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WIREs Syst Biol Med
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Intercellular adhesion: mechanisms for growth and metastasis of epithelial cancers

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Abstract Cell–cell adhesion molecules (CAMs) comprise a broad class of linker proteins that are crucial for the development of multicellular organisms, and for the continued maintenance of organ and tissue structure. Because of its pivotal function in tissue homeostasis, the deregulation of intercellular adhesion is linked to the onset of most solid tumors. The breakdown of homeostatic cell adhesions in highly ordered epithelial sheets is directly implicated in carcinogenesis, while continued changes in the adhesion profile of the primary tumor mass facilitate growth and expansion into adjacent tissue. Intercellular adhesion molecules are also involved in each subsequent phase of metastasis, including transendothelial migration, transit through the bloodstream or lymphatics, and renewed proliferation in secondary sites. This review addresses various roles of cadherin‐ and selectin‐mediated intercellular adhesion in tumor initiation and malignant transformation, and discusses the mechanisms for the arrest and adhesion of circulating tumor cells to the vessel endothelium. Considering the contributions of these CAMs to cancer progression in the context of a systematic biological framework may prove valuable in identifying new ways to diagnose and treat cancer. WIREs Syst Biol Med 2012, 4:171–181. doi: 10.1002/wsbm.160 This article is categorized under: Biological Mechanisms > Cell Fates Biological Mechanisms > Cell Signaling Laboratory Methods and Technologies > Macromolecular Interactions, Methods

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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.

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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).

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Biological Mechanisms > Cell Signaling
Laboratory Methods and Technologies > Macromolecular Interactions, Methods
Biological Mechanisms > Cell Fates

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