Connective tissue dysplasias and the TGF-β paradox: a new concept of the H. pylori-independent Correa cascade (review, perspectives) and therapeutic targeting - Part III

Accumulating experimental and clinicopathological evidence supports the concept of an H. pylori-independent variant of the Correa cascade - an alternative pathway of gastric carcinogenesis observed in patients with heritable and undifferentiated connective tissue dysplasias (HCTD/UDCTD). Part III of the review summarizes both literature data and the author’s own findings supporting this concept. According to the proposed model, the initiating event of the pathological process is the chronic hyperactivation of the transforming growth factor-β (TGF-β) signaling pathway against the background of congenital structural deficiency of the extracellular matrix (ECM) - a phenomenon referred to as the “TGF-β paradox.” This condition gives rise to an H. pylori-independent variant of precancerous transformation of the gastric mucosa, characterized by a stepwise morphogenetic evolution from atrophy to intestinal metaplasia and dysplasia. Stromal mechanisms in HCTD/UDCTD create a protumorigenic microenvironment and accelerate neoplastic progression. The proposed concept expands the current etiopathogenetic paradigm of gastric cancer, identifying a distinct cohort of patients with HCTD/UDCTD who require early surveillance and personalized management. Clinical implications include targeted endoscopic risk stratification (OLGA/OLGIM), site-specific biopsy, and morphological verification of atrophic and metaplastic foci in patients with HCTD/UDCTD, irrespective of H. pylori status. Therapeutic implications encompass targeting of the TGF-β axis (TGF-βRI inhibitors, ligand traps, and combinations with immune checkpoint inhibitors), antifibrotic strategies (including sartans), as well as approaches directed toward cancer-associated fibroblasts (CAFs) and the extracellular and extracellular matrix remodeling. Priorities for translational research and evaluation of combined treatment regimens are outlined.

TGF-β, TGF-β paradox, TGF-β signaling hyperactivation, connective tissue dysplasia (HCTD/UDCTD), Marfan syndrome, Marfan-like phenotypes, extracellular matrix (ECM), fibrillin-1 (FBN1), TGF-β receptors (TGFBR1/2), cancer-associated fibroblasts (CAF), ECM remodeling, chronic gastritis, gastric mucosal atrophy, intestinal metaplasia, gastric dysplasia, Correa cascade, H. pylori-independent carcinogenesis, gastric cancer, immunosuppression, epithelial-mesenchymal transition (EMT), endothelial-mesenchymal transition (EndoMT), FAK/LOX axis, chemoresistance, targeted therapy, TGF-β inhibitors, sartans as an antifibrotic strategу

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