Claudin18.2: An Emerging Stomach Cancer Biomarker

A biomarker refers to any biological characteristic found in your tissues or bodily fluids that can be measured and evaluated objectively. Examples of biomarkers used in clinical practice include your blood pressure and heart rate.

Biomarkers serve as indicators of normal or abnormal processes, conditions, or diseases such as cancer. In oncology, biomarkers can come in the form of proteins, nucleic acids (DNA and RNA) and many other biological molecules derived from your blood, urine, saliva, and tumor tissues.

These biomarkers are typically involved in the formation of cancer or are released due to the presence of the disease. Therefore, testing for cancer biomarkers in your blood or tissue samples can reveal important details about the cancer you’ve been diagnosed with.

Claudins are a family of transmembrane proteins present throughout our bodies. They are embedded in our cell membranes and typically function as gateways, permitting the transport of specific substances across the membranes. Different types of claudins are expressed in different tissues, which include gastric, pancreatic and lung tissues.

One member of this protein family is Claudin18.2 and it is predominantly expressed in epithelial cells lining the gastric mucosa. Its role is to control the movement of molecules between the epithelial cells and maintain the barrier function of the gastric mucosa by promoting cell-cell adhesion and cell polarity. In normal and healthy gastric epithelial tissues, adjacent epithelial cells in the gastric mucosa stick together to form organized tissues which makes Claudin18.2 largely inaccessible as it would be embedded in tight junctions between the cells. However, perturbations to the gastric mucosa due to cancer exposes the Claudin18.2 proteins and enables detection of the aberrant epithelial cells.

Claudin18.2 overexpression has been identified in various types of cancer, such as gastric, esophageal, and pancreatic cancers. In the case of stomach (or gastric) cancer, Claudin18.2 is found not only in primary gastric tumors but also in metastatic disease.

In normal and healthy tissue, adjacent epithelial cells in the gastric mucosa stick together to form organized tissues in cell-cell adhesion. However, when these cells turn cancerous, they lose their normal structure and cell-cell adhesion may be disrupted. This exposes Claudin18.2 proteins on the surfaces of the epithelial cells, where they can be readily detected.

The aberrant expression of Claudin18.2 in these tumor tissues disrupts the tight junctions between the gastric epithelial cells. Tight junctions are protein complexes that act as barriers between two neighboring epithelial cells. They prevent any leakage of substances through the cell membranes. When these tight junctions are dysfunctional, it can affect numerous cell signaling pathways, some of which are involved in cancer progression. For this reason, Claudin18.2 was reported to contribute to various carcinogenic processes, such as cancer cell proliferation and migration.

Diagnosing CLDN18.2-positive gastric cancers

Diagnosing gastric cancers with Claudin18.2 overexpression starts with biomarker testing, also commonly known as molecular testing or tumor profiling. These comprehensive tests carried out on your tumor tissues can determine whether your cancer cells express high amounts of Claudin18.2. The molecular technique routinely used to measure expression levels of Claudin18.2 in cells is called an immunohistochemistry (IHC) staining.

Determining Claudin18.2 levels in gastric cancers

Results of Claudin18.2 IHC testing are reported on a scale from 0 to 3+. The higher the number, the greater the amount of Claudin18.2 protein expressed.

• 0: Claudin18.2 is not expressed by the cancer cells.
• 1+: Low levels of Claudin18.2 expression.
• 2+: Moderate levels of Claudin18.2 expression.
• 3+: Strong levels of Claudin18.2 expression.

Claudin18.2 positivity is defined as ≥75% of tumor cells in the biopsy sample demonstrating moderate to strong Claudin18.2 expression in the IHC staining.

Targeting Claudin18.2 for cancer treatment

Claudin18.2 is not feasible as a drug target when it is confined to the tight junctions between cells in healthy gastric epithelium. However, the exposure of Claudin18.2 on the cell surface of cancerous epithelial cells makes it available for binding and enables it to be a druggable target. Coupled with the protein’s abnormal overexpression in gastric cancer, Claudin18.2 becomes an attractive and novel target for targeted cancer therapy. Moreover, the inaccessibility of Claudin18.2 in normal and healthy tissues suggests that off-target effects can be significantly reduced.

A type of targeted drug therapy known as monoclonal antibodies can be used to target Claudin18.2. In the context of gastric cancer, these antibodies, which are man-made versions of immune system proteins, can recognise and bind to Claudin18.2 exposed on the surface of gastric cancer cells. This binding will then trigger cell death and thus, slow the growth of the cancer cells.

Numerous monoclonal antibodies targeting Claudin18.2 are currently being studied in clinical trials. Zolbetuximab is one of such drugs that has shown particularly promising results and is expected to be approved for use in gastric cancer in the near future.

Claudin18.2 as a gastric cancer biomarker

High expression levels of Claudin18.2 in cancer cells have been associated with a better response to Claudin18.2-targeted therapy thus, making it an attractive predictive biomarker of treatment response in gastric cancer. However, high Claudin18.2 expression was more frequently reported in diffuse types of gastric cancer. Therefore, more research needs to be done on this unique molecular target before it cements itself as an established gastric cancer biomarker. Nevertheless, this is encouraging news for the future of cancer treatments as it expands the options available to patients and may potentially improve the treatment outcomes for those affected.