Risk factors in gastric cancer

STATE OF THE ART: Gastric cancer (GC) is still a major health problem worldwide due to its frequency, poor prognosis and limited treatment options. At present prevention is likely to be the most effective means of reducing the incidence and mortality from this disease. The most important etiological factors implicated in gastric carcinogenesis are diet and Helicobacter pylori (H. pylori) infection. High intake of salted, pickled or smoked foods, as well as dried fish and meat and refined carbohydrates significantly increased the risk of developing GC while fibers, fresh vegetables and fruit were found to be inversely associated with GC risk. Epidemiological investigations (retrospective, case-control and prospective) and several meta-analyses have demonstrated that concurrent or previous H. pylori infection is associated with an increased risk of GC in respect to uninfected people. H. pylori colonizes gastric mucosa where it induces a complex inflammatory and immune reaction that on time leads to a severe mucosal damage i.e., atrophy, intestinal metaplasia (IM) and dysplasia. The risk of GC is closely related to the grade and extension of gastric atrophy, IM and dysplasia. PERSPECTIVES AND CONCLUSIONS: Today a plausible program for GC prevention means: (1) a correct dietary habit since childhood increasing vegetables and fruit intake, (2) a decrease of H. pylori spread improving family and community sanitation and hygiene, (3) a search and treat H. pylori strategy in offspring of GC, (4) a search and treat H. pylori strategy in patients with chronic atrophic gastritis and intestinal metaplasia (IM), (5) a careful endoscopic and histologic follow-up if precancerous lesions persist irrespective of H. pylori eradication

The human gastric microbiota: Is it time to rethink the pathogenesis of stomach diseases?

NTRODUCTION: Although long thought to be a sterile organ, due to its acid production, the human stomach holds a core microbiome. AIM: To provide an update of findings related to gastric microbiota and its link with gastric diseases. METHODS: We conducted a systematic review of the literature. RESULTS: The development of culture-independent methods facilitated the identification of many bacteria. Five major phyla have been detected in the stomach: Firmicutes, Bacteroidites, Actinobacteria, Fusobacteria and Proteobacteria. At the genera level, the healthy human stomach is dominated by Prevotella, Streptococcus, Veillonella, Rothia and Haemophilus; however, the composition of the gastric microbiota is dynamic and affected by such factors as diet, drugs and diseases. The interaction between the pre-existing gastric microbiota and Helicobacter pylori infection might influence an individual's risk of gastric disease, including gastric cancer. CONCLUSIONS: The maintenance of bacterial homeostasis could be essential for the stomach's health and highlights the chance for therapeutic interventions targeting the gastric microbiota, even if gastric pH, peristalsis and the mucus layer may prevent bacteria colonization; and the definition of gastric microbiota of the healthy stomach is still an ongoing challenging task

Non-Steroidal Anti-Inflammatory Drugs in the Carcinogenesisof the Gastrointestinal Tract

It is estimated that underlying infections and inflammatory responses are linked to 15–20% of all deaths from cancer worldwide. Inflammation is a physiologic process in response to tissue damage resulting from microbial pathogen infection, chemical irritation, and/or wounding. Tissues injured throughout the recruitment of inflammatory cells such as macrophages and neutrophils, generate a great amount of growth factors, cytokines, and reactive oxygen and nitrogen species that may cause DNA damage that in turn predisposes to the transformation from chronic inflammation to neoplasia. Cyclooxygenase (COX), playing a key role in cell homeostasis, angiogenesis and tumourigenesis, may represent the link between inflammation and cancer. Currently COX is becoming a pharmacological target for cancer prevention and treatment

Protective effects of Lactobacillus paracasei F19 in a rat model of oxidative and metabolic hepatic injury

