**1. Introduction**

Gastric adenocarcinoma (GC) is the second most common cause of cancer-related mortality in the world, with developing countries being the most affected regions [1, 2]. GC is a complex disease influenced by different environmental and genetic factors. Among them, *Helicobacter pylori* (*H. pylori*) is the main etiological agent of gastrointestinal infections in children and adults and the prevalence of infection varies considerably across different geographical regions [3]. Natural acquisition of *H. pylori* infection occurs, for the most part, in childhood [4]. Infection with *Helicobacter pylori* (*H. pylori*) promotes chronic inflammation and sequential histological changes of chronic active gastritis, atrophic gastritis, intestinal metaplasia, dysplasia and ultimately invasive carcinoma [2]. Symptomatic diseases occur in approximately 10% of infected individuals, and in these cases, the risk of gastric adenocarcinoma is higher in persons carrying certain strain types as, for example, those that contain cagA or vacA alleles [1].

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Gastric cancer accounts for around 10% of all new cancers (one million per year), and it is the second leading cause of cancer death globally (700,000 deaths per year). The prognosis of CG is very poor, with a survival rate below 30% at 5 years post diagnosis [1, 2]. It is usually asymptomatic or causes nonspecific symptoms at early stages. When symptoms appear, the cancer has usually reached an advanced stage and there is presence of metastasis, being this dissemination a main cause of the severe prognosis. GC-associated high mortality is the result of its silent nature and the extremely high heterogeneity exhibited between individuals and also within gastric tumors. This heterogeneity involves, at the molecular level, a broad variety of gene mutations, amplifications and/or expression alterations, diverse DNA methylation profiles and differences in the activation or inactivation of particular signaling pathways. Thus, in the last years there has been substantial progress in the elucidation of the genomic landscape of GC due to advances in high-throughput technologies and the effort of international consortiums. Consequently, gastric cancer has been recently reclassified and stratified into several distinct subtypes based on molecular and genetic/epigenetic alterations [5, 6]. In particular, GCs have been classified according to defined genetic signatures, the status of *TP53* and the presence of microsatellite instability [5, 6]. Importantly, the heterogeneity in GC involves critical consequences in terms of differential response to therapy, resistance and recurrence [6]. Nevertheless, current therapeutic strategies in GC are not adapted to GC heterogeneity and depend on the stage of the tumor. Clinically, first-line treatment consists of surgical resection (except in cases with advanced metastasis), followed by chemotherapy with cytostatic agents such as cisplatin, 5-fluorouracil (5-FU), taxanes or irinotecan, or in combinations as ECF (epirubicin, cisplatin and 5-FU) and 5-FU plus docetaxel or cisplatin (or irinotecan) [1, 7]. These treatments have been internationally and generally accepted and used since last century. In the case of metastatic dissemination, patients whose tumors exhibit high levels of HER2 receptor expression also receive Trastuzumab, a monoclonal antibody against HER2. Initially, patients respond to chemotherapy, but cancer cells eventually become resistant, facilitating the occurrence of relapses. Even with the increase in survival facilitated by the incorporation of chemotherapy, the median overall survival of patients with CG remains low, being one of the survivals associated with cancer lower.

It has been noticed that the incidence of GC has declined over time mostly in developed countries, due to improving living standards. However, and despite increasing knowledge and improvements in the standard of care, therapy resistance and metastasis remain the main causes of treatment failure and death in GC patients and GC as a disease remains a serious and significant social concern. Consequently, identifying the major GC drivers and the molecular and cellular mechanisms responsible for the GC heterogeneity and maintenance is crucial to understand the pathobiology of GC and establish optimal therapies that able to improve the prognosis of patients.

#### **2. Cancer stem cells in gastric cancer**

Several types of solid cancers, including gastric cancers, contain phenotypically and functionally heterogeneous cancer cells [8]. These cancers present a small subpopulation of cells that display characteristics similar to normal stem cells, including unlimited self-renewal, proliferation and multi-lineage differentiation. These cells are called cancer stem cells (CSCs), which are supposed to maintain long-term tumor growth, recurrence and chemotherapy resistance. The origin of gastric CSCs is not completely clear, but it has been observed that this subpopulation of cells can derive from the differentiated gastric epithelial cells, local progenitor cells in the gastric mucosa and bone marrow-derived cells (BMDCs) [9]. In line with this idea, chronic infection of C57BL/6 mice with *Helicobacter felis* results in chronic inflammation and injury in gastric mucosa, which leads to the loss of resident gastric stem cells, followed by hyperplasia, metaplasia, dysplasia and, ultimately, gastric cancer [10, 11]. *H. pylori* can attach and invade *Lgr5+* gastric stem cells and this residency results in more susceptibility to DNA damage and cancer initiation [12, 13]. This suggests that *H. pylori* infection directly affects epithelial stem cells in the stomach and plays an important role in transforming resident stem cells into tumor cells. In addition, *H. pylori cag*A virulence factor unveils CSC-like properties by induction of EMT-like changes in gastric epithelial cancer cells [14]. Increasing studies support the existence of these cancer cells exhibiting stem cell characteristics and involved in GC metastasis [14]. Among the underlying mechanisms of chemoresistance, CG cells resistant to 5-Fluoroacyl (5-FU) or cisplatin therapy have been identified as exhibiting high expression of stem cell markers such as BMI1, CD44, CD133 or SOX9. In addition, the inhibition of these regulators reverses the chemoresistance. This resistance is due in part to the acquisition or presence of quiescence and self-renewal characteristics by the small percentage of gCSCs. It is well known that conventional chemo and radiotherapy therapies have maximum efficacy in proliferative cells and when target events are present in all cancer cells. However, they do not affect the quiescent cells and do not take into account inter and intratumoral heterogeneity at the cellular and molecular level. Thus, identifying the major regulators of gastric CSCs is a prominent need in order to understand GC pathobiology and identify novel therapeutic targets. In this sense, in the last years, the identification of several stem cell-related genes or transcription factors has provided relevant information of the impact of gCSCs in GC initiation and progression, and how *H. pylori* or chronic inflammation affects gastric stem cells. This chapter summarizes the impact of some of the most relevant genes in gastric CSCs and gastric cancer pathobiology, including LGR5, CD133, CD44, SOX2 and SOX9.

#### **2.1. Regulators of gastric cancer stem cells**
