Abstract
P-cadherin is a classical cell-to-cell adhesion molecule with a homeostatic function in several normal tissues. However, its behaviour in the malignant setting is notably dependent on the cellular context. In some tumour models, such as melanoma and oral squamous cell carcinoma, P-cadherin acts as a tumour suppressor, since its absence is associated with a more aggressive cancer cell phenotype; nevertheless, the overexpression of this molecule is linked to significant tumour promoting effects in the breast, ovarian, prostate, endometrial, skin, gastric, pancreas and colon neoplasms. Herein, we review the role of P-cadherin in cancer cell invasion, as well as in loco-regional and distant metastatic dissemination. We focus in P-cadherin signalling pathways that are activated to induce invasion and metastasis, as well as cancer stem cell properties. The signalling network downstream of P-cadherin is notably dependent on the cellular and tissue context and includes the activation of integrin molecules, receptor tyrosine kinases, small molecule GTPases, EMT transcription factors, and crosstalk with other cadherin family members. As new oncogenic molecular pathways mediated by P-cadherin are uncovered, putative therapeutic options can be tested, which will allow for the targeting of invasion or metastatic disease, depending on the tumour model.
Highlights
P-cadherin was described for the first time in 1986, as part of “a novel class of cadherins that appeared in developing mouse embryos” and its name is derived from the site where this adhesion molecule was firstly characterized, the placenta [1]
We have shown that P-cadherin overexpression promotes cell invasion, migration and motility accompanied by the secretion of MMP1 and MMP2, which lead to P-cadherin ectodomain cleavage, releasing the soluble P-cadherin fragment [75]
We showed that P-cadherin is essential for the adhesion of cancer cells to extracellular matrix substrates that are critical for metastatic dissemination, namely laminin, vitronectin and fibronectin
Summary
P-cadherin was described for the first time in 1986, as part of “a novel class of cadherins that appeared in developing mouse embryos” and its name is derived from the site where this adhesion molecule was firstly characterized, the placenta [1]. Using a model of human ovarian cancer metastasis, in which Caov-3 cells were intraperitoneally injected in nude mice, forming multiple secondary tumours on the mesenterium and small bowel, Cheung and colleagues showed that P-cadherin silencing leads to a significant decrease in the number of metastatic cells present in the ascitic fluid.
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