Emerging role of spasmolytic polypeptide-expressing metaplasia in gastric cancer

Gastric cancer (GC) ranks among the top five most diagnosed cancers globally, with particularly high incidence and mortality rates observed in Asian regions. Despite certain advancements achieved through early screening and treatment strategies in many countries, GC continues to pose a significant public health challenge. Approximately 20% of patients infected with Helicobacter pylori develop precancerous lesions, among which metaplasia is the most critical. Except for intestinal metaplasia (IM), which is characterized by goblet cells appearing in the stomach glands, one type of mucous cell metaplasia, spasmolytic polypeptide-expressing metaplasia (SPEM), has attracted much attention. SPEM represents a specific epithelial cell alteration within the gastric mucosa, characterized by the expressing trefoil factor 2 (TFF2) in basal glands, resembling the basal metaplasia of deep antral gland cells. It primarily arises from the transdifferentiation of mature chief cells, mucous neck cells (MNCs), or isthmus stem cells. SPEM is commonly regarded as a precursor lesion in the development of gastric inflammation and subsequent carcinogenesis. The formation of SPEM is intricately associated with chronic gastric inflammation, Helicobacter pylori infection, and various other environmental and genetic factors. Recently, with the profound exploration of the biological and molecular mechanisms underlying SPEM, a deeper understanding of its role in GC initiation and progression has emerged. This review summarizes the role, molecular mechanisms, and clinical significance of SPEM in the onset and progression of GC.