title: Schwann Cells Increase Prostate and Pancreatic Tumor Cell Invasion Using Laminin Binding A6 Integrin.
abstract: Human pancreatic and prostate cancers metastasize along nerve axons during perineural invasion. The extracellular matrix laminin class of proteins is an abundant component of both myelinated and non-myelinated nerves. Analysis of human pancreatic and prostate tissue revealed both perineural and endoneural invasion with Schwann cells surrounded or disrupted by tumor, respectively. Tumor and nerve cell co-culture conditions were used to determine if myelinating or non-myelinating Schwann cell (S16 and S16Y, respectively) phenotype was equally likely to promote integrin-dependent cancer cell invasion and migration on laminin. Conditioned medium from S16 cells increased tumor cell (DU145, PC3, and CFPAC1) invasion into laminin approximately 1.3-2.0 fold compared to fetal bovine serum (FBS) treated cells. Integrin function (e.g., ITGA6p formation) increased up to 1.5 fold in prostate (DU145, PC3, RWPE-1) and pancreatic (CFPAC1) cells, and invasion was dependent on ITGA6p formation and ITGB1 as determined by function-blocking antibodies. In contrast, conditioned medium isolated from S16Y cells (non-myelinating phenotype) decreased constitutive levels of ITGA6p in the tumor cells by 50% compared to untreated cells and decreased ITGA6p formation 3.0 fold compared to S16 treated cells. Flow cytometry and western blot analysis revealed loss of ITGA6p formation as reversible and independent of overall loss of ITGA6 expression. These results suggest that the myelinating phenotype of Schwann cells within the tumor microenvironment increased integrin-dependent tumor invasion on laminin.
authors.affiliation: Department of Pharmacology, University of Arizona College of Medicine, Tucson, Arizona, 85724.
authors.forename: Isis C
authors.initials: IC
authors.lastname: Sroka
authors.affiliation: Department of Pathology, University of Arizona College of Medicine, Tucson, Arizona, 85724.
authors.forename: Harsharon
authors.initials: H
authors.lastname: Chopra
authors.affiliation: University of Arizona Cancer Center, 1515 North Campbell Avenue, Tucson, Arizona, 85724.
authors.forename: Lipsa
authors.initials: L
authors.lastname: Das
authors.affiliation: University of Arizona Cancer Center, 1515 North Campbell Avenue, Tucson, Arizona, 85724.
authors.forename: Jaime M C
authors.initials: JM
authors.lastname: Gard
authors.affiliation: Department of Pathology, University of Arizona College of Medicine, Tucson, Arizona, 85724.
authors.forename: Raymond B
authors.initials: RB
authors.lastname: Nagle
authors.affiliation: University of Arizona Cancer Center, 1515 North Campbell Avenue, Tucson, Arizona, 85724.|Department of Cellular and Molecular Medicine, University of Arizona College of Medicine, Tucson, Arizona, 85724.
authors.forename: Anne E
authors.initials: AE
authors.lastname: Cress
mesh_terms: D045744:Cell Line, Tumor; D002465:Cell Movement; D018920:Coculture Techniques; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D039503:Integrin alpha6 / Q000378:metabolism*; D019012:Integrin beta1 / Q000378:metabolism*; D008297:Male; D009361:Neoplasm Invasiveness; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D012583:Schwann Cells / Q000502:physiology*
chemical_list: C588002:ITGA6 protein, human; D039503:Integrin alpha6; D019012:Integrin beta1
keywords: A6B1; LAMININ; METASTASIS; MICROENVIRONMENT; PERINEURAL INVASION; SCHWANN CELLS