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PubMed2026

Reframing early gastric carcinogenesis through lineage, niche, and evolution.

Early gastric cancer is still commonly conceptualized as the endpoint of a linear sequence from chronic gastritis to intestinal metaplasia, dysplasia, and invasion. Yet recent single-cell, spatial, genomic, and functional studies indicate that this model incompletely captures the biology of early gastric carcinogenesis. Malignant potential is established progressively within a precancerous gastric field already shaped by somatic evolution, chronic inflammatory injury, and epithelial lineage distortion. Within this field, progression is concentrated in a restricted set of precursor states, particularly incomplete, hybrid, and stem-like metaplastic populations that display plasticity, persistence, and increasing compatibility with a supportive microenvironment. Fibroblast niche remodeling, immune protection loss, endothelial rewiring, genomic instability, epigenetic drift, and selective retention of advantageous molecular alterations further promote malignant commitment. In parallel, diffuse gastric cancer appears to follow a distinct route that may arise independently of conventional intestinal metaplasia through E-cadherin-deficient epithelial transformation and downstream chromatin reprogramming. Here, we synthesize recent evidence to propose an updated framework for early gastric carcinogenesis based on field evolution, lineage instability, ecosystem support, and pathway divergence. Rather than replacing the classical Correa cascade, this framework seeks to refine it by shifting the unit of risk assessment from histologic stage alone to biologically defined precursor states shaped by lineage instability, clonal persistence, niche permissiveness, and pathway-specific molecular constraints. This perspective shifts the emphasis of prevention from detecting smaller cancers to identifying and intercepting biologically committed precursor states before invasion occurs.

Humans↗

PubMedDate not supplied

Role of therapy or monitoring in preventing progression to gastric cancer.

It is generally accepted that intestinal-type gastric adenocarcinoma arises through a multistep process originating with chronic gastritis, progressing through stages of atrophy, intestinal metaplasia, and dysplasia and finally invasive carcinoma. This sequential process, known as the "Correa cascade" is in many instances initiated by Helicobacter pylori infection and perpetuated by a number of environmental and host factors. Given that the development of carcinoma can be the end point of this sequential process, there is great interest in determining which if any of these steps may be reversible. Clinical studies have shown that the eradication of H. pylori can lead to resolution of chronic gastritis, and a few studies have suggested some improvement in gastric atrophy. Intestinal metaplasia, however, does not appear to be as reversible. Nevertheless, results of several intriguing studies of high-risk populations support the notion that eradication of H. pylori may decrease or delay progression to gastric carcinoma despite the inability to reverse all mucosal damage. The applicability of these findings to low-risk countries such as the United States and the United Kingdom remain uncertain. Currently, in the United States, there is no widely accepted screening program for H. pylori infection in asymptomatic individuals, and consensus regarding surveillance for gastric intestinal metaplasia or dysplasia is lacking. The purpose of this report is to evaluate the available data regarding the epidemiology of H. pylori and associated carcinoma, discuss relevant human and animal data that address eradication strategies in the prevention of gastric carcinoma, and finally discuss current recommendations regarding screening programs aimed at high-risk populations.

Adenocarcinoma↗

PubMed2002

Review article: intestinal metaplasia and gastric carcinogenesis.

Gastric intestinal metaplasia, an intermediate step in Correa's cascade of gastric carcinogenesis, is generally regarded as a pre-malignant lesion. Epidemiological studies suggest that patients with intestinal metaplasia have more than a 10-fold increased risk of developing gastric cancer. Within the subclassification of intestinal metaplasia, incomplete or type III intestinal metaplasia appears to be associated with even higher malignant potential. The topographical distribution of intestinal metaplasia may also have prognostic implications. Certain genetic and epigenetic alterations have been demonstrated in gastric intestinal metaplasia which straddle into gastric cancer. These findings suggest that genetic changes occur early in the multistep gastric carcinogenesis process. Unlike Barrett's oesophagus and colonic polyp, which have well-defined surveillance guidelines, there is no widely accepted surveillance programme for gastric intestinal metaplasia. An annual surveillance programme may allow early detection of gastric cancer, which theoretically may improve survival. It remains elusive whether the treatment of Helicobacter pylori infection may reverse gastric intestinal metaplasia or reduce the subsequent risk of cancer development. Further controlled studies with longer follow-up are needed to resolve this controversy. The role of chemo-prophylactic agents, e.g. cyclo-oxygenase-2 inhibitor, should be investigated.

Disease Progression↗

PubMed2006

Early diagnosis of early gastric cancer.

