CLDN18, or Claudin-18, is a protein produced by the CLDN18 gene. It belongs to the claudin family. This protein helps maintain the structure and function of various cells throughout the body. CLDN18 contributes to bodily processes by forming barriers and regulating cellular activities.
Understanding Claudin Proteins and Tight Junctions
Claudin proteins are integral membrane proteins, embedded within the cell membrane. These proteins are fundamental components of tight junctions, which are present in epithelial cells. Epithelial cells form sheets that line body cavities and external surfaces, such as the skin, digestive tract, and lungs.
Tight junctions function as a physical barrier between cells, controlling what substances can pass through them. They regulate the movement of solutes and water, ensuring that tissues maintain their proper internal environment. These junctions also help maintain cell polarity, keeping the distinct top and bottom sides of a cell organized for specific functions.
Specific Roles of CLDN18 in the Body
CLDN18 exists in two variants due to alternative splicing. Claudin-18a1 is found predominantly in the lung, while claudin-18a2 is highly expressed in the stomach. These distinct locations suggest specialized functions for each variant.
CLDN18 contributes to several physiological processes beyond its general role in tight junctions. In the lungs, it helps maintain fluid balance in air sacs (alveolar fluid homeostasis) and aids in their development (lung alveolarization). CLDN18 also regulates the growth of epithelial progenitor cells, which can develop into various mature cell types. Additionally, CLDN18 negatively regulates the differentiation of osteoclasts, cells responsible for breaking down bone tissue.
CLDN18 and Human Disease
Changes in CLDN18 expression or function have been linked to several human diseases, particularly various cancers. Claudin 18.2, which is isoform 2 of CLDN18, is frequently found in high amounts in gastric tumors, making it a notable marker in gastric and gastroesophageal junction cancers.
CLDN18 is also upregulated in patients with ulcerative colitis, a chronic inflammatory bowel disease. It is found in infiltrating ductal adenocarcinomas and may play a role in biliary carcinogenesis (cancer development in the bile ducts). Research also links CLDN18 to a less favorable outlook for patients with colorectal cancer.
CLDN18 as a Therapeutic Target
The specific expression patterns and roles of CLDN18 in diseases make it an area of interest for new treatments. Claudin 18.2, in particular, is a promising target for therapies, especially in gastric and gastroesophageal junction cancers. The protein’s unique exposure on the surface of malignant cells, which is typically hidden in healthy tissues, makes it accessible for drug intervention.
One example of a therapeutic approach is the drug Zolbetuximab. This medication specifically targets Claudin 18.2. By binding to CLDN18.2 on cancer cells, Zolbetuximab aims to initiate an immune response that destroys tumor cells. Clinical trials have shown that Zolbetuximab, when combined with chemotherapy, can improve outcomes for patients with CLDN18.2-positive, HER2-negative gastric or gastroesophageal junction adenocarcinomas.