Diffuse gastric cancer: Emerging mechanisms of tumor initiation and progression

Gastric cancer is globally the fourth leading cause of cancer-related deaths. Patients with diffuse-type gastric cancer (DGC) particularly have a poor prognosis that only marginally improved over the last decades, as conventional chemotherapies are frequently ineffective and specific therapies are unavailable. Early-stage DGC is characterized by intramucosal lesions of discohesive cells, which can be present for many years before the emergence of advanced DGC consisting of highly proliferative and invasive cells. The mechanisms underlying the key steps of DGC development and transition to aggressive tumors are starting to emerge. Novel mouse and organoid models for DGC, together with multi-omic analyses of DGC tumors, revealed contributions of both tumor cell-intrinsic alterations and gradual changes in the tumor microenvironment to DGC progression. In this review, we will discuss how these recent findings are leading towards an understanding of the cellular and molecular mechanisms responsible for DGC initiation and malignancy, which may provide opportunities for targeted therapies.

Automated summary

Gastric cancer is the fourth leading cause of cancer-related deaths worldwide, and patients with diffuse-type gastric cancer have a poor prognosis with limited effectiveness of conventional chemotherapies. However, recent advancements in mouse and organoid models, as well as multi-omic analyses, are shedding light on the mechanisms responsible for DGC initiation and progression, offering potential opportunities for targeted therapies.