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Cell adhesion and signalling by cadherins and Ig-CAMs in cancer

Key Points

  • Cell-adhesion molecules of the cadherin and immunoglobulin-like cell-adhesion molecule (Ig-CAM) superfamilies not only exert their functions by mediating cell–cell and cell–matrix adhesion, but also by directly eliciting signals that are involved in tissue morphogenesis and tumour progression.

  • In addition, signalling molecules are also able to modulate the adhesion status of the cell by acting on cell-adhesion molecules themselves, or on other components of signalling complexes.

  • The function of epithelial (E)-cadherin is altered in most epithelial tumours during the progression to tumour malignancy. E-cadherin function can be disrupted by various genetic and epigenetic mechanisms, including modulation by signalling molecules.

  • Loss of E-cadherin function elicits active signals that support tumour-cell migration, invasion and metastatic dissemination.

  • In several cancer types, loss of E-cadherin function is accompanied by the gain of expression of mesenchymal cadherins, for example, neuronal (N)-cadherin and cadherin-11, in a process that is known as the cadherin switch.

  • N-cadherin interacts with members of the fibroblast growth factor receptor (FGFR) family, thereby inducing pro-migratory and invasive signalling cascades.

  • Neural CAM (NCAM) also associates with FGFRs. Loss of NCAM function during tumour progression affects cell–matrix adhesion through the loss of FGFR-induced, integrin-mediated cell–matrix adhesion.

  • Several other members of the cadherin and Ig-CAM families interact with signalling molecules, thereby modulating physiological and pathological processes.

Abstract

In addition to their adhesive functions, cell-adhesion molecules modulate signal-transduction pathways by interacting with molecules such as receptor tyrosine kinases, components of the WNT signalling pathway and RHO-family GTPases. So, changes in the expression of cell-adhesion molecules affect not only the adhesive repertoire of a cell, but also its signal-transduction status. Conversely, signalling pathways can modulate the function of cell-adhesion molecules, altering the interactions between cells and their environment. Recent experimental evidence indicates that such processes have a crucial role in tumour progression, in particular during invasion and metastasis.

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Figure 1: Model of cell–cell and cell–matrix adhesion by cadherins and NCAM.
Figure 2: Loss of E-cadherin expression during tumour progression.
Figure 3: Potential signalling pathways affected by loss of E-cadherin function.

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Acknowledgements

We apologize to all colleagues whose important work could not be cited. We are grateful to A. Kren and I. Crnic for critical comments on the manuscript, and to M. Herzig for providing figure 2. Work in the author's laboratory is supported by the Swiss National Science Foundation, Krebsliga Beider Basel and Roche Research Foundation.

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Correspondence to Gerhard Christofori.

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DATABASES

Cancer.gov

bladder cancer

breast cancer

colon cancer

melanoma

pancreatic cancer

prostate cancer

renal-cell cancer

skin cancer

thyroid cancer

LocusLink

AKT

APC

cadherin-11

c-CBL

CD44

CDC42

CEACAM1

c-MET

DCC

E-cadherin

EGFR

FER

FGF2

FGFR1

FGFR4

GSK-3β

IGF1R

IGF2

IQGAP1

L1

Mel-CAM

MMP14

MMP2

MMP9

N-cadherin

NCAM

PTP1B

RAC1

RHOA

SIP1

SRC

T-cadherin

TIAM1

FURTHER INFORMATION

Cancer.gov clinical trials

IARC unit of Descriptive Epidemiology Information

The Internet Pathology Laboratory

Roel Nusse's WNT web site

Glossary

TIGHT JUNCTIONS

(TJs). Specialized intercellular junctions that are formed by several proteins in which two plasma membranes form a sealing gasket around a cell (also known as zonula occludens). Prevent fluid moving through the intercellular gap and lateral diffusion of membrane proteins between the apical and basolateral membranes.

ADHERENS JUNCTIONS

(AJs). Specialized cell–cell junctions that are formed by cadherins and additional associated proteins into which actin filaments are inserted (also known as zonula adherens).

DESMOSOMES

Specialized cell junctions that are formed by desmosomal cadherins and additional associated proteins into which intermediate filaments are inserted. Also known as macula adherens junctions or spot desmosomes.

RIP1TAG2

A transgenic mouse line that expresses the simian virus 40 large T antigen (Tag) under the control of the rat insulin II promoter (Rip) in the β-cells of pancreatic islets of Langerhans. Carcinomas develop in the pancreatic islets by progression through characteristic tumour stages.

XENOGRAFT TRANSPLANTATION

Transplantation of tissue or cells from one species to another. In cancer research, most xenografts are human cancer cell lines or human tumours that have been transplanted to immunodeficient rodents.

E3 LIGASE

The third enzyme in a series — the first two are designated E1 and E2 — that are responsible for ubiquitylation of target proteins. E3 enzymes provide platforms for binding E2 enzymes and specific substrates, thereby coordinating ubiquitylation of the selected substrates.

PROTEASOME

A 26S multiprotein complex that catalyses the breakdown of polyubiquitylated proteins.

EPITHELIAL–MESENCHYMAL TRANSITION

(EMT). Conversion from an epithelial to a mesenchymal phenotype, which is a normal process of embryonic development. In carcinomas, this transformation results in altered cell morphology, the expression of mesenchymal proteins and increased invasiveness.

WNT SIGNALLING PATHWAY

A developmental pathway of key importance for the patterning and specification of body axes in embryogenesis through activation of genes regulated by the TCF family of transcription factors. Deregulated WNT signalling has been implicated in various human tumours, most notably colon cancer, potentially by deregulating the balance between cell proliferation and differentiation.

LIPID RAFTS

Membrane microdomains that are distinguished from the rest of the plasma membrane by their lipid composition. They usually contain high levels of cholesterol (cholesterol-rich lipid rafts). Depending on their function or biochemical characteristics, such as lipid anchoring, proteins are differentially integrated into lipid rafts.

HAEMORRHAGIC LACUNAE

Increased permeability or disruption of the endothelial lining of vascular or lymphatic vessels leads to leakage of blood or lymphatic fluid into the surrounding tissue, which, due to fluid pressure, results in the formation of fluid-filled lacunae.

LOSS OF HETEROZYGOSITY

(LOH). In cells that carry a mutated allele of a tumour-suppressor gene, the gene becomes fully inactivated when the cell loses a large part of the chromosome carrying the wild-type allele. Regions with high frequency of LOH are believed to harbour tumour-suppressor genes.

APCMIN/+ MOUSE

Mouse mode in which the adenomatous polyposis colon (Apc) tumour-suppressor gene carries a truncating mutation, resulting in a defective protein. These mice develop several benign polyps (adenomas) of the colon.

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Cavallaro, U., Christofori, G. Cell adhesion and signalling by cadherins and Ig-CAMs in cancer. Nat Rev Cancer 4, 118–132 (2004). https://doi.org/10.1038/nrc1276

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