Introduction to Cell Adhesion Molecules

Cell adhesion molecules (CAMs) are transmembrane glycoproteins that enable cells to bind together and attach to the extracellular matrix. Dysregulation of CAMs has been linked to conditions including rheumatoid arthritis, Parkinson’s disease, and cancer, making them promising therapeutic targets.

What are the different types of cell adhesion molecules?

CAMs are classified on the basis of structure into four main groups:

Cadherins are characterized by an extracellular domain containing multiple repeats of approximately 100 residues, interspersed with calcium-binding pockets that enable their homophilic or heterophilic interaction with other cells. Over 100 human cadherins have been described. These include the type I classical cadherins epithelial (E) cadherin, neural (N) cadherin, and placental (P) cadherin, as well as members of the other cadherin sub-families.

Selectins are another family of calcium-dependent CAMs, comprising just three members: E-selectin, L-selectin, and P-selectin. These are respectively expressed by endothelial cells, leukocytes, and platelets. The extracellular domain of each selectin consists of an N-terminal region homologous to C-type lectins, an adjacent epidermal growth factor-like domain, and a variable number of repeats with homology to complement proteins. Selectins participate exclusively in heterophilic cell–cell binding via lectin–glycan interactions.

Immunoglobulin super family CAMs (IgSF CAMs) have an extracellular domain containing one or more immunoglobulin-like repeats. Members of the IgSF CAM family include intercellular adhesion molecule 1 (ICAM-1), neural CAM 1 (NCAM-1), and vascular CAM 1 (VCAM-1), which each mediate calcium-independent interactions between different cell types. For example, ICAM-1 expression is required for keratinocyte/leukocyte interactions, such as those that help initiate inflammatory responses, whereas VCAM-1 is an endothelial cell protein that binds lymphocytes.

Integrins are similar to IgSF CAMS because they function independently of calcium. The main difference between integrins and the other types of CAMs is that integrins mediate interactions between cells and the extracellular matrix. In addition, rather than having a single-chain structure, integrins are heterodimers of non-covalently associated α and β subunits. In humans, at least 18 α and 8 β subunits have been identified to date that generate 24 functional heterodimers. These include α5β1 (fibronectin receptor), αLβ2 (lymphocyte function associated antigen-1), and αVβ8, a key activator of transforming growth factor β (TGF-β).

Table 1. Functional properties of the four cell adhesion molecule families

How are cell adhesion molecules studied?

Many immunoassay techniques are used to study CAMs under conditions of both health and disease. Flow cytometry enables identification of the cell types that express specific molecules and can show how changing expression mediates key cellular processes. Immunohistochemical analysis offers insight into the cellular interactions within different tissues and may reveal how aberrant CAM expression contributes to disease pathogenesis. Other widely used techniques for studying CAMs include enzyme-linked immunosorbent assay (ELISA), immunocytochemistry, and western blot, as well as label-free methods such as surface plasmon resonance.

Cell adhesion molecules in immune and cancer therapy

Although CAMs have been implicated in multiple disease states, they are especially interesting to researchers because of their potential as therapeutic targets for cancer. Many CAMs have central roles in tumor cell proliferation, survival, migration, invasion, and metastasis, and their effects are often mediated by the immune response. The following examples highlight just some of the ways in which CAMs are being targeted within the immune and tumor microenvironment:

• Systemic thermal therapy (elevation of the core body temperature to 39.5°C ± 0.5°C for 6 hours) in tumor-bearing mice has been shown to promote E/P-selectin and ICAM-1-dependent extravasation of cytotoxic T cells in tumors through activation of IL-6 signaling, suggesting that the unique IL-6–rich tumor microenvironment might be exploited to boost T-cell–mediated anti-tumor immunity.

• Treatment of squamous cell carcinoma samples with the TLR-7 agonist, imiquimod, has resulted in upregulated E-selectin expression, leading to increased efflux of CLA + (skin homing) cytotoxic T cells into tumors and subsequent tumor regression.

• An Fc fusion protein based on 2.5F, a peptide that targets multiple human integrins and is widely used for tumor imaging, has been proven to control tumor growth in three mouse models of cancer by eliciting protective adaptive immune responses. In the same study, the Fc fusion protein improved therapeutic responses when administered in combination with an anti-PD-1 antibody.

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