Molecular gastric carcinogenesis: formation of a protumor microenvironment in heritable connective (dysplasia) tissue disorders - Part II

A comprehensive review of contemporary Russian and international literature (PubMed, eLibrary, Scopus) is presented, integrating the author’s own observations collected over the past 20 years. The molecular mechanisms underlying the formation of the protumor stroma of the stomach are examined, including cases of hereditary connective tissue disorders (HCTD) such as Marfan syndrome and Marfan-like phenotypes (undifferentiated connective tissue dysplasia). The molecular mechanisms of the TGF-β signaling pathway are discussed, demonstrating a functional shift from tumor-suppressive to pro-oncogenic effects: transdifferentiation of fibroblasts and endothelial cells into tumor-associated fibroblasts (α-SMA⁺ myofibroblasts), activation of epithelial- and endothelial-to-mesenchymal transition, stimulation of angio- and lymphangiogenesis, and the formation of an immunosuppressive tumor microenvironment. A detailed analysis of gastric stromal remodeling toward an HCTD-associated protumor phenotype is provided, including original data (immunohistochemical assessment of TGF-β1, α-SMA, and type III collagen expression) confirming the key role of TGF-β-mediated fibrogenesis in establishing a unique model of the early stage of molecular HCTD-related gastric carcinogenesis. Part II presents evidence that constitutive hyperactivation of the TGF-β signaling pathway in HCTD is accompanied by altered functional activity of major stromal cell populations, leading to impaired epithelial restitution, pathological extracellular matrix remodeling, and early development of fibrotic changes in the gastric mucosa. Overexpression of TGF-β1, predominantly in the subepithelial stroma, correlated with an increase in α-SMA⁺ cells (r≈0.74; p<0.05) and accumulation of type III collagen (r≈0.3; p<0.02). Increased stiffness of the connective tissue matrix enhances mechanotransduction and TGF-β activation, forming a self-perpetuating cycle of stromal activation. The described changes define a morphogenetic variant of chronic gastritis with early signs of neoplastic transformation - multifocal atrophy and intestinal metaplasia - characterized in young HCTD patients by a fibrotic periglandular-subepithelial pattern that promotes accelerated progression along the Correa cascade under H. pylori-negative conditions. Translational research priorities are outlined, emphasizing the need for validation of TGF-β and related biomarkers as risk predictors, which opens perspectives for early screening, prevention, and the development of targeted therapeutic strategies.

gastric cancer, molecular carcinogenesis, heritable connective tissue disorders (HCTD), connective tissue dysplasia, Marfan syndrome, TGF-β, α-SMA, myofibroblasts, cancer-associated fibroblasts (CAF), type III collagen, stromal and extracellular matrix (ECM) remodeling, tumor microenvironment (TME), epithelial-mesenchymal transition (EMT), Endothelial-to-Mesenchymal Transition (EndMT), angiogenesis, lymphangiogenesis, fibrosis, gastric mucosal atrophy, intestinal metaplasia, gastric dysplasia, immunosuppression, Correa cascade, H. pylori-negative gastritis

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