Role of claudin-6 in high-grade endometrial carcinoma: Implications for risk stratification and personalized treatment strategies

Abstract

This commentary discusses the groundbreaking study by Ebrahim et al on the role of claudin-6 (CLDN6) in high-grade endometrial carcinoma, addressing a significant gap in current knowledge. Their research reveals that overexpression of CLDN6 is linked to unfavorable pathological features. Moreover, multivariate analysis establishes CLDN6 as an independent predictor of disease-free survival, with a hazard ratio of 68.98. These results highlight the promise of CLDN6 in improving risk stratification and as a potential therapeutic target, especially with the development of CLDN6-directed antibody-drug conjugates. To advance CLDN6 towards clinical application, further validation in prospective patient cohorts and studies exploring its interactions with other molecular pathways are essential.

Key Words: Claudin-6; High-grade endometrial carcinoma; Risk stratification; Therapeutic target; Prognosis

Core Tip: This editorial focuses on the expression and clinical importance of the tight junction protein claudin-6 (CLDN6) in high-grade endometrial carcinoma. It demonstrates that CLDN6 overexpression independently correlates with aggressive pathological characteristics and poor patient outcomes. These findings underscore CLDN6’s value as a prognostic biomarker and highlight its potential as a therapeutic target, opening new possibilities for improved risk stratification and personalized treatment strategies in high-grade endometrial carcinoma.

INTRODUCTION

Endometrial cancer (EC) is the sixth most common cancer among women worldwide, with its incidence steadily increasing due to factors like obesity, metabolic syndrome, and an aging population[1]. Within its subtypes, high-grade endometrial carcinoma (HGEC), which includes type II carcinomas such as serous and clear cell carcinoma, carcinosarcoma, as well as dedifferentiated and undifferentiated carcinomas, accounts for a disproportionately high number of deaths despite its relatively low prevalence[2-4]. These tumors often harbor tumor protein 53 mutations and complex copy number alterations, contributing to their aggressive nature, early metastasis, and high rates of recurrence[5].

The current standard treatment for HGEC primarily involves radical surgical resection, often followed by adjuvant radiotherapy and/or chemotherapy[6,7]. Recent advances in precision medicine have introduced immunotherapy for select molecular subtypes[8], while personalized treatment approaches based on molecular profiles, such as tumor protein 53 and polymerase epsilon mutations, are actively being explored[5,9]. Prognostic evaluation integrates traditional histopathological classification[6,10], molecular subtyping according to The Cancer Genome Atlas[10,11], and biomarker analyses including programmed death ligand-1, L1 cell adhesion molecule, and microRNA profiles[12-14], alongside imaging surveillance and conventional tumor marker monitoring[15].

Despite advances, several challenges remain in managing HGEC. Response rates to standard adjuvant chemoradiotherapy[16] are not well established, and immunotherapy has demonstrated consistent effectiveness primarily in specific subgroups, such as deficient mismatch repair/microsatellite instability-high tumors[8]. Traditional pathological classification offers limited predictive accuracy for tumor behavior[10], while emerging biomarkers like L1 cell adhesion molecule[13] and autophagy-related genes still need validation through prospective studies[17].

In this context, a recent study by Ebrahim et al[18] published in the World Journal of Clinical Oncology, provides valuable new insights. Their research shows that overexpression of claudin-6 (CLDN6) is independently linked to aggressive pathological features and poor prognosis in HGEC. These results highlight CLDN6’s potential not only as a prognostic biomarker but also as a promising therapeutic target, offering opportunities to improve risk stratification and personalize treatment strategies for patients.

THE POTENTIAL MECHANISM OF CLDN6 IN TUMOR PROGRESSION

The claudin family consists of transmembrane proteins that serve as essential components of tight junctions. Comprising about 27 members, each with a molecular weight near 25 kDa, these proteins are vital for maintaining tissue barrier integrity by regulating paracellular permeability in epithelial and endothelial cells[19,20]. Claudins display tissue-specific expression patterns, often differing significantly between normal tissues and various cancers, making them promising candidates for cancer diagnostic biomarkers and therapeutic targets[19,21]. Among them, CLDN6 is minimally expressed in most healthy adult tissues but is markedly upregulated in several cancers, including ovarian and ECs, indicating its important role in tumor development[22,23].