The liver is susceptible to such oxidative and metabolic stresses as ischemia-reperfusion (I/R) and fatty acid accumulation. Probiotics are viable microorganisms that restore the gut microbiota and exert a beneficial effect on the liver by inhibiting bacterial enzymes, stimulating immunity, and protecting intestinal permeability. We evaluated Lactobacillus paracasei F19 (LP-F19), for its potential protective effect, in an experimental model of I/R (30 min ischemia and 60 min reperfusion) in rats fed a standard diet or a steatogen [methionine/choline-deficient (MCD)] diet. Both groups consisted of 7 sham-operated rats, 10 rats that underwent I/R, and 10 that underwent I/R plus 8 wk of probiotic dietary supplementation. In rats fed a standard diet, I/R induced a decrease in sinusoid perfusion (P < 0.001), severe liver inflammation, and necrosis besides an increase of tissue levels of malondialdehyde (P < 0.001), tumor necrosis factor-alpha (P < 0.001), interleukin (IL)-1beta (P < 0.001), and IL-6 (P < 0.001) and of serum levels of transaminase (P < 0.001) and lipopolysaccharides (P < 0.001) vs. sham-operated rats. I/R also induced a decrease in Bacterioides, Bifidobacterium, and Lactobacillus spps (P < 0.01, P < 0.001, and P < 0.001, respectively) and an increase in Enterococcus and Enterobacteriaceae (P < 0.01 and P < 0.001, respectively) on intestinal mucosa. The severity of liver and gut microbiota alterations induced by I/R was even greater in rats with liver inflammation and steatosis, i.e., MCD-fed animals. LP-F19 supplementation significantly reduced the harmful effects of I/R on the liver and on gut microbiota in both groups of rats, although the effect was slightly less in MCD-fed animals. In conclusion, LP-F19 supplementation, by restoring gut microbiota, attenuated I/R-related liver injury, particularly in the absence of steatosis

Contribution of gut microbiota to colonic and extracolonic cancer development.

It is estimated that 20% of malignancies worldwide can be attributed to infections, i.e. about 1.2 million cases per year. A typical example of the association between bacterial infection and gastrointestinal malignancies is Helicobacter pylori infection with both gastric cancer and mucosa-associated lymphoid tissue lymphoma. Bacteria are an important component of the human body. The human intestine contains >500 different types of microorganisms, the 'gut microbiota', that play important functions such as energetic metabolism, proliferation and survival of epithelial cells, and protection against pathogens. Chronic alteration of intestinal microbiota homeostasis, 'dysbiosis', could promote many diseases, including cancer. The mechanisms by which bacteria may induce carcinogenesis include chronic inflammation, immune evasion, and immune suppression. There are three effector pathways of T helper (Th) cell differentiation: Th1 responses promoted by procarcinogenic signal transducer and activator of transcription (Stat)1 and Stat4 signaling, Th2 responses promoted by Stat6 signaling, and Th17 responses promoted by Stat3 signaling. Interestingly, Th1 responses, driven by IL-12 and characterized by IFN-γ production, are typically anticarcinogenic, whereas Th17 responses are activated in various cancers. Furthermore, a T regulatory response, driven by IL-10 and TGF-β, counterbalances the proinflammatory effect of Th17 responses. Elevated numbers of T regulatory cells suppress the innate and adaptive immune responses, thereby contributing to tumor progression. The emerging relationship between gut microbiota and cancer has prompted new ways of thinking about cancer prevention and has led to the development of noninvasive diagnostic tests and innovative treatments, such as with probiotics. However, although in vitro and animal model studies suggest a protective anticancer effect of probiotics, the results of human epidemiological studies are controversial

The bacteria hypothesis of colorectal cancer: pathogenetic and therapeutic implications

It is estimated that up to 20% of malignancies worldwide can be attributed to infections. The most convincing evidence, in this context, is the link between Helicobacter pylori and both gastric cancer and mucosa-associated lymphoid tissue (MALT) lymphoma. A growing body of evidence in the last years has raised up the question of the putative causal role of gut microbiota in the carcinogenetic process. Bacteria are an important component of the human body. The human intestine contains >500 different types of microorganisms, usually referred to as the commensal intestinal microbiota. A chronic alteration of the intestinal microbiota homeostasis or dysbiosis” underlies many diseases, including cancer. The main mechanisms by which bacteria may induce carcinogenesis include chronic inflammation, immune evasion and immune suppression. If the microbiota is involved in cancer development, being the colon the site where the microbiota reaches its highest concentration, it is expected to be its major site of action. Numerous data from experimental, animal model and human studies support the gut-bacteria hypothesis of colorectal cancer (CRC). Germ-free rats, compared with conventionally reared animals, develop fewer and smaller tumors both spontaneously and after chemically-induced CRC. The absence of the physiological inflammation caused by the commensal microbiota may explain the capability of the germ-free rats to develop a more efficacious anti-cancer immune response. Several microorganisms, including Streptococcus bovis, Bacteroides fragilis and Escherichia coli have been implicated in the pathogenesis of CRC. The emerging relationship between gut microbiota and cancer prompts new ways of thinking about cancer prevention and leads to the development of innovative treatments such as probiotics. However, although in vitro and animal model studies suggest a protective anticancer effect of probiotics, the results of human epidemiological studies are still controversial and very few data are available from interventional studies

