Cell Surface Adhesion Molecules

Many stages of the metastatic cascade depend upon adhesive interactions between tumour cells and other tumour cells, normal host cells, basement membrane components and the components that comprise the extracellular matrix. A wide range of cell-surface adhesion molecules facilitates these interactions, each with their own ligand specificity (24, 25, 26, 27). These adhesion molecules can be generally separated into four families: the cadherins, the immunoglobulin superfamily, the integrins and the selectins.

Cadherins

The cadherins are a group of calcium-dependant cell surface adhesion molecules whose role is to mediate homotypic cell-cell adhesions (25). At least 11 different types of human cadherins have been identified according to their tissue distribution including epithelial (E-), neural (N-), and placental (P-) cadherin. E-cadherin plays a central role in maintaining the integrity of cell-cell junctions, cell and tissue morphology and cell sorting during development. Most importantly, several studies have shown a correlation between loss of E-cadherin within tumours and a gain in tumour cell invasiveness (28, 29).

A significant amount of evidence demonstrates the role of E-cadherin as a regulator of cell-cell adhesion (30, 31, 32, 33) and may be summarised as follows: cells lacking E-cadherin expression do not aggregate/adhere to each other whereas cells possessing E-cadherin strongly adhere together. E-cadherin is mainly distributed at the cell border, particularly at regions of cell-cell contact.

neutralising the function of E-cadherin with anti-E-cadherin antibodies or deletion of its encoding gene causes cells to dissociate from each other, mutation of the E-cadherin protein or depriving the molecule of extracellular Ca2+ leads to cell dissociation, transfection of E-cadherin negative cells with E-cadherin DNA reverses their non-adhesive status.

The function of E-cadherin as a mediator of cell-cell adhesion is dependent upon its intercellular interactions with a family of protein molecules termed catenins. Studying proteins that co-immunoprecipitated with E-cadherin initially identified the catenins as integral components of the cadherin adhesion system. E-cadherin and catenins form complexes in the cellular membrane that ultimately serve as cell-cell adhesion complexes. The role of catenins in cadherin function has been further demonstrated in studies that show that cadherin mutants generated by deletion of their catenin-binding domains fail to mediate cell-cell adhesion (32, 34, 35).

fi-catenin was originally described as an intracellular protein essential for the correct function of the E-cadherin cell-cell adhesion complex. However, a number of recent studies have implicated this molecule in the process of tumour progression via its involvement with the APC, Wnt and Tcf-Lef proteins. The adenomatous polyposis coli (APC) gene is frequently mutated or deleted in colon cancers. In addition to being involved in non-inherited cases of this common cancer type, inherited mutations of the APC gene are responsible for a rare hereditary form of colon cancer, termed familial adenomatous polyposis (FAP). Individuals with this condition develop hundreds of benign colon adenomas or polyps, some of which will progress to malignancy (36). Little is known about how the APC protein functions within the cell. However, studies have shown that APC, following phosphorylation by glycogen synthase kinase-3 binds directly to P-catenin via its NH2 terminus (37). Thus APC, together with the regulates the levels of free

-catenin within the cell. A possible role for this may be that the APC protein acts to sequester negative regulatory variants of P-catenin within the cells and thus prevent their interaction with E-cadherin (38, 39). Under normal circumstances, free is bound by and

APC and targeted for destruction (39, 40). However, in tissue obtained from polyposis patients and in colorectal cancer cells, the APC product is frequently mutated and fails to bind This results in a dramatic increase in the amount of free in the cell. The possibility therefore arises that an increase in may play a role in the development of benign colon polyps.

The process of APC-mediated catenin degradation is antagonised by Wnt-based signalling, possibly via inhibition of GSK-3P function (40). In mammalian cells, Wnts are secreted signalling proteins that become associated with the cell surface or extracellular matrix (41), although the exact mechanism by which this occurs is not yet known. Wnt appears to function in intercellular communication by interaction with serpentine receptor homologues of the Drosophilla frizzled family (42). Upon Wntsignalling, p-catenin is stabilized and accumulates in the cytoplasm in a monomeric form (43,44). Wnt signal transduction also promotes the association of free P-catenin with proteins of the T cell factor-lymphoid enhancing factor (Tcf-Lef) group of DNA-binding transcription factors. Studies have shown that DNA transcription occurs only if catenin is bound to Tcf-Lef. These observations suggest that interacts with Tcf-Lef and activates gene expression within the cell (45, 46). Korinek et al (47) observed that the nuclei of colon carcinoma cells contained a catenin-Tcf complex that was constitutively active. Interestingly, when APC was introduced into these cells, the result was a removal of P-catenin from Tcf and loss of this transcriptional stimulus. These results further implicate APC in the regulation of normal cell function by interacting with and suppression of P-catenin-Tcf4 signalling. Together, these observations suggest that is involved not only in cell-cell adhesion but also the activation of gene transcription and Wnt-1 signalling. This provides compelling evidence for the role of as a mediator of tumour development.

