Intercellular adhesion: mechanisms for growth and metastasis of epithelial cancers

Neoplastic transformation and malignant conversion are driven by the loss of epithelial adhesions. (a) Epithelial cells are depicted schematically as polarized cells that adhere basolaterally to one another atop a basement membrane (BM), forming a barrier that separates the lumen and stromal compartments of parenchymal tissues. (b) Progressive loss of tight junctions and adherens junctions accompanies proliferation in situ. As the primary tumor expands, cells respond to the loss of E‐cadherin and release of β‐catenin by undergoing an epithelial‐to‐mesenchymal transition that enables the redistribution of integrin profiles to release from the BM, secretion of proteases to degrade the stroma, and upregulation of N‐cadherin to facilitate interactions with mesenchymal cells during subsequent invasion.

Mechanisms of circulating tumor cell (CTC) adhesion. (a) Schematic illustration showing active and passive mechanisms of CTC arrest. Tumor cells may be passively introduced to the circulation at sites of tumoral vascularization, or they may actively seek out nearby blood vessels (‘migration’, ‘invasion’, and ‘intravasation’). In the passive model (blue‐dotted line), cells may be deposited as homotypic clusters that lodge in narrow capillaries due to size restriction (I). In the active model (green‐dotted line), invasive tumor cells extend dynamic microtentacle projections and heterotypically associate with platelets and leukocytes to maximize contact with the vessel wall. Tumor cell platelet–leukocytes emboli adhere to endothelial L‐selectin ligands (II), while tumor cells can also directly tether to arrested platelets and fibrin that concentrate at sites of tissue injury (III). (b) Fluorescence micrograph of microtentacles on the surface of an invasive MDA‐MB‐436 breast tumor cell. The pictured cell is in the process of adhering to an endothelial monolayer on its ventral surface (not pictured) (scale bar = 10 µm).