Cadherins and Metastasis

Cadherins (named for "calcium-dependent adhesion") are a class of type-1 transmembrane proteins. They play important roles in cell adhesion, forming adherens junctions to bind cells within tissues together. They are dependent on calcium (Ca2+) ions to function, hence their name. Cell-cell adhesion is mediated by extracellular cadherin domains, whereas the intracellular cytoplasmic tail associates with a large number of adaptor and signaling proteins, collectively referred to as the cadherin adhesome.

Cadherins are approximately 720–750 amino acids long. Each cadherin has a small cytoplasmic component, a transmembrane component, and the remaining bulk of the protein is extra-cellular (outside the cell). To date, over 100 types of cadherins in humans have been identified and sequenced.

Role of E- Cadherin in Metastasis

Metastasis is the cause of approximately 90 percent of deaths among cancer patients. The steps involved in metastatic include loss of cell-cell adhesion, increased motility and invasiveness, entry into and survival in the circulation, dispersion to distant anatomic sites, extravasation, and colonization of some of those sites. The E-cadherin - catenin complex plays a key role in cellular adhesion; loss of this function has been associated with greater tumour metastasis. This requires the coordinated regulation of both E-cadherin-mediated cell-cell-adhesions and integrin mediated adhesions that contact the surrounding ECM (extra cellular matrix).

P-Cadhedrin and Cancer

Concerning carcinogenesis, the role of P-cadherin is still an object of debate, since it can behave differently depending on the molecular context and tumour cell model studied. In melanoma, non-small cell lung carcinoma, oral squamous cell carcinoma and hepatocarcinoma, P-cadherin has a similar tumour suppressive behaviour to E-cadherin. However in bladder, prostate and colon carcinomas, opposing effects have been found for P-cadherin, with some studies pointing to an associated tumour suppressive effect and others pointing to the induction of aggressive behaviour of cancer. Secifically in breast cancer P-Cadherin has received more attention and the mechanisms leading to the major tumour promoting effects have been widely characterized. P-cadherin aberrant expression is associated with breast carcinomas of high histological grade, as well as with the expression of well established markers associated to poor patient prognosis (Ref 1)

Microtubules and Cadherin

Although cadherins are best understood to cooperate with the actin cytoskeleton, there is increasing evidence supporting a role of the microtubules in regulating cadherin biology. Indeed, the cross-talk between microtubule networks and cell-cell adhesion sites profoundly impact upon these structures and is essential for proper cell organization, polarization and motility.

Role for p120-catenin in cell adhesion and cancer

"...p120-catenin (p120) is now known to regulate cell–cell adhesion through its interaction with the cytoplasmic tail of classical and type II cadherins. New evidence indicates that p120 regulates cadherin turnover at the cell surface, thereby controlling the amount of cadherin available for cell–cell adhesion. This function is necessary but not sufficient to promote strong adhesion, which is further controlled by signals acting on the amino-terminal p120 regulatory domain. p120 also modulates the activities of RhoA, Rac, and Cdc42, suggesting that along with other Src substrates, p120 regulates actin dynamics. Thus, p120 is a master regulator of cadherin abundance and activity, and likely participates in regulating the balance between adhesive and motile cellular phenotypes..." (reference 7)


Readings and References

1- P-cadherin and the journey to cancer metastasis