The prognosis of gastric cancer is closely related to the stage of disease at diagnosis. Early gastric cancer, whereby disease is limited to mucosa and submucosa, confers a survival rate of greater than 90% in 5 years in many centres. Gastric cancer is still a major cause of cancer mortality worldwide. In high incidence areas such as Japan, screening of asymptomatic population has been advocated. However, in Western countries, mass screening is not cost-effective. Hence, strategy has been directed to screen symptomatic individuals who are at higher risk of gastric cancer. Most patients with early gastric cancer present with symptoms indistinguishable from benign peptic ulcer disease. Screening for this group of patients improves detection rate of early gastric cancer and therefore its prognosis. Endoscopy for surveillance of premalignant lesions has been explored with this objective in mind. Serology testing for biomarkers such as pepsinogen, anti-Helicobacter pylori antibody and gastrin has been studied as an alternative to endoscopy. There is compelling evidence for the role of H. pylori in the initiation of Correa's cascade (stepwise progression from chronic active gastritis, atrophic gastritis, intestinal metaplasia, dysplasia and finally adenocarcinoma). Regression of premalignant lesions has been demonstrated with H. pylori eradication. However, it is not known whether this might effectively prevent gastric cancer in either low or high-risk population.

Early Diagnosis↗

PubMed2004

[Gastric preneoplastic changes].

Gastric cancer (GC) is the second most common cause of cancer related death worldwide. The 5-year relative survival rate ranges from 10 to 20% of cases. Therefore, it is necessary to diagnose gastric non invasive neoplasia (formerly dysplasia). Correa suggested more than 20 years ago that there was a histological cascade leading to GC: chronic active gastritis --> atrophy (AG) --> achlorydria with nitrocompounds increase --> intestinal metaplasia (IM) type I --> IM type III --> low grade dysplasia (LGD) --> high grade dysplasia (HGD) --> GC. The discovery of Helicobacter pylori infection has imposed a revision of the various pathogenetic stages: 1) GC may arise in the same context as IM and dysplasia, but without any documentable precursor. GC can develop in a context of normochloridria; 2) there are not sufficient data to support endoscopic surveillance for patients with AG; 3) there are doubts about the real necessity to operate histologically a subdivision of IM in subtypes: probably it is more important the extent of IM; 4) dysplasia is the only true histological marker of CG. In fact, LGD is associate or progressed to GC in the 9% of cases, HGD is associated or progressed to GC in the 74% of cases. It emerges the real oncologic risk of dysplasia. Such data are confirmed by immunohistochemical study of the dysplastic lesions. Therefore, an appropriate follow-up of non invasive neoplasia increases the likelihood of CG being detected in its potentially curable stage.

Cell Division↗

PubMed2006

Gastric cancer and Helicobacter pylori infection.

The Nobel prize in Physiology and Medicine in 2005 was presented to Barry Marshall and Robin Warren for their discovery of Helicobacter pylori (Hp), but only the involvement of this germ in gastritis and peptic ulcer has been mentioned in the award sentence, while numerous epidemiological, clinical and experimental studies and reports emphasized the crucial role of Hp in pathogenesis of gastric cancer (GC). This review is based on the old concept proposed by P. Correa much before the discovery of spiral bacteria in the stomach, postulating the cascade of mucosal changes from acute/chronic gastritis into the atrophic gastritis with intestinal metaplasia and finally to dysplasia and GC. It is now widely accepted view that Hp infection is the major initiator of the inflammatory and atrophic changes in gastric mucosa accompanied by an over-expression of certain growth factors such as gastrin as well as of cyclooxygenase-2 (COX-2) and anti-apoptotic proteins including survivin and B-cl(2), leading to proliferation of mutated atrophic cells, excessive angiogenesis, inhibition of apoptosis and formation of gastric tumour. All the morphological and biochemical changes associated with the transformation of mucosal cells into the cancer cells can be traced in excellent experimental model of gastric cancerogenesis induced by infection of Hp in Mongolian gerbils. Since the eradication therapy was proved in several prospective clinical trials to greatly reduce the incidence of GC and this was confirmed on the gerbil model of Hp-induced GC, it has been postulated; a) that Hp is the major causal factor in pathogenesis of GC and b) that the only rational approach in attempt to reduce the occurrence of GC is the global eradication of Hp.

Animals↗

PubMed2004

The sodium-driven flagellar motor controls exopolysaccharide expression in Vibrio cholerae.

Vibrio cholerae causes the life-threatening diarrheal disease cholera. This organism persists in aquatic environments in areas of endemicity, and it is believed that the ability of the bacteria to form biofilms in the environment contributes to their persistence. Expression of an exopolysaccharide (EPS), encoded by two vps gene clusters, is essential for biofilm formation and causes a rugose colonial phenotype. We previously reported that the lack of a flagellum induces V. cholerae EPS expression. To uncover the signaling pathway that links the lack of a flagellum to EPS expression, we introduced into a rugose flaA strain second-site mutations that would cause reversion back to the smooth phenotype. Interestingly, mutation of the genes encoding the sodium-driven motor (mot) in a nonflagellated strain reduces EPS expression, biofilm formation, and vps gene transcription, as does the addition of phenamil, which specifically inhibits the sodium-driven motor. Mutation of vpsR, which encodes a response regulator, also reduces EPS expression, biofilm formation, and vps gene transcription in nonflagellated cells. Complementation of a vpsR strain with a constitutive vpsR allele likely to mimic the phosphorylated state (D59E) restores EPS expression and biofilm formation, while complementation with an allele predicted to remain unphosphorylated (D59A) does not. Our results demonstrate the involvement of the sodium-driven motor and suggest the involvement of phospho-VpsR in the signaling cascade that induces EPS expression. A nonflagellated strain expressing EPS is defective for intestinal colonization in the suckling mouse model of cholera and expresses reduced amounts of cholera toxin and toxin-coregulated pili in vitro. Wild-type levels of virulence factor expression and colonization could be restored by a second mutation within the vps gene cluster that eliminated EPS biosynthesis. These results demonstrate a complex relationship between the flagellum-dependent EPS signaling cascade and virulence.