Cancer stem cell hypothesis and gastric carcinogenesis: Experimental evidence and unsolved questions

Traditionally, the clonal evolution model has been used to explain gastric cancer (GC) growth dynamics. According to this model, GC cells result from multiple mutations over time resulting in a population of continually diversifying cells. This heterogeneity enables the survival of different clones under particular conditions allowing growth at metastatic locations or resistance to chemotherapeutics. Cancer stem cell (CSC) theory completely overturns this traditional understanding of cancer suggesting that only CSCs can self-renew and promote tumor growth. CSCs are relatively refractory to conventional therapies, thus explaining why anti-cancer therapies are far from curative and why relapses of cancer are frequent. The identification of the CSC component of a tumor might, thus, open new therapeutic perspective based on the selective targeting of this small population of cells. In this review we examine the current scientific evidence supporting the existence of CSC in gastric tumors and analyze the main unsolved questions of this difficult field of cancer research

The Psyche and Gastric Functions

Although the idea that gastric problems are in some way related to mental activity dates back to the beginning of the last century, until now it has received scant attention by physiologists, general practitioners and gastroenterologists. The major breakthrough in understanding the interactions between the central nervous system and the gut was the discovery of the enteric nervous system (ENS) in the 19th century. ENS (also called 'little brain') plays a crucial role in the regulation of the physiological gut functions. Furthermore, the identification of corticotropin-releasing factor (CRF) and the development of specific CRF receptor antagonists have permitted to characterize the neurochemical basis of the stress response. The neurobiological response to stress in mammals involves three key mechanisms: (1) stress is perceived and processed by higher brain centers; (2) the brain mounts a neuroendocrine response by way of the hypothalamic-pituitary-adrenal axis (HPA) and the autonomic nervous system (ANS), and (3) the brain triggers feedback mechanisms by HPA and ANS stimulation to restore homeostasis. Various stressors such as anger, fear, painful stimuli, as well as life or social learning experiences affect both the individual's physiologic and gastric function, revealing a two-way interaction between brain and stomach. There is overwhelming experimental and clinical evidence that stress influences gastric function, thereby outlining the pathogenesis of gastric diseases such as functional dyspepsia, gastroesophageal reflux disease and peptic ulcer disease. A better understanding of the role of pathological stressors in the modulation of disease activity may have important pathogenetic and therapeutic implication

A microbiota-centric view of diseases of the upper gastrointestinal tract

The distinctive anatomy and physiology of the upper gastrointestinal tract and the difficulty of obtaining samples led to the theory that it was bacteria free. However, multiomics studies are indicating otherwise. Although influenced by both oral and gastric bacteria, the resident microbial ecosystem in the oesophagus is dominated by Streptococcus. A shift from Gram-positive to Gram-negative bacteria occurs in oesophagitis and Barrett's oesophagus, and this shift might be involved in the pathogenesis of oesophageal adenocarcinoma. The gastric microenvironment is populated by microbial communities mainly of the Firmicutes, Actinobacteria, Bacteroidetes, and Proteobacteria phyla and species of the Lactobacillus, Streptococcus, and Propionibacterium genera. The composition of gastric microbiota is highly dynamic, and is influenced by acid suppression, gastric inflammation, and Helicobacter pylori. Duodenal microbes are also implicated in the onset and outcome of coeliac disease. Bacteria of the genera Bacteroides, Clostridium, and Staphylococcus dominate the duodenal flora in active coeliac disease whereas lactobacilli and bifidobacteria decrease. Although knowledge of the composition of the microbiota of the upper gastrointestinal tract has advanced substantially, this information is far from being translated to the clinical setting. In this Review, we assess the data related to the potential contribution of microbes to the susceptibility for and pathogenesis of upper gastrointestinal diseases