Cadherin-17 (CDH17) as a Therapeutic Target

Abstract

Cadherin-17 (CDH17), a member of the 7D-cadherin family, has recently emerged as a potential therapeutic target for the treatment of cancers in the gastrointestinal (GI) tract. Unlike classical cadherins that possess a cytoplasmic domain required for direct adhesion to the actin cytoskeleton, CDH17 does not, yet functions in tissue integrity, polarity, and cell migration. CDH17 is highly expressed in the small intestine and colon, aberrantly re-expressed in GI cancers such as gastric, pancreatic, and colorectal cancers, and is nearly silenced in the majority of normal adult tissues. This unusual expression pattern forms the basis for it being a selective drug target and biomarker.

Recent studies suggest CDH17 facilitates tumor progression by promoting cell adhesion, proliferation, and resistance to apoptosis. Additionally, it modulates Wnt/β-catenin signaling and contributes to metastasis. Given its limited expression in non-pathological tissues, CDH17 offers a window for highly specific antibody-based therapies that minimize off-target effects.

Monoclonal antibodies targeting CDH17 have demonstrated promising preclinical efficacy, inducing tumor cell death and reducing metastasis in xenograft models. Advances in antibody–drug conjugates (ADCs), chimeric antigen receptor T (CAR-T) cells, and bispecific antibodies offer further therapeutic avenues. Despite the promise, challenges remain in optimizing antibody design, improving delivery in solid tumors, and overcoming immune suppression in the tumor microenvironment.

This paper explores the molecular biology of CDH17, its role in GI malignancies, and the current landscape of antibody-based strategies targeting it. By bridging molecular insights with translational applications, CDH17 stands at the forefront of precision oncology for GI cancers.

Introduction to Cadherins and CDH17

Cadherins are a family of calcium-dependent transmembrane proteins that mediate cell-cell adhesion. These proteins are vital for maintaining tissue architecture, regulating developmental processes, and controlling cell polarity. Classical cadherins, such as E-cadherin and N-cadherin, are well-studied in the context of epithelial-mesenchymal transition (EMT), a process often hijacked by cancer cells to facilitate metastasis.

Among the diverse cadherin family is Cadherin-17 (CDH17), also known as Liver–Intestine Cadherin (LI-cadherin). Unlike classical cadherins, CDH17 lacks a catenin-binding domain, which means it does not directly interact with the actin cytoskeleton. Instead, it belongs to the 7D-cadherin subfamily, characterized by seven extracellular cadherin repeats, a single-pass transmembrane region, and a short cytoplasmic tail. This structure suggests a role in adhesion that is structurally distinct and potentially more flexible than classical cadherins.

CDH17 expression is largely restricted to epithelial cells of the gastrointestinal tract, particularly in the small intestine and colon. It functions in maintaining luminal barrier integrity and mediating ion transport. However, its re-expression in GI tumors has attracted attention due to its tumor-specific expression and apparent involvement in tumorigenesis.

CDH17’s restricted physiological expression and aberrant activation in malignancies make it an appealing target for drug development. Over the past decade, researchers have investigated its role not only as a marker of malignant transformation but also as an active player in tumor growth and progression. Understanding the biology of CDH17 is crucial for developing targeted therapies that can selectively attack tumor cells while sparing normal tissues — a core principle of modern oncology.

Molecular Structure and Expression Profile of CDH17

CDH17 encodes a 7-domain cadherin protein, approximately 87 kDa in size. Its extracellular domain comprises seven tandemly arranged cadherin repeats, responsible for homophilic and heterophilic cell-cell interactions. The transmembrane segment anchors the protein to the cell membrane, while the cytoplasmic domain, shorter than those of classical cadherins, lacks a β-catenin binding site — suggesting limited participation in canonical adhesion pathways.

Despite its atypical structure, CDH17 contributes to epithelial cohesion, particularly in the absorptive regions of the small intestine and colon. In normal tissues, CDH17 expression is regulated developmentally and spatially, largely confined to the brush-border membranes of enterocytes. Notably, CDH17 expression is absent or minimally expressed in adult liver, pancreas, and stomach under physiological conditions.

