spasmolytic polypeptide-expressing metaplasia (SPEM) (mainly in the corpus). These metaplastic lesions can further progress into dysplasia and ultimately into an intestinal-type carcinoma according to the Lauren classification [29, 30]. So, chronic atrophic gastritis is considered to be the first step of gastric adenocarcinomas. All of these lesions are well characterized histologically and can be reproduced experimentally in Mongolian gerbils [31] and in mice [32, 33] in response to *H. pylori* and *Helicobacter felis* infection. Gastric carcinoma of the diffuse type or signet ring cell carcinoma corresponds to poorly differentiated adenocarcinomas for which the glandular structure has disappeared. It is the second most frequent histological subtype of gastric tumors, which is frequently linked to sporadic or hereditary mutations of the *CDH1* gene encoding E-cadherin, and appears most of the time without precancerous lesions.

*H. pylori* is mainly present at the surface of gastric units but also as microcolonies deep in the stomach glands; the bacteria can interact directly with gastric stem/progenitor cells in the stomach of mice and humans. Regarding their long lifetime and high division ability, stem cells are more susceptible to accumulate genetic/epigenetic modifications than their progeny. Some current evidence suggests that, in the context of chronic *H. pylori* infection, gastric cancer stem cells originate from the transformation of stem cells of two different origins: local, for most of the cases, and to a lesser extent from bone marrow-derived stem cells that home into the gastric mucosa in response to the chronic injury mediated by *Helicobacter*, contributing to metaplasia and dysplasia [34–36]. It is important, however, to distinguish between the origin of cancer cells which initiate and drive the primary tumor development and those which accumulate and contribute to tumor growth once the process is initiated. These two main mechanisms leading to the emergence of gastric cancer cells will be discussed below.
