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Gastric adenocarcinoma is the most common type of pathology in gastric cancer (about 90% of all gastric cancers). The occurrence of gastric adenocarcinoma begins with the normal gastric mucosa and undergoes a gradual development process of "chronic inflammation→ atrophic gastritis→ intestinal metaplasia→ dysplasia (intraepithelial neoplasia)", each stage is accompanied by abnormal accumulation at the molecular level. The core mechanism can be divided into three major links: external triggering, chronic inflammatory drive, and molecular genetic abnormalities [1, 2].

External environmental factors are the core causes of gastric adenocarcinoma, among which Helicobacter pylori (Hp) infection is the most definitive class I carcinogenic factor (identified by WHO), and other factors exacerbate damage through synergistic or superimposing effects, such as long-term intake of a high-salt diet and genetic predisposition [3].

• Mucosal barrier destruction and epithelial atrophy: inflammatory factors (such as IL-1β, TNF-α) inhibit the proliferation and differentiation of gastric mucosal epithelial cells, leading to fundic gland atrophy (decreased gastric acid secretion), further reducing the resistance of the mucosa to damaging factors;

• Intestinal metaplasia (IM): In order to adapt to the environment of gastric acid reduction, the gastric mucosal epithelium is replaced by the intestinal epithelium (such as the appearance of goblet cells and absorbing cells), and this process is accompanied by changes in gene expression patterns (such as the expression of intestinal epithelial markers such as CDX2 and MUC2 is up-regulated), and the intestinal metaplasia epithelium has higher proliferative activity and is more prone to accumulation of mutations.

• Dysplasia (intraepithelial neoplasia): Intestinal metaplasia further develops, epithelial cells have morphological and structural abnormalities (such as large nuclei, obvious nucleoli, and disordered arrangement), and cell proliferation is out of control (such as elevated Ki-67 index), but has not yet broken through the basement membrane (belongs to "precancerous lesions"), this stage is a key node in reversing cancer, and if not intervened, about 5%-10% of moderate to severe dysplasia will progress to adenocarcinoma within 5 years [4].

With the accumulation of mucosal damage, gastric mucosal cells gradually develop genetic mutations, chromosomal abnormalities, and epigenetic changes, ultimately leading to malignant phenotypes such as "unlimited proliferation, anti-apoptosis, and invasive metastasis".

• RAS-MAPK pathway activation: Approximately 10%-20% of gastric adenocarcinomas have KRAS or NRAS gene mutations, leading to continuous activation of the pathway, promoting cell proliferation and inhibiting apoptosis.

• PI3K-AKT-mTOR pathway activation: Approximately 30%-40% of gastric adenocarcinomas have PIK3CA gene mutations (encoding PI3K catalytic subunits) or PTEN gene inactivation (negatively regulating the PI3K pathway), which can promote cell metabolism, angiogenesis and invasion after pathway activation.

• TP53 gene mutation: One of the most common mutations in gastric adenocarcinoma (incidence of about 50%-60%), TP53 is the "genome guardian" that loses the function of DNA damage repair and induce apoptosis after mutation, allowing abnormal cells to survive and accumulate more mutations;

• Epstein-Barr virus (EBV) infection: Approximately 10% of gastric adenocarcinomas are associated with EBV infection (EBV-associated gastric cancer), which activates pathways such as NF-κB and PI3K by encoding proteins such as latent membrane protein 1 (LMP1), promoting inflammation and cell proliferation, while EBV infection can lead to abnormal DNA methylation (such as silencing tumor suppressor genes) [5].

• DNA methylation: For example, the hypermethylation of the promoter region of tumor suppressor genes p16INK4a and MLH1 leads to gene silencing (unable to express proteins) and losing cell cycle regulation and DNA repair functions, respectively.

• Histone modifications: such as histone deacetylate (HDAC) leads to chromatin concentration, and transcription of tumor suppressor genes is inhibited.

• CAFs secrete ECM components such as collagen and fibronectin, forming a physical barrier that prevents immune cell infiltration. At the same time, it secretes cytokines such as IL-6 and TGF-β to promote the proliferation and invasion of tumor cells.

• Immunosuppressive cells (such as Tregs) secrete IL-10, TGF-β, which inhibit effector T cell function, leading to "immune escape" and allowing tumor cells to grow.

Diagram: Pathogenesis of Gastric Adenocarcinoma (Hp infection, high-salt diet, inflammatory response, genetic & epigenetic changes)

Flora Flora is a technical support expert at EnkiLife, familiar with immunology and neuroscience, dedicated to providing customers with high-quality product combinations and technical support to help achieve research in neurodegenerative diseases and other neuroscience areas.

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