Pathological studies have revealed a distinct pattern: CDH17 is aberrantly overexpressed in a range of gastrointestinal cancers, including gastric, colorectal, and pancreatic adenocarcinomas. This aberrant expression is often correlated with poor prognosis, lymph node metastasis, and tumor aggressiveness.

Importantly, immunohistochemical analyses across various tumor panels have shown high expression levels of CDH17 in GI tumors but very limited or no expression in surrounding normal tissues. This cancer-specific expression profile lays the groundwork for its use as a diagnostic marker and as a target for antibody-mediated therapies.

Further investigation into transcriptional and post-transcriptional regulation of CDH17 suggests its expression is modulated by factors such as GATA6, and may be epigenetically deregulated in tumors. These findings reinforce the view that CDH17 plays a functional role in tumor development and is not merely a bystander molecule.

Functional Role of CDH17 in Gastrointestinal Tissues

In normal physiology, CDH17 maintains epithelial cell polarity and barrier integrity within the gastrointestinal tract. It facilitates weak intercellular adhesion and regulates paracellular permeability — a critical function in the intestinal epithelium where nutrient absorption and protection from microbial invasion are tightly controlled.

Unlike classical cadherins that form adherens junctions with actin filaments, CDH17 may mediate more transient or dynamic interactions. This flexibility is likely advantageous in intestinal environments characterized by high turnover and mechanical stress. CDH17 also appears to be involved in ion transport and signal transduction related to epithelial maintenance.

Interestingly, its expression is spatially restricted to absorptive regions, suggesting a specialized role in nutrient transport and mucosal function. Knockout studies in murine models have shown mild phenotypes, indicating redundancy with other cadherins, yet its absence does impact barrier function and intestinal morphology.

In disease states, especially in gastrointestinal cancers, CDH17 re-emerges as a marker of dedifferentiated epithelial cells. Its re-expression suggests a potential switch in its role — from maintaining homeostasis to supporting pathological remodeling, aiding in cancer progression and metastasis.

CDH17 in Gastrointestinal Malignancies

The involvement of CDH17 in gastrointestinal cancers has been documented extensively over the past decade. In colorectal cancer (CRC), CDH17 is overexpressed in approximately 60–80% of cases, and its expression correlates with advanced tumor stage, lymph node metastasis, and poor patient outcomes. A similar pattern is observed in gastric cancer, where CDH17 positivity is associated with greater tumor invasiveness and lower survival rates.

In pancreatic ductal adenocarcinoma, a notoriously aggressive cancer with limited therapeutic options, CDH17 expression has also been noted, particularly in poorly differentiated tumor cells. This suggests that CDH17 may play a role in sustaining tumor cell survival in harsh microenvironments.

Mechanistically, CDH17 overexpression enhances cell proliferation, migration, and resistance to anoikis — a form of programmed cell death triggered by detachment from the extracellular matrix. This ability to avoid anoikis is critical for metastasis, allowing tumor cells to survive in circulation and colonize distant organs.

Furthermore, CDH17 has been linked to activation of oncogenic signaling pathways. It has been shown to potentiate Wnt/β-catenin signaling, a central driver in many GI cancers. By stabilizing β-catenin or facilitating its nuclear translocation, CDH17 can drive the expression of pro-proliferative genes such as cyclin D1 and c-Myc.

Studies using RNA interference or CRISPR-Cas9-mediated gene knockdown have shown that silencing CDH17 results in decreased proliferation and increased apoptosis in tumor cell lines. This genetic evidence strengthens the case for CDH17 as a functional oncogene in GI malignancies.

Due to its high expression in tumors and low presence in normal tissues, CDH17 is increasingly used as a diagnostic biomarker. It also has potential as a tool for identifying circulating tumor cells (CTCs) or as a radiotracer target for imaging modalities in precision oncology.