E-cadherin Is Critical for Collective Sheet Migration and Is Regulated by the Chemokine CXCL12 Protein During Restitution

Hwang, Soonyean; Zimmerman, Noah P.; Agle, Kimberle; Turner, Jerrold R.; Kumar, Suresh; Dwinell, Michael B.

doi:10.1074/jbc.m112.367979

Cited by 47 publications

(46 citation statements)

References 67 publications

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“…19 Because CXCL12 regulates E-cadherin expression and localization in migrating epithelial cells, 22 we tested a role of VE-cadherin in the CXCL12/CXCR4-mediated control of endothelial permeability. In hAoECs, CXCL12 increased transcript and protein expression of VE-cadherin (Figure 4F, Supplemental Figure 4I).…”

Section: Resultsmentioning

confidence: 99%

Vascular CXCR4 Limits Atherosclerosis by Maintaining Arterial Integrity

Döring¹,

Noels²,

Vorst³

et al. 2017

Circulation

146

147

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Background The CXCL12/CXCR4 chemokine ligand/receptor axis controls (progenitor) cell homeostasis and trafficking. So far, an atheroprotective role of CXCL12/CXCR4 has only been implied through pharmacological intervention, particularly as the somatic deletion of the CXCR4 gene in mice is embryonically lethal. Moreover, cell-specific effects of CXCR4 in the arterial wall and underlying mechanisms remain elusive, prompting us to investigate the relevance of CXCR4 in vascular cell types for atheroprotection. Methods We examined the role of vascular CXCR4 in atherosclerosis and plaque composition by inducing an endothelial cell (EC, BmxCreERT2-driven)-specific or smooth muscle cell (SMC, SmmhcCreERT2- or TaglnCre-driven)-specific-deficiency of CXCR4 in an apolipoprotein E-deficient mouse model. To identify underlying mechanisms for effects of CXCR4, we studied endothelial permeability, intravital leukocyte adhesion, involvement of the Akt/WNT/β-catenin signaling pathway and relevant phosphatases in VE-cadherin expression and function, vascular tone in aortic rings, cholesterol efflux from macrophages, and expression of SMC phenotypic markers. Finally, we analyzed associations of common genetic variants at the CXCR4 locus with the risk for coronary heart disease, along with CXCR4 transcript expression in human atherosclerotic plaques. Results The cell-specific deletion of CXCR4 in arterial ECs (n=12-15) or SMCs (n=13-24) markedly increased atherosclerotic lesion formation in hyperlipidemic mice. Endothelial barrier function was promoted by CXCL12/CXCR4, which triggered Akt/WNT/β-catenin-signaling to drive VE-cadherin expression and stabilized junctional VE-cadherin complexes through associated phosphatases. Conversely, endothelial CXCR4-deficiency caused arterial leakage and inflammatory leukocyte recruitment during atherogenesis. In arterial SMCs, CXCR4 sustained normal vascular reactivity and contractile responses, whereas CXCR4-deficiency favored a synthetic phenotype, the occurrence of macrophage-like SMCs in the lesions, and impaired cholesterol efflux. Regression analyses in humans (n=259,796) identified the C-allele at rs2322864 within the CXCR4 locus to be associated with increased risk for coronary heart disease. In line, C/C risk genotype carriers showed reduced CXCR4 expression in carotid artery plaques (n=188), which was furthermore associated with symptomatic disease. Conclusions Our data clearly establish that vascular CXCR4 limits atherosclerosis by maintaining arterial integrity, preserving endothelial barrier function, and a normal contractile SMC phenotype. Enhancing these beneficial functions of arterial CXCR4 by selective modulators might open novel therapeutic options in atherosclerosis.