Animals↗

PubMed2003

Family history of gastric cancer: should we test and treat for Helicobacter pylori?

A close link has been established between infection and gastric cancer. In this article, we suggest that using a risk stratification technique (like that for colorectal cancer), the high-risk group of first-degree relatives of patients with gastric cancer can be separated out for testing and treatment. This would be more manageable and more cost-effective than screening the whole population, in which the mortality from distal gastric cancer has declined concomitant with the eradication of infection. Support for the feasibility of this approach is derived from studies showing that the family is the core unit of transmission and that childhood colonization, especially with a virulent strain, is apparently a major risk factor for disease progression to the neoplastic stage. When there is a case of gastric cancer in the family, first-degree relatives, who might be infected by a bacterium with an identical genetic fingerprint, are at higher risk than normal for developing gastric cancer. Furthermore, genetic and epidemiologic studies based on the Correa model have shown that both primary and secondary prevention of gastric cancer is possible. Calculations done in high-risk populations, such as Japanese-Americans, confirm the savings in cost and the safety of the test-and-treat strategy. Considering that eradication should be done as early as possible, at a point in the cascade when the changes are still reversible, and that gastric cancer is associated with a high mortality rate, we suggest that this strategy be applied to this high-risk population.

Helicobacter Infections↗

PubMed2006

Essential role of tuberous sclerosis genes TSC1 and TSC2 in NF-kappaB activation and cell survival.

The TSC1-TSC2 complex has recently been implicated in cell survival responses. We observed that NF-kappaB signaling is attenuated in TSC1- and TSC2-deficient MEFs concomitant with reduced survival following DNA damage or TNFalpha stimulation. Reconstitution of TSC2 expression in TSC2(-/-) MEFs rescued survival in an NF-kappaB activity-dependent manner. Furthermore, in TSC2(-/-) MEFs, the rapamycin-mediated inhibition of deregulated mTOR activity restored NF-kappaB activation and survival. This rapamycin-mediated effect was reversed by inhibition of NF-kappaB transcriptional activation or by inhibition of ERK1/2 MAP kinase or PI-3K pathways, which lie on signaling cascades that lead to NF-kappaB activation. These results provide evidence for a crosstalk between the TSC/Rheb/mTOR pathway and the NF-kappaB induction pathways and indicate that NF-kappaB functions as an important survival factor that regulates TSC2-dependent cell survival.

Animals↗

PubMed2006

Dopaminergic intracellular signal integrating proteins: relevance to schizophrenia.

Changes in dopaminergic function can be regulated by receptor-receptor interaction, or interaction with other proteins with dopamine receptors, and/or elements of the downstream signaling cascades. The complexity of dopaminergic signaling is far from being completely elucidated. It could, however, hold the key to the comprehension of the pathophysiology of neurological and psychiatric disorders, as well as to the identification of putative new targets for, and development of, more efficacious and selective drugs. Here, we review some of the current evidence and new ideas that are being proposed as a result, as well as future perspectives that are now being recognized.

Animals↗

PubMed1999

Evidence that thrombin present in lungs of patients with pulmonary metastasis may contribute to the development of the disease.

Early cellular events in the lung which may lead to the development of pulmonary metastases (PM) are still poorly understood. Thrombin, a key component of the coagulation cascade, may be involved in the development of PM as it has been shown to be an enhancer of platelet-tumor interaction in vitro and metastasis in vivo, and because it has been found in high levels in lungs from patients with PM. In this study, we assessed the potential role of thrombin in promoting PM by inducing an enhancement of tumor cell adhesion to platelets and tumor cell chemoinvasion and proliferation. We used bronchoalveolar lavage fluid (BALF) from 20 patients with PM. Results were compared with those from healthy controls. We found an enhancement of adhesion of PM-BALF-treated tumor cells to untreated platelets. BALF from patients with PM significantly increased chemoinvasion and proliferation in three human tumor cell lines. These activities were attenuated significantly by a thrombin inhibitor: hirudin. These results indicate that the thrombin present in the lungs of patients with PM is, at least in part, responsible for their adhesive, invasive and mitogenic activity on three different tumor cell lines. They also suggest that thrombin may be involved in the development of PM.

Adhesiveness↗