E-cadherin–integrin crosstalk in cancer invasion and metastasis

Abstract

Summary E-cadherin is a single-pass transmembrane protein that mediates homophilic cell-cell interactions. Tumour progression is often associated with the loss of E-cadherin function and the transition to a more motile and invasive phenotype. This requires the coordinated regulation of both E-cadherin-mediated cell-cell adhesions and integrin-mediated adhesions that contact the surrounding extracellular matrix (ECM). Regulation of both types of adhesion is dynamic as cells respond to external cues from the tumour microenvironment that regulate polarity, directional migration and invasion. Here, we review the mechanisms by which tumour cells control the crossregulation between dynamic E-cadherin-mediated cell-cell adhesions and integrin-mediated cell-matrix contacts, which govern the invasive and metastatic potential of tumours. In particular, we will discuss the role of the adhesion-linked kinases Src, focal adhesion kinase (FAK) and integrin-linked kinase (ILK), and the Rho family of GTPases. Key words: E-cadherin, Integrins, Cancer, Invasion Introduction Understanding the processes by which tumour cells invade and metastasise to distant sites (and how to target them), is one of the great challenges in cancer research, as metastatic spread is responsible for ,90% of cancer-related mortality. Tumour cell invasion and metastasis is a complex process that involves multiple steps, including local migration and invasion, dissemination of malignant tumour cells through the lymphatic or haematogenous systems, and the resulting growth or colonization of micrometastatic lesions and their development into macro-metastases. In common with other 'hallmarks' of cancer (Hanahan and Weinberg, 2011), understanding and inhibiting invasion and metastasis are complicated by the multiplicity of underlying mechanisms, the plasticity of cancer cell behaviour and the evolving nature of the microenvironment. One trait that underpins the ability of cancer cells to metastasise is their ability to change the way in which they interact with the surrounding ECM and with adjacent tumour and stromal cells. E-cadherin is a key mediator of cell-cell adhesions in epithelial tissues, and loss of E-cadherin can promote invasive and metastatic behaviour in many epithelial tumours (Birchmeier and Behrens, 1994). However, it is clear that tumour cells can invade with fully intact and functional cell-cell adhesions as collective groups of cells, and that a loosening of cell-cell contacts is sufficient to permit this collective migration and invasion. This requires coordination of cues from the surrounding tumour environment, to regulate both cell-cell and cell-ECM interactions. Here, we review the role of E-cadherin in tumour cell invasion and metastasis, with particular emphasis on the interplay between E-cadherin and cell-ECM interactions that are mediated by integrin matrix receptors. We discuss the key signalling intermediates that regulate this crosstalk, as well as recent work that supports a physical interaction between integrin-and E-cadherin-

Scattering of Cell Clusters in Confinement

“…In multicell clusters, the integrin-cadherin crosstalk (18,19) dictates that greater number of CC junctions (b) slows down CE bond formation. We combine these two influences of cell-ECM and cellcell interactions to describe the rate of formation of CE bonds for each node (a) as follows:…”

“…According to the known integrin-cadherin crosstalk (18,19), the cell-ECM adhesions (greater b a) oppose the formation of CC junctions. Thus, the net rate of change of the number of CC junctions at any node is as follows:…”

Roles of extracellular nucleotides and P2 receptors in ectodomain shedding

“…CD324 (E-cadherin) is a type I integral membrane glycoprotein that mediates cell-to-cell adhesion in epithelial tissues, while loss of this molecule promotes cell migration including epithelial tumour metastasis [74]. In contrast to most studies that use exogenous ATP to induce ectodomain shedding, one study showed that melittin, the major component of bee venom, induced the rapid shedding of CD324 from human HaCaT keratinocytes via a purinergic pathway [75].…”

Reggie-1/Flotillin-2 regulates integrin trafficking and focal adhesion turnover via Rab11a

“…Moreover, RCP/Rab11-driven recycling of ␣5␤1-integrin controls the activation of Rac and RhoA in different cell lines (A2780, MDA-MB-231 and HT1080 cells) (Jacquemet et al, 2013). The recycling of ␤1-integrin is known to be regulated by Arf6 and Rab11 (Eva et al, 2010(Eva et al, , 2012Powelka et al, 2004) and Rab11 was also implied in the targeted delivery of Src tyrosine kinases to FAs (Bach et al, 2014) where Src contributes to the phosphorylation of FAK (Canel et al, 2013). In addition, ␤1-integrin recruitment can lead to an activation of Rac1 in HeLa cells (O'Toole et al, 2011).…”