title: Loss of the EPH receptor B6 contributes to colorectal cancer metastasis.
abstract: Although deregulation of EPHB signaling has been shown to be an important step in colorectal tumorigenesis, the role of EPHB6 in this process has not been investigated. We found here that manipulation of EPHB6 levels in colon cancer cell lines has no effect on their motility and growth on a solid substrate, soft agar or in a xenograft mouse model. We then used an EphB6 knockout mouse model to show that EphB6 inactivation does not efficiently initiate tumorigenesis in the intestinal tract. In addition, when intestinal tumors are initiated genetically or pharmacologically in EphB6+/+and EphB6-/-mice, no differences were observed in animal survival, tumor multiplicity, size or histology, and proliferation of intestinal epithelial cells or tumor cells. However, reintroduction of EPHB6 into colon cancer cells significantly reduced the number of lung metastasis after tail-vein injection in immunodeficient mice, while EPHB6 knockdown in EPHB6-expressing cells increased their metastatic spread. Consistently, although EPHB6 protein expression in a series of 130 primary colorectal tumors was not associated with patient survival, EPHB6 expression was significantly lower in lymph node metastases compared to primary tumors. Our results indicate that the loss of EPHB6 contributes to the metastatic process of colorectal cancer.
authors.affiliation: Group of Biomedical Research in Digestive Tract Tumors, CIBBIM-Nanomedicine, Vall d'Hebron University Hospital, Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Silvia
authors.initials: S
authors.lastname: Mateo-Lozano
authors.affiliation: Group of Biomedical Research in Digestive Tract Tumors, CIBBIM-Nanomedicine, Vall d'Hebron University Hospital, Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Sarah
authors.initials: S
authors.lastname: Bazzocco
authors.affiliation: Group of Biomedical Research in Digestive Tract Tumors, CIBBIM-Nanomedicine, Vall d'Hebron University Hospital, Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Paulo
authors.initials: P
authors.lastname: Rodrigues
authors.affiliation: Group of Biomedical Research in Digestive Tract Tumors, CIBBIM-Nanomedicine, Vall d'Hebron University Hospital, Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Rocco
authors.initials: R
authors.lastname: Mazzolini
authors.affiliation: Group of Biomedical Research in Digestive Tract Tumors, CIBBIM-Nanomedicine, Vall d'Hebron University Hospital, Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Andretta
authors.affiliation: Group of Biomedical Research in Digestive Tract Tumors, CIBBIM-Nanomedicine, Vall d'Hebron University Hospital, Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Higinio
authors.initials: H
authors.lastname: Dopeso
authors.affiliation: CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Spain.|Group of Drug Delivery and Targeting, CIBBIM-Nanomedicine, Vall d'Hebron University Hospital, Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.|Functional Validation &Preclinical Research (FVPR), Vall d'Hebron University Hospital, Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Fernández
authors.affiliation: Group of Biomedical Research in Digestive Tract Tumors, CIBBIM-Nanomedicine, Vall d'Hebron University Hospital, Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Edgar
authors.initials: E
authors.lastname: Del Llano
authors.affiliation: Group of Biomedical Research in Digestive Tract Tumors, CIBBIM-Nanomedicine, Vall d'Hebron University Hospital, Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Josipa
authors.initials: J
authors.lastname: Bilic
authors.affiliation: CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Spain.|Group of Drug Delivery and Targeting, CIBBIM-Nanomedicine, Vall d'Hebron University Hospital, Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Lucía
authors.initials: L
authors.lastname: Suárez-López
authors.affiliation: Group of Biomedical Research in Digestive Tract Tumors, CIBBIM-Nanomedicine, Vall d'Hebron University Hospital, Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Irati
authors.initials: I
authors.lastname: Macaya
authors.affiliation: Group of Biomedical Research in Digestive Tract Tumors, CIBBIM-Nanomedicine, Vall d'Hebron University Hospital, Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Fernando
authors.initials: F
authors.lastname: Cartón-García
authors.affiliation: Group of Biomedical Research in Digestive Tract Tumors, CIBBIM-Nanomedicine, Vall d'Hebron University Hospital, Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Rocio
authors.initials: R
authors.lastname: Nieto
authors.affiliation: Group of Biomedical Research in Digestive Tract Tumors, CIBBIM-Nanomedicine, Vall d'Hebron University Hospital, Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Lizbeth M
authors.initials: LM
authors.lastname: Jimenez-Flores
authors.affiliation: Group of Biomedical Research in Digestive Tract Tumors, CIBBIM-Nanomedicine, Vall d'Hebron University Hospital, Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Priscila Guimarães
authors.initials: PG
authors.lastname: de Marcondes
authors.affiliation: Group of Biomedical Research in Digestive Tract Tumors, CIBBIM-Nanomedicine, Vall d'Hebron University Hospital, Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Yaiza
authors.initials: Y
authors.lastname: Nuñez
authors.affiliation: Group of Biomedical Research in Digestive Tract Tumors, CIBBIM-Nanomedicine, Vall d'Hebron University Hospital, Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Elsa
authors.initials: E
authors.lastname: Afonso
authors.affiliation: Department of Pathology, Vall d'Hebron Hospital, Barcelona, Spain (CIBERONC).
authors.forename: Karina
authors.initials: K
authors.lastname: Cacci
authors.affiliation: Department of Pathology, Vall d'Hebron Hospital, Barcelona, Spain (CIBERONC).
authors.forename: Javier
authors.initials: J
authors.lastname: Hernández-Losa
authors.affiliation: Department of Pathology, Vall d'Hebron Hospital, Barcelona, Spain (CIBERONC).
authors.forename: Stefania
authors.initials: S
authors.lastname: Landolfi
authors.affiliation: CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Spain.|Group of Drug Delivery and Targeting, CIBBIM-Nanomedicine, Vall d'Hebron University Hospital, Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Ibane
authors.initials: I
authors.lastname: Abasolo
authors.affiliation: Department of Pathology, Vall d'Hebron Hospital, Barcelona, Spain (CIBERONC).
authors.forename: Santiago
authors.initials: S
authors.lastname: Ramón Y Cajal
authors.affiliation: Olivia Newton-John Cancer Research Institute and School of Cancer Medicine, La Trobe University, Melbourne, Australia.
authors.forename: John M
authors.initials: JM
authors.lastname: Mariadason
authors.affiliation: CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Spain.|Group of Drug Delivery and Targeting, CIBBIM-Nanomedicine, Vall d'Hebron University Hospital, Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Simo
authors.initials: S
authors.lastname: Schwartz
authors.affiliation: Hematology, Department of Medicine, Kobe University Graduate School of Medicine, Chuo-ku, Kobe, Japan.
authors.forename: Toshimitsu
authors.initials: T
authors.lastname: Matsui
authors.affiliation: Group of Biomedical Research in Digestive Tract Tumors, CIBBIM-Nanomedicine, Vall d'Hebron University Hospital, Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Diego
authors.initials: D
authors.lastname: Arango
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D004195:Disease Models, Animal; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D011379:Prognosis; D036081:Receptors, Eph Family / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; C106797:EPHB6 protein, human; D036081:Receptors, Eph Family