Abstract
Cell-cell adhesion molecules (cadherins) and cell-extracellular matrix adhesion proteins (integrins) play a critical role in the regulation of cancer invasion and metastasis. Although significant progress has been made in the characterization of multiple members of the cadherin superfamily, most of the published work continues to focus in the switch E-/N-cadherin and its role in the epithelial–mesenchymal transition. Here, we will discuss the structural and functional properties of a subset of cadherins (cadherin 17, cadherin 5 and cadherin 6) that have an RGD motif in the extracellular domains. This RGD motif is critical for the interaction with α2β1 integrin and posterior integrin pathway activation in cancer metastatic cells. However, other signaling pathways seem to be affected by RGD cadherin interactions, as will be discussed. The range of solid tumors with overexpression or “de novo” expression of one or more of these three cadherins is very wide (gastrointestinal, gynaecological and melanoma, among others), underscoring the relevance of these cadherins in cancer metastasis. Finally, we will discuss different evidences that support the therapeutic use of these cadherins by blocking their capacity to work as integrin ligands in order to develop new cures for metastatic patients.
Highlights
Metastasis initiation is enabled by cellular plasticity, including the mesenchymal-to-epithelial transition (MET) and the gain of stem-cell-like properties by cells in the metastatic organ site [1]
Many cancer-related studies have mainly focused on this cadherin switch from E-cadherin, which is highly expressed in epithelial cells, to the N-cadherin, which is preferentially expressed in cells with a more mesenchymal phenotype [9]
There are very few data about the relationship between cadherin 17 (CDH17) expression and proteins involved in the regulation of Ca2+ levels, it is noteworthy that a number of alterations in these proteins have been routinely observed in colorectal cancer metastasis
Summary
Metastasis initiation is enabled by cellular plasticity, including the mesenchymal-to-epithelial transition (MET) and the gain of stem-cell-like properties by cells in the metastatic organ site [1]. Epithelial cadherin (E-cadherin, CDH1) is considered the prototype cadherin due to its early identification and exhaustive characterization [6]. It has been involved in stem cell maintenance and differentiation [7]. We will discuss the structural and functional properties of cadherin 5 (CDH5), cadherin 6 (CDH6) and cadherin 17 (CDH17), as well as their pathological implications in cancer progression and metastasis. These cadherins have, in common, the presence of RGD motifs within their sequence.
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