E-cadherin and catenins may act as tumour suppressors

Whilst up-regulation of the expression of certain cell adhesion molecules (mainly those involved in cell-matrix interactions) may promote their motility and invasion and thus enhance the metastatic potential of tumour cells, elevation of other adhesion molecules, particularly those involved in cell-cell adhesion, may inhibit tumour cell invasion. The function of E-cadherin is to mediate tight cell-cell adhesions within tissues. As tumour cell metastasis depends in part on the loss of cell-cell adhesion within the tumour mass, factors that promote up-regulation of this molecule may act to suppress the early stages of this process. Studies on several human carcinomas have shown an inverse relationship between E-cadherin levels and tumour invasiveness (48,49). Transfection of a highly invasive tumour cell line with E-cadherin mRNA has been shown to reduce the invasiveness of tumour cells (36). This data suggests that up-regulation of E-cadherin within the primary tumour mass would enhance the capacity of tumour cells to bind to one another and thus inhibit their invasion into the surrounding tissue. The function of E-cadherin as a suppressor molecule of tumour development has thus been proposed.

Expression of E-cadherin and catenins in tumour tissues

From the evidence discussed so far, it would be natural to assume that well differentiated, non-invasive and non-metastatic carcinomas will express normal or relatively high levels of cadherins, whereas tumours that are poorly differentiated and possess a high metastatic potential will not. This correlation has been shown to hold true for several tumour types including squamous cell carcinomas of the head and neck (49), lung cancer (50), prostate and bladder carcinomas (51, 52), pancreatic cancer (53) and lobular breast cancer (29).

Mutations of E-cadherin have been recently reported by a number of different groups, which may bear importance in tumour spread (54,55). Becker et al (53) show that there is in-frame skipping of exon 8 or 9 together with deletion of exon 10 in patients with diffused type gastric cancer, a mutation seen in over 50% of the diffuse type carcinomas and 14% of cancers of mixed origin. Aberrant alpha catenin mRNA expression in cancer cells has also been reported by Oda et al (56) and this may lead to impaired E-cadherin function. An increase in urinary excretion of soluble E-cadherin has also been observed in some cancer patients (57, 58), suggesting that this molecule may be shed from the cell surface in these cases. This observation has been confirmed in bladder cancer by Banks et al (59).

The interaction of E-cadherin and catenins in rumour tissue needs to be explored fully. Whilst the loss of E-cadherin and/or catenins leads to increased cell dissociation and motility/invasion, certain factors may cause cell dissociation and enhance motility without apparent change of E-cadherin/catenin levels. These factors may exert their effects by modifying the interaction between catenins and cadherins/cytoskeletal proteins. Recent work by Brady-Kalnay et al (60) indicates that the phosphorylation state of this adhesion molecule complex can be regulated by cytokines and protein tyrosine phosphatases (PTPs). The role of PTPs as regulators of cadherin adhesive function via modulating the phosphorylation status of the complex thus presents an interesting area for future research.

Due to its potential role as a metastasis suppressor molecule and the relationship between E-cadherin levels and metastatic potential, its use as a prognostic indicator has been speculated. However, studies indicating a correlation of this type are very limited, mainly because of the short history of the molecule since its discovery. Some studies have shown that E-cadherin mRNA levels in patients surviving longer than five years are significantly higher than those with survival rate of less than 5 years. Such a relationship has also been reported in patients with head and neck squamous cell carcinoma (61), bladder cancer (51), gastric tumours (62) and prostate cancer (63, 64).

These observations thus show the important consequences of E-cadherin loss in tumour tissue. Established cell-cell adherens junctions may prevent initial stages of tumour dissemination and local invasion and the studies above have demonstrated an inverse correlation between cadherin molecules and metastatic spread in some human cancers. Further investigations will determine the value of the molecular components of the cadherin adhesion complex as indicators of patient survival.

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