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Section: Resultsmentioning

confidence: 99%

Vascular CXCR4 Limits Atherosclerosis by Maintaining Arterial Integrity

Döring¹,

Noels²,

Vorst³

et al. 2017

Circulation

146

147

View full text Add to dashboard Cite

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“…26 Moreover, E-cad expression mediating cell-cell adhesion between leader and follower cells is required for the appropriate collective cell migrations occurring in a wide variety of cell types including carcinoma cells. 58,59 These findings raise the possibility that mesenchymal tumor cell populations serve as leader cells directing the multicellular CTCs toward chemoattractants in the bloodstream. However, the roles of the E/M state in CRC clusters as leader cells await further clarification.…”

Section: Discussionmentioning

confidence: 99%

Metastatic seeding of human colon cancer cell clusters expressing the hybrid epithelial/mesenchymal state

Mizukoshi

Okazawa

Haeno

et al. 2019

Intl Journal of Cancer

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Emerging evidence supports the theory that tumor cell clusters efficiently metastasize to distant organs. However, the roles of epithelial‐to‐mesenchymal transition (EMT) in metastasizing tumor cell clusters have not yet been fully elucidated. To investigate this issue, tumor fragments were dissected from 40 colorectal cancer (CRC) patients and implanted subcutaneously into immunodeficient mice. We observed that tumors developed from the tumor fragments obtained from 28 of the 40 CRC patients. The tumors were then dissociated into cell suspensions to be orthotopically injected into secondary mice. The tumors from 13 of the 28 patients progressed. Furthermore, metastases formed spontaneously in the liver and lungs from the tumor fragments obtained from 8 of these 13 patients. Moreover, employing a mathematical analysis, we showed that tumor cell clusters seeded these metastases significantly more often than did single tumor cells. Membrane E‐cadherin‐ and nuclear ZEB1‐positive tumor cells indicating the hybrid epithelial/mesenchymal state were also detected in primary tumors of various CRC patients, and in the corresponding patient‐derived xenografts (PDXs) and circulating tumor cell clusters in the bloodstreams of mice. In contrast, ZEB1 staining was barely detectable in the patient‐matched liver metastases presumably developing through mesenchymal‐to‐epithelial transition. Inhibition of E‐cadherin or ZEB1 expression by shRNA notably prevented the PDX‐derived tumor organoids from colonizing the liver, when injected intrasplenically into mice, indicating E‐cadherin and ZEB1 expressions to be required for their metastatic colonization. Taken together, these findings suggest that the epithelial/mesenchymal state mediates metastatic seeding of human CRC cell clusters into distant organs.

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“…CXCL12 binding to CXCR4 may also play a role in enhancing epithelial barrier integrity as CXCL12 regulates E-cadherin sheet migration during restitution. Results indicate that CXCL12-CXCR4 stimulates E-cadherin localization and monolayer tightening through Rho-associated protein kinase activation and F-actin reorganization (99). The parallelism between actions of CXCL12 and TFF peptides supports the hypothesis that they act via the same receptor.…”

Section: Trefoil Factor Peptides and Cell Migrationmentioning

confidence: 99%

Trefoil Factor Peptides and Gastrointestinal Function

Aihara

Engevik²,

Montrose³

2017

Annu. Rev. Physiol.

150

123

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Trefoil factor (TFF) peptides, containing a 40-amino acid motif, including six conserved cysteine residues that form intramolecular disulfide bonds, are a family of mucin-associated secretory molecules mediating many physiological roles that maintain and restore gastrointestinal (GI) mucosal homeostasis. TFF peptides play important roles in response to GI mucosal injury and inflammation. In response to acute GI mucosal injury, TFF peptides accelerate cell migration to seal the damaged area from luminal contents, whereas chronic inflammation leads to increased TFF expression to prevent further progression of disease. Although much evidence supports the physiological significance of TFF peptides in mucosal defenses, the molecular and cellular mechanisms of TFF peptides in the GI epithelium remain largely unknown. In this review, we summarize the functional roles of TFF1, 2, and 3 and illustrate their action mechanisms, focusing on defense mechanisms in the GI tract.

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E-cadherin Is Critical for Collective Sheet Migration and Is Regulated by the Chemokine CXCL12 Protein During Restitution

Cited by 47 publications

References 67 publications

Vascular CXCR4 Limits Atherosclerosis by Maintaining Arterial Integrity

Vascular CXCR4 Limits Atherosclerosis by Maintaining Arterial Integrity

Metastatic seeding of human colon cancer cell clusters expressing the hybrid epithelial/mesenchymal state

Trefoil Factor Peptides and Gastrointestinal Function

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