title: VE-cadherin RGD motifs promote metastasis and constitute a potential therapeutic target in melanoma and breast cancers.
abstract: We have investigated the role of vascular-endothelial (VE)-cadherin in melanoma and breast cancer metastasis. We found that VE-cadherin is expressed in highly aggressive melanoma and breast cancer cell lines. Remarkably, inactivation of VE-cadherin triggered a significant loss of malignant traits (proliferation, adhesion, invasion and transendothelial migration) in melanoma and breast cancer cells. These effects, except transendothelial migration, were induced by the VE-cadherin RGD motifs. Co-immunoprecipitation experiments demonstrated an interaction between VE-cadherin and α2β1 integrin, with the RGD motifs found to directly affect β1 integrin activation. VE-cadherin-mediated integrin signaling occurred through specific activation of SRC, ERK and JNK, including AKT in melanoma. Knocking down VE-cadherin suppressed lung colonization capacity of melanoma or breast cancer cells inoculated in mice, while pre-incubation with VE-cadherin RGD peptides promoted lung metastasis for both cancer types. Finally, an in silico study revealed the association of high VE-cadherin expression with poor survival in a subset of melanoma patients and breast cancer patients showing low CD34 expression. These findings support a general role for VE-cadherin and other RGD cadherins as critical regulators of lung and liver metastasis in multiple solid tumours. These results pave the way for cadherin-specific RGD targeted therapies to control disseminated metastasis in multiple cancers.
authors.affiliation: Department of Cellular and Molecular Medicine, Centro de Investigaciones Biológicas (CIB-CSIC), Ramiro de Maeztu, Madrid, Spain.
authors.forename: Rubén A
authors.initials: RA
authors.lastname: Bartolomé
authors.affiliation: Department of Cellular and Molecular Medicine, Centro de Investigaciones Biológicas (CIB-CSIC), Ramiro de Maeztu, Madrid, Spain.
authors.forename: Sofía
authors.initials: S
authors.lastname: Torres
authors.affiliation: Department of Cellular and Molecular Medicine, Centro de Investigaciones Biológicas (CIB-CSIC), Ramiro de Maeztu, Madrid, Spain.
authors.forename: Soledad
authors.initials: S
authors.lastname: Isern de Val
authors.affiliation: Department of Cellular and Molecular Medicine, Centro de Investigaciones Biológicas (CIB-CSIC), Ramiro de Maeztu, Madrid, Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Escudero-Paniagua
authors.affiliation: Department of Cellular and Molecular Medicine, Centro de Investigaciones Biológicas (CIB-CSIC), Ramiro de Maeztu, Madrid, Spain.
authors.forename: Eva
authors.initials: E
authors.lastname: Calviño
authors.affiliation: Department of Cellular and Molecular Medicine, Centro de Investigaciones Biológicas (CIB-CSIC), Ramiro de Maeztu, Madrid, Spain.
authors.forename: Joaquín
authors.initials: J
authors.lastname: Teixidó
authors.affiliation: Department of Cellular and Molecular Medicine, Centro de Investigaciones Biológicas (CIB-CSIC), Ramiro de Maeztu, Madrid, Spain.
authors.forename: J Ignacio
authors.initials: JI
authors.lastname: Casal
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D015820:Cadherins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D064593:Heterografts; D006801:Humans; D016023:Integrins / Q000378:metabolism; D008545:Melanoma / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality / Q000473:pathology*; D051379:Mice; D008954:Models, Biological; D058990:Molecular Targeted Therapy; D009362:Neoplasm Metastasis; D009842:Oligopeptides; D011379:Prognosis; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D060066:Protein Interaction Maps; D015398:Signal Transduction; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D000970:Antineoplastic Agents; D015820:Cadherins; D016023:Integrins; D009842:Oligopeptides; D000099152:Cadherin 5; C047981:arginyl-glycyl-aspartic acid
keywords: RGD motif; VE-cadherin; breast cancer; melanoma; metastasis