Abstract

Chile is a young country that has made an enormous progress in social development, including education and health coverage, being distinguished as one of the most stable economies in Latin America. However, similarly to developed countries, the Chilean economic progress, plus the increasing population average of age, has boosted the number of people suffering from chronic diseases during the last decades, including obesity, cardiovascular diseases, chronic respiratory diseases and cancer (Ferreccio et al., 2016). Within the common cancer-types detected in Chile, stomach cancer is located at the first place of the list (MINSAL, 2016). Worldwide 8.8% of the diagnosed cancers correspond to stomach cancer and is the third cancer with highest mortality (International Agency for Research on Cancer, 2014; World-Health-Organization, 2015). Within Latin America, Chile shows one of the highest incidence and mortality of gastric cancer in men (International Agency for Research on Cancer, 2014). Although, the incidence of this cancer in Chile is projected to diminish from 19.3 in 2008 to 14.3 in 2020 (rate in 100.000 inhabitants), it is still killing 3500 people per year approximately (Departamento de Epidemiología, 2013; MINSAL, 2016). Stomach cancer has been related to several factors, including genetic background, eating and drinking habits, smoking and infection with the bacterial pathogen Helicobacter pylori. Indeed, within the causes of gastric cancer, H. pylori infection seems to be predominant, where the 60% of gastric cancers have been related to it (Bessede, Dubus, Megraud & Varon, 2015; Hoffmann, 2015; International Agency for Research on Cancer, 2014; Parkin, 2006). Chile possesses a very high incidence of H. pylori infection worldwide (den Hoed & Kuipers, 2016; Torres et al., 2013). Although, it is possible to eradicate the infection by getting treated with antibiotics, whether eradication will prevent stomach from developing cancer is still under debate and the main issue consists in its late detection (den Hoed & Kuipers, 2016). Unless a patient suffering from gastritis, ulcer or another condition gets requested being examined by endoscopy, this person can live infected for years, decades and even a whole life without notice it (den Hoed & Kuipers, 2016; Koch, Mollenkopf, & Meyer, 2016). Indeed, it is estimated that a 50% of the worldwide population lives infected with H. pylori (Koch et al., 2016). It remains still unclear how a person responds to the infection and how the stomach cancer could be then induced. Different steps have been proposed to describe how an infection with H. pylori may eventually induce stomach cancer, where superficial and atrophic gastritis could be initially triggered, followed by intestinal metaplasia and then dysplasia and adenocarcinoma, process which is known as Correa cascade (Bessede et al., 2015; Hoffmann, 2015; Ishaq & Nunn, 2015; Nagashima et al., 2015). The immune system protects our body from external pathogens and keeps its balance by preventing the emergence of cellular malformations that could result in cancer as well as self-attacks, as it happens during auto-immune diseases (Koch, Meyer, & Moss, 2013; Lebeis, Sherman, & Kalman, 2008). When a pathogen is recognised, immune cells are recruited to the infection site while alerting others by the secretion of inflammatory mediators (Basset, Holton, O’Mahony, & Roitt, 2003; Kinnebrew & Pamer, 2012). Although is known that H. pylori infection produces DNA damage (Koeppel, Garcia-Alcalde, Glowinski, Schlaermann, & Meyer, 2015) and the inflammation-induced cell damage is a known factor that could induce cellular carcinogenic features (Landskron, De la Fuente, Thuwajit, Thuwajit, & Hermoso, 2014), the H. pylori-induced inflammatory responses and their connection to cancer remain unclear. Specifically, it is not totally understood what the role of the immune system is during the modelling of the stomach microenvironment upon H. pylori infection. Wnt signallingis well-known to contribute to the embryo development, tissue homeostasis and cell differentiation (Logan & Nusse, 2004). For example, mutations in different components of Wnt signalling cascades have been related to cancer and embryonic malformation (Clevers & Nusse, 2012; Green, Nusse, & van Amerongen, 2014). Wnt signalling also plays an important role in stomach tissue modelling and development of stomach cancer (Shi et al., 2011). During the last decade Wnt signalling has been related to infection-associated responses and sterile inflammation, where increased Wnt gene expression has been observed in samples from patients suffering from acute and chronic infections as well as chronic inflammatory disorders (Blumenthal et al., 2006; Christman et al., 2008; Malgor et al., 2014; Malini Sen, 2001; Miyoshi, Ajima, Luo, Yamaguchi, & Stappenbeck, 2012; Pereira, Schaer, Bachli, Kurrer, & Schoedon, 2008; Rauner et al., 2012; Reischl et al., 2007). Thus, in addition to their well-understood functions in the embryo development and tissue homeostasis, Wnt proteins are emerging as novel regulators of immune responses to infection and inflammation. The functions of Wnt proteins and the downstream signalling events in immune responses during inflammation and infection, however, are not well understood. Studies from my PhD suggest that Wnt signalling components perpetuate pro-inflammatory responses during bacterial infection. Preliminary results from our lab suggest that Wnt proteins are responsive to H. pylori infection in the stomach. However, it remains unknown what is their role during the H. pylori-induced immune responses. The main aim of this work is to study whether the stomach inflammatory responses to H. pylori infection are instructed by the immune system and how this could be then connected to the development of cancer. The contribution of Wnt signalling to the stomach tissue/immune system interface will be specifically analysed. Stomach and immune cells will be confronted by a novel in vitro co-culture system and Wnt signalling will be targeted by commercially available drugs. The contribution of Wnt signalling activation by immune cells to the H. pylori-induced inflammatory responses will be also analysed in vivo. For countries with high incidence of H. pylori infection such as Chile, this represents novel opportunities of improving the control of inflammation in patients suffering from H. pylori-induced pathologies such as superficial gastritis or peptic ulcer and then the detrimental cellular effects that could be linked to the induction of carcinogenic features.