The mechanisms driving CLDN6-mediated tumor progression are not yet fully understood, but current research suggests it promotes malignancy through multiple pathways. CLDN6 has been shown to enhance malignant characteristics in EC by recruiting and activating src family kinases. Its overexpression disrupts tight junction integrity, weakens cell-to-cell adhesion, and facilitates cancer cell migration, invasion, and metastasis[24-26]. Additionally, CLDN6 may influence the tumor microenvironment or contribute to immune evasion, indirectly supporting tumor growth[25,27]. Importantly, because of its tumor-specific overexpression and minimal expression in normal tissues, CLDN6 has emerged as a highly promising target for antibody-drug conjugates (ADCs) and chimeric antigen receptor T-cell (CAR-T) therapies[23,28].

Research on CLDN6 is still in early stages, with its molecular mechanisms and regulatory networks in cancer development requiring deeper exploration. In comparison to more extensively studied claudins like claudin-18.2, CLDN6 exhibits substantial clinical promise due to its exceptional tumor specificity. However, a systematic understanding of it signaling pathways and biological functions remains essential for advancing therapeutic applications.

HIGHLINGTS AND CLINICAL IMPLICATIONS OF THE STUDY

The study by Ebrahim et al[18] examines the expression and clinical relevance of the tight junction protein CLDN6 in HGEC. It addresses a key gap in understanding this protein’s role in such aggressive cancers while providing fresh insights into the invasive processes driving EC progression. Its primary contributions emerge in several key areas: First, the study by Ebrahim et al[18] clearly associates CLDN6 overexpression with several aggressive pathological features, including non-endometrioid histology, deep myometrial invasion, and lymph node metastasis, challenging the limitations of using histological grading and the International Federation of Gynecology and Obstetrics staging for prognosis. In multivariate analysis, patients with elevated CLDN6 expression faced a nearly 69-fold higher risk of recurrence and a 24-fold higher risk of death. These findings strongly support CLDN6 as an independent prognostic biomarker, offering a molecular foundation to guide personalized treatment strategies in HGEC. Second, the study effectively bridges clinical and basic research through its robust methodology. Researchers applied a semi-quantitative immunohistochemistry scoring system to assess CLDN6 expression, combining staining intensity with the proportion of positive tumor cells to yield an [immunoreactivity score (IRS), range 0-12]. Patients were then categorized into CLDN6-low (IRS < 8) and CLDN6-high (IRS ≥ 8) groups, with the system showing strong associations with tumor histology, stage, lymph node metastasis, and survival outcomes, reinforcing CLDN6’s practical and biological importance in HGEC.

However, several limitations and controversies warrant careful consideration. Although the exceptionally high hazard ratio (hazard ratio = 68.98) achieved statistical significance, its biological plausibility raises questions, possibly signaling collinearity in the multivariate model or sample bias. The retrospective design, modest sample size (n = 80), and absence of in vitro or in vivo functional validation further limit the findings’ generalizability. Notably, CLDN6 showed no significant difference in Kaplan-Meier survival curves yet emerged as a strong predictor in multivariate analysis. This may reflect the “hidden” prognostic role of CLDN6 within complex clinical settings, which still requires validation through larger, multi-center studies.

Table 1 summarizes the key findings of this research for quick reference. The study by Ebrahim et al[18] identifies CLDN6 as a novel biomarker while shedding new light on the aggressive biology of HGEC, establishing a foundation for tailored CLDN6-targeted therapies. Looking ahead, CLDN6 could enhance prognostic risk stratification and emerge as a precision therapy target, such as with ADCs or CAR-T cells, especially for HGEC patients facing limited options and poor outcomes.

Table 1 Summary of key findings and clinical implications of claudin-6 in high-grade endometrial carcinoma from Ebrahim et al[18].

Category	Key findings	Clinical implications
Study population and CLDN6 expression	Among 80 HGEC patients, 30% (n = 24) exhibited high CLDN6 expression (IRS ≥ 8). Strong histologic subtype association: High expression was predominantly found in aggressive subtypes like serous carcinoma (38%), carcinosarcoma (50%), and clear cell carcinoma, but was absent in high-grade endometrioid carcinoma	CLDN6 is aberrantly overexpressed in a clinically significant subset of HGEC
CLDN6 expression and pathological features	Deep myometrial invasion (≥ 50%, P = 0.038). Lymph node metastasis (P < 0.001). Lymphovascular space invasion (P = 0.024). Advanced FIGO stage (P = 0.015)	High CLDN6 expression is significantly correlated with established indicators of tumor aggressiveness
Prognostic significance	Multivariate cox regression: Disease-free survival (HR = 68.98, P = 0.022); overall survival (HR = 24.023, P = 0.038). No significant difference in Kaplan-Meier analysis	CLDN6 is an independent prognostic factor indicating high risk of recurrence and mortality
Clinical translation	Biomarker potential: Useful for risk stratification and guiding personalized treatment strategies in HGEC. Therapeutic target potential: A promising target for novel therapies like ADCs (e.g., CLDN6-23-ADC) and CAR-T. A relevant phase I clinical trial (NCT05103683) is ongoing	Offers new avenues for precision therapy, particularly in refractory HGEC cases

CLDN6: Claudin-6; HGEC: High-grade endometrial carcinoma; IRS: Immunoreactivity score; FIGO: International Federation of Gynecology and Obstetrics; HR: Hazard ratio; ADCs: Antibody-drug conjugates; CAR-T: Chimeric antigen receptor T-cell.

FUTURE PERSPECTIVES: OPPORTUNITIES AND CHALLENGES

CLDN6, a tight junction protein predominantly expressed during embryonic development and largely silenced in adult tissues, is aberrantly reactivated in various malignancies. This unique expression pattern presents both promising opportunities and challenges for research. Future studies on CLDN6 in HGEC and other solid tumors should concentrate on several key areas to better understand its roles and therapeutic potential.

At the mechanistic level, the link between CLDN6 and HGEC aggressiveness has been initially established[18], yet its exact molecular contributions to tumorigenesis and progression remain unclear. Future research must clarify how CLDN6 influences key downstream pathways, such as phosphatidylinositol 3-kinase/protein kinase B, Wnt/β-catenin, and transforming growth factor-beta, and determine if its interaction with estrogen receptor α drives hormone-independent growth in HGEC[24]. Additionally, CLDN6’s influence on the tumor microenvironment, including immune cell infiltration, angiogenesis, and extracellular matrix remodeling, requires thorough exploration.

On the translational front, CLDN6 emerges as an attractive therapeutic target given its limited expression in normal adult tissues but frequent overexpression in refractory tumors like HGEC. CLDN6-directed therapies, such as ADCs (e.g., CLDN6-23-ADC) and CAR-T cells, have demonstrated encouraging safety and efficacy in early-phase clinical trials for solid tumors[23,28]. Accelerating clinical evaluation in EC, ovarian cancer, and other gynecologic malignancies is essential, especially for recurrent or refractory cases, while developing standardized immunohistochemistry scoring for CLDN6 to complement HGEC molecular classification and pinpoint responsive patients.

Advances in technologies like single-cell sequencing and spatial transcriptomics will provide detailed multi-omics profiles of CLDN6 expression and regulatory networks across EC subtypes. Artificial intelligence-driven analysis of pathological images also offers potential for automating CLDN6 quantification and prognostic predictions, improving diagnostic accuracy and reproducibility.

Despite progress, major challenges remain. First, CLDN6’s substantial heterogeneity, both within tumors and across patients, demands precise definitions of “CLDN6-high” expression along with standardized interpretation criteria to enable broad clinical use. Second, CLDN6-targeted therapies risk triggering clonal selection or alternative signaling pathways that foster acquired resistance. Finally, although CLDN6 dysregulation appears in cancers like gastric, lung, and liver tumors, additional evidence is needed to confirm its potential as a pan-cancer target.

CONCLUSION

Ebrahim et al[18] establish CLDN6 as a promising prognostic biomarker and therapeutic target in HGEC. Its robust links to aggressive clinicopathological traits and independent survival prediction highlight its capacity to sharpen risk stratification and inform personalized therapies. Priority should go to validating these results in expansive cohorts, standardizing CLDN6 evaluation methods, and accelerating CLDN6-targeted treatments toward clinical use to achieve better outcomes for this formidable cancer.