Quantitative <i>In vivo</i> Imaging of the Effects of Inhibiting Integrin Signaling via Src and FAK on Cancer Cell Movement: Effects on E-cadherin Dynamics

Self Cite

552

411

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-

Section: Integrin-mediated Adhesionsmentioning

confidence: 99%

E-cadherin–integrin crosstalk in cancer invasion and metastasis

Canel

Serrels

Frame

et al. 2013

Self Cite

552

411

“…FAK also has a role in regulating the surface expression of E-cadherin, as impairment of FAK attenuates internalization of E-cadherin upon EMT induction (Cicchini et al, 2008). Furthermore, impaired E-cadherin internalization can be seen when FAK is inhibited in a mouse model (Canel et al, 2010), but the underlying mechanism remains to be determined.…”

Section: The Role Of Fak and Ilk In Coupling Anoikis Resistance With Emtmentioning

confidence: 99%

Mechanisms that link the oncogenic epithelial–mesenchymal transition to suppression of anoikis

Frisch

Schaller

Cieply

2013

249

217

SummaryThe oncogenic epithelial-mesenchymal transition (EMT) contributes to tumor progression in various context-dependent ways, including increased metastatic potential, expansion of cancer stem cell subpopulations, chemo-resistance and disease recurrence. One of the hallmarks of EMT is resistance of tumor cells to anoikis. This resistance contributes to metastasis and is a defining property not only of EMT but also of cancer stem cells. Here, we review the mechanistic coupling between EMT and resistance to anoikis. The discussion focuses on several key aspects. First, we provide an update on new pathways that lead from the loss of E-cadherin to anoikis resistance. We then discuss the relevance of transcription factors that are crucial in wound healing in the context of oncogenic EMT. Next, we explore the consequences of the breakdown of cell-polarity complexes upon anoikis sensitivity, through the Hippo, Wnt and transforming growth factor b (TGF-b) pathways, emphasizing points of crossregulation. Finally, we summarize the direct regulation of cell survival genes through EMT-inducing transcription factors, and the roles of the tyrosine kinases focal adhesion kinase (FAK) and TrkB neurotrophin receptor in EMT-related regulation of anoikis. Emerging from these studies are unifying principles that will lead to improvements in cancer therapy by reprogramming sensitivity of anoikis.

“…Potentially, by regulating c-Src, RPTPa could control events in the endocytic pathway, given the implication of the former in epithelial E-cadherin endocytosis (Canel et al, 2010;Swaminathan and Cartwright, 2012) and in neuronal neurotransmitter receptor trafficking in neurons (Ohnishi et al, 2011).…”

Section: Functions Of Rptpa At the Epithelial Junctionsmentioning

confidence: 99%

Receptor protein tyrosine phosphatase RPTPα controls epithelial adherens junctions, linking E-cadherin engagement to c-Src signaling to cortactin

Truffi

Dubreuil

Liang

et al. 2014

Epithelial junctions are fundamental determinants of tissue organization, subject to regulation by tyrosine phosphorylation. Homophilic binding of E-cadherin activates tyrosine kinases, such as Src, that control junctional integrity. Protein tyrosine phosphatases (PTPs) also contribute to cadherin-based adhesion and signaling, but little is known about their specific identity or functions at epithelial junctions. Here, we report that the receptor PTP RPTPa (human gene name PTPRA) is recruited to epithelial adherens junctions at the time of cell-cell contact, where it is in molecular proximity to E-cadherin. RPTPa is required for appropriate cadherin-dependent adhesion and for cyst architecture in three-dimensional culture. Loss of RPTPa impairs adherens junction integrity, as manifested by defective E-cadherin accumulation and peri-junctional F-actin density. These effects correlate with a role for RPTPa in cellular (c)-Src activation at sites of E-cadherin engagement. Mechanistically, RPTPa is required for appropriate tyrosine phosphorylation of cortactin, a major Src substrate and a cytoskeletal actin organizer. Expression of a phosphomimetic cortactin mutant in RPTPa-depleted cells partially rescues F-actin and E-cadherin accumulation at intercellular contacts. These findings indicate that RPTPa controls cadherinmediated signaling by linking homophilic E-cadherin engagement to cortactin tyrosine phosphorylation through c-Src.