Cell adhesion in cancer: Beyond the migration of single cells

Abstract

Homeostasis in healthy tissues strongly relies on cell-to-cell adhesion and cell-to-extracellular matrix interactions. For instance, normal epithelial cells maintain tissue structure by adhering to each other and to the extracellular matrix. The proteins that mediate these distinct interactions are collectively called cell adhesion molecules and are divided into four major groups: cadherins, integrins, selectins, and immunoglobulins. They not only physically anchor cells, but also critically integrate signaling between the extracellular microenvironment and cells. These signals include biochemical cues, as adhesion proteins can both act as ligand-activated receptors and activate mechanotransduction triggered by changes in the physical environment. Molecular mechanisms related to cell adhesion signaling have been extensively studied, especially because mutations and changes in expression of these proteins, particularly cadherins and integrins, are frequently associated with diseases ranging from developmental intellectual disability to cancer. In fact, two major hallmarks of cancer, loss of cell-to-cell adhesion and anchorage-independent growth, are both dependent on cell adhesion molecules. Despite many studies elucidating the relationships between malignant transformation and metastasis and cellular adhesion processes, several areas still await exploration. Here, we highlight recently discovered roles of adhesion molecules in collective cancer cell migration and discuss the utility of three-dimensional models in studying cell-cell adhesion. We also describe recent therapeutic approaches targeting adhesion molecules.

Keywords: cadherin; cancer; cancer biology; cancer stem cells; cell adhesion; cell adhesion molecules; collective migration; epithelial-mesenchymal transition; integrin; organoids; targeted treatment.

Figure 1.

Cell adhesion molecules in normal and cancer cells A, schematic representation of the structure of four major classes of cell adhesion molecules. B, interactions between cell adhesion molecules on the cell surface create different types of cellular adhesions, including adherens junctions, gap junctions, desmosomes, and hemidesmosomes. C, alterations in cell adhesion molecules in the transition between the normal epithelial cell state (left) and malignancy (right). The localization of the distinct cell adhesion complex types is shown. EGF, epidermal growth factor; CRP, complement regulatory protein domains.

Figure 2.

Cancer cell clusters, spheres, and organoids. Shown are aspects of cancer cell biology where cell adhesion is crucial yet not well-understood.

Figure 3.

Different drug discovery approaches to targeting integrin for cancer therapy. A, conjugate presenting a selective binder for the extracellular region of integrin aVb3 (black) covalently linked to sunitinib (blue) (79). B, amphiphilic dendrimer composed with a dual-targeting peptide bearing an Arg-Gly-Asp-Lys (RGDK) lipopeptide (red) (C) (81). D, atorvastatin identified as a novel candidate for drug repurposing for undruggable integrins (82).