title: Elevated CDCP1 predicts poor patient outcome and mediates ovarian clear cell carcinoma by promoting tumor spheroid formation, cell migration and chemoresistance.
abstract: Hematogenous metastases are rarely present at diagnosis of ovarian clear cell carcinoma (OCC). Instead dissemination of these tumors is characteristically via direct extension of the primary tumor into nearby organs and the spread of exfoliated tumor cells throughout the peritoneum, initially via the peritoneal fluid, and later via ascites that accumulates as a result of disruption of the lymphatic system. The molecular mechanisms orchestrating these processes are uncertain. In particular, the signaling pathways used by malignant cells to survive the stresses of anchorage-free growth in peritoneal fluid and ascites, and to colonize remote sites, are poorly defined. We demonstrate that the transmembrane glycoprotein CUB-domain-containing protein 1 (CDCP1) has important and inhibitable roles in these processes. In vitro assays indicate that CDCP1 mediates formation and survival of OCC spheroids, as well as cell migration and chemoresistance. Disruption of CDCP1 via silencing and antibody-mediated inhibition markedly reduce the ability of TOV21G OCC cells to form intraperitoneal tumors and induce accumulation of ascites in mice. Mechanistically our data suggest that CDCP1 effects are mediated via a novel mechanism of protein kinase B (Akt) activation. Immunohistochemical analysis also suggested that CDCP1 is functionally important in OCC, with its expression elevated in 90% of 198 OCC tumors and increased CDCP1 expression correlating with poor patient disease-free and overall survival. This analysis also showed that CDCP1 is largely restricted to the surface of malignant cells where it is accessible to therapeutic antibodies. Importantly, antibody-mediated blockade of CDCP1 in vivo significantly increased the anti-tumor efficacy of carboplatin, the chemotherapy most commonly used to treat OCC. In summary, our data indicate that CDCP1 is important in the progression of OCC and that targeting pathways mediated by this protein may be useful for the management of OCC, potentially in combination with chemotherapies and agents targeting the Akt pathway.
authors.affiliation: Mater Research Institute-University of Queensland, Translational Research Institute, Woolloongabba, Queensland, Australia.
authors.forename: Y
authors.initials: Y
authors.lastname: He
authors.affiliation: Mater Research Institute-University of Queensland, Translational Research Institute, Woolloongabba, Queensland, Australia.
authors.forename: A C
authors.initials: AC
authors.lastname: Wu
authors.affiliation: Mater Research Institute-University of Queensland, Translational Research Institute, Woolloongabba, Queensland, Australia.
authors.forename: B S
authors.initials: BS
authors.lastname: Harrington
authors.affiliation: