Claudin 18.2 Gastric Cancer: Mechanisms and Prognostic Impact

Claudin 18.2 is an emerging biomarker in gastric cancer research, gaining attention for its role in tumor progression and potential as a therapeutic target. As a tight junction protein variant, it is normally restricted to gastric epithelial cells but becomes aberrantly expressed in malignancies, making it a promising focus for diagnostics and treatment strategies.

Biological Mechanisms

Claudin 18.2, a splice variant of the CLDN18 gene, plays a structural role in maintaining gastric epithelial tight junctions. Under normal conditions, it is exclusively expressed in differentiated gastric mucosal cells, contributing to a selective permeability barrier. This localization is tightly controlled, preserving the distinct function of the gastric epithelium. However, during malignant transformation, regulatory mechanisms break down, leading to its aberrant presence in neoplastic cells. This shift is associated with the loss of epithelial polarity and increased cellular plasticity, both hallmarks of tumor progression.

Dysregulation of Claudin 18.2 in gastric cancer is linked to alterations in tight junction architecture, facilitating tumor cell detachment and invasion. Studies indicate that downregulation of tight junction components correlates with increased metastatic potential. However, Claudin 18.2 persists in transformed cells, potentially due to epigenetic modifications or changes in transcriptional control. This persistence may contribute to tumor cell cohesion in early-stage lesions while also enabling localized breaches in adhesion that promote dissemination.

Beyond its structural role, Claudin 18.2 influences intracellular signaling pathways linked to tumorigenesis. Aberrant expression has been shown to modulate oncogenic pathways, including Rho GTPases, which regulate cytoskeletal dynamics and cell motility. Additionally, interactions with other tight junction proteins may activate PI3K/AKT and MAPK pathways, both commonly dysregulated in gastric cancer. These pathways enhance proliferation, survival, and resistance to apoptosis, reinforcing the malignant phenotype.

Expression Patterns in Gastric Tissues

Claudin 18.2 is normally confined to differentiated epithelial cells lining the gastric mucosa, maintaining the stomach’s barrier function. Immunohistochemical analyses of healthy gastric tissues reveal strong membranous staining on the luminal surface of gastric glands, with little to no expression in other gastrointestinal or extra-gastrointestinal compartments. This restricted distribution is due to tissue-specific regulation of the CLDN18 gene, which is active in gastric epithelial cells that have not undergone intestinal metaplasia or neoplastic transformation.

In gastric cancer, Claudin 18.2 is frequently detected beyond its native epithelial boundaries, appearing in both primary tumors and metastatic lesions. Immunohistochemistry and RNA sequencing studies indicate that up to 70% of gastric adenocarcinomas exhibit moderate to strong Claudin 18.2 expression, with a subset showing nearly uniform positivity across tumor cells. Notably, its expression varies by histological subtype; diffuse-type gastric carcinomas, characterized by poorly cohesive cells, tend to express lower levels compared to intestinal-type tumors, which retain more defined epithelial features.

The spatial distribution of Claudin 18.2 within tumors is also heterogeneous. Some studies report stronger staining at the invasive front, suggesting a link to tumor progression. This pattern may reflect microenvironmental influences such as hypoxia or stromal interactions, which modulate tight junction protein expression. Additionally, metastatic lesions in lymph nodes and distant organs frequently maintain Claudin 18.2 positivity, reinforcing its potential as a therapeutic target.

Role in Malignant Transformation

The transition from normal gastric epithelium to malignancy involves molecular and structural alterations, with Claudin 18.2 playing a role in this process. As epithelial cells transform, their adhesive properties shift, disrupting gastric mucosal organization. Claudin 18.2, normally restricted to differentiated gastric cells, becomes aberrantly expressed in neoplastic contexts, coinciding with the loss of epithelial polarity and the acquisition of invasive traits.

The persistence of Claudin 18.2 during tumor progression suggests a complex interplay between its structural role and cellular plasticity. Unlike many tight junction proteins that are downregulated to promote invasion, Claudin 18.2 remains detectable in a significant proportion of gastric tumors. This retention may be influenced by epigenetic modifications or oncogenic signaling pathways that sustain its expression despite broader tight junction disruption.

Claudin 18.2 dysregulation extends beyond adhesion, as altered expression has been linked to increased motility and tumor cell dissemination. Experimental models show that Claudin 18.2 influences cytoskeletal reorganization, facilitating a transition from an epithelial to a more migratory phenotype. This shift is particularly evident in invasive tumor fronts, where cells exhibit partial epithelial-mesenchymal transition (EMT) characteristics. The ability of Claudin 18.2-expressing cells to retain adhesion while acquiring motile properties underscores its dual role in maintaining tumor integrity and enabling metastasis.

Clinicopathologic Correlations

Claudin 18.2 expression in gastric cancer correlates with tumor histology, disease stage, and patient prognosis. It is more frequently observed in well-differentiated and moderately differentiated adenocarcinomas, where tumor cells retain epithelial characteristics. In contrast, poorly cohesive carcinomas, including signet ring cell variants, tend to exhibit lower or more heterogeneous expression, suggesting a link between Claudin 18.2 levels and tumor differentiation.

Beyond histology, Claudin 18.2 expression has been associated with tumor invasion depth and lymph node involvement. Analyses of resected gastric cancer specimens indicate that strong Claudin 18.2 positivity is more common in advanced T stages, suggesting a role in disease progression. However, its relationship with lymphatic or distant metastasis remains unclear, with conflicting reports regarding its association with nodal spread. These inconsistencies may stem from differences in detection methods, patient populations, or tumor microenvironmental factors.

Approaches for Laboratory Testing

Detection of Claudin 18.2 in gastric cancer relies on standardized laboratory techniques assessing protein expression in tumor tissues. Immunohistochemistry (IHC) is the most widely used method, providing a practical approach for evaluating Claudin 18.2 levels in formalin-fixed, paraffin-embedded (FFPE) specimens. Antibodies specific to Claudin 18.2 bind to the protein, allowing visualization within tumor cells. Scoring systems consider staining intensity and the percentage of positive cells, with strong expression typically defined by membranous staining in more than 50% of tumor cells. While IHC provides valuable data, variability in staining protocols and interpretation criteria underscores the need for standardized guidelines.

Beyond IHC, molecular techniques such as quantitative PCR and RNA sequencing assess Claudin 18.2 expression at the transcriptional level. These methods offer higher sensitivity and detect subtle gene expression changes that may not be evident at the protein level. However, because post-transcriptional modifications influence protein availability, mRNA-based assays are generally considered complementary rather than definitive diagnostic tools. Mass spectrometry-based proteomics has also been explored for quantification, though its application remains primarily in research settings. As targeted therapies against Claudin 18.2 gain clinical relevance, refining laboratory testing methodologies will be essential for identifying patients most likely to benefit.

Prognostic Considerations

The prognostic significance of Claudin 18.2 expression in gastric cancer remains under investigation, with studies yielding variable findings. Some suggest that high expression correlates with more aggressive tumor behavior, including deeper invasion and a greater likelihood of lymph node metastasis. In these cases, strong expression may reflect a tumor phenotype that retains epithelial adhesion while facilitating localized invasion, contributing to disease progression.

Conversely, other analyses indicate that patients with Claudin 18.2-positive tumors experience longer overall survival, particularly in well-differentiated cases. This apparent contradiction highlights the context-dependent nature of Claudin 18.2’s role in tumor biology, where its influence on prognosis may vary based on molecular subtypes and coexisting genetic alterations.