title: Integrin α4 Enhances Metastasis and May Be Associated with Poor Prognosis in MYCN-low Neuroblastoma.
abstract: High-risk neuroblastoma is associated with an overall survival rate of 30-50%. Neuroblastoma-expressed cell adhesion receptors of the integrin family impact cell adhesion, migration, proliferation and survival. Integrin α4 is essential for neural crest cell motility during development, is highly expressed on leukocytes, and is critical for transendothelial migration. Thus, cancer cells that express this receptor may exhibit increased metastatic potential. We show that α4 expression in human and murine neuroblastoma cell lines selectively enhances in vitro interaction with the alternatively spliced connecting segment 1 of fibronectin, as well as vascular cell adhesion molecule-1 and increases migration. Integrin α4 expression enhanced experimental metastasis in a syngeneic tumor model, reconstituting a pattern of organ involvement similar to that seen in patients. Accordingly, antagonism of integrin α4 blocked metastasis, suggesting adhesive function of the integrin is required. However, adhesive function was not sufficient, as mutants of integrin α4 that conserved the matrix-adhesive and promigratory function in vitro were compromised in their metastatic capacity in vivo. Clinically, integrin α4 is more frequently expressed in non-MYNC amplified tumors, and is selectively associated with poor prognosis in this subset of disease. These results reveal an unexpected role for integrin α4 in neuroblastoma dissemination and identify α4 as a potential prognostic indicator and therapeutic target.
authors.affiliation: Division of Gynecologic Oncology, Department of Reproductive Medicine, UCSD School of Medicine, 9500 Gilman Drive, La Jolla, California, 92093, United States of America; University of California San Diego Moores Cancer Center, 3855 Health Sciences Drive, La Jolla, California, 92093, United States of America.
authors.forename: Shanique A
authors.initials: SA
authors.lastname: Young
authors.affiliation: Division of Gynecologic Oncology, Department of Reproductive Medicine, UCSD School of Medicine, 9500 Gilman Drive, La Jolla, California, 92093, United States of America; University of California San Diego Moores Cancer Center, 3855 Health Sciences Drive, La Jolla, California, 92093, United States of America.
authors.forename: Katelyn E
authors.initials: KE
authors.lastname: McCabe
authors.affiliation: Division of Gynecologic Oncology, Department of Reproductive Medicine, UCSD School of Medicine, 9500 Gilman Drive, La Jolla, California, 92093, United States of America.
authors.forename: Alena
authors.initials: A
authors.lastname: Bartakova
authors.affiliation: Division of Gynecologic Oncology, Department of Reproductive Medicine, UCSD School of Medicine, 9500 Gilman Drive, La Jolla, California, 92093, United States of America; University of California San Diego Moores Cancer Center, 3855 Health Sciences Drive, La Jolla, California, 92093, United States of America.
authors.forename: Joe
authors.initials: J
authors.lastname: Delaney
authors.affiliation: University of California San Diego Center for Advanced Laboratory Medicine, 10300 Campus Point Drive, MC7210, Room 1253, San Diego, CA, 92121, United States of America; Department of Pathology, UCSD School of Medicine, 9500 Gilman Drive, La Jolla, California, 92093, United States of America.
authors.forename: Donald P
authors.initials: DP
authors.lastname: Pizzo
authors.affiliation: Department of Pathology, UCSD School of Medicine, 9500 Gilman Drive, La Jolla, California, 92093, United States of America.
authors.forename: Robert O
authors.initials: RO
authors.lastname: Newbury
authors.affiliation: University of California San Diego Moores Cancer Center, 3855 Health Sciences Drive, La Jolla, California, 92093, United States of America; Department of Pathology, UCSD School of Medicine, 9500 Gilman Drive, La Jolla, California, 92093, United States of America.
authors.forename: Judith A
authors.initials: JA
authors.lastname: Varner
authors.affiliation: Division of Gynecologic Oncology, Department of Reproductive Medicine, UCSD School of Medicine, 9500 Gilman Drive, La Jolla, California, 92093, United States of America; University of California San Diego Moores Cancer Center, 3855 Health Sciences Drive, La Jolla, California, 92093, United States of America.
authors.forename: David D
authors.initials: DD
authors.lastname: Schlaepfer
authors.affiliation: Division of Gynecologic Oncology, Department of Reproductive Medicine, UCSD School of Medicine, 9500 Gilman Drive, La Jolla, California, 92093, United States of America; University of California San Diego Moores Cancer Center, 3855 Health Sciences Drive, La Jolla, California, 92093, United States of America.
authors.forename: Dwayne G
authors.initials: DG
authors.lastname: Stupack
mesh_terms: D000818:Animals; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D039441:Integrin alpha4 / Q000235:genetics* / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000556:secondary; D008207:Lymphatic Metastasis; D051379:Mice; D000071447:N-Myc Proto-Oncogene Protein; D009368:Neoplasm Transplantation; D009423:Nervous System Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009447:Neuroblastoma / Q000235:genetics* / Q000378:metabolism / Q000556:secondary; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D015513:Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D011379:Prognosis; D015398:Signal Transduction; D016019:Survival Analysis; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D010455:Peptides; D019010:Vascular Cell Adhesion Molecule-1; C076687:CS1 peptide; D039441:Integrin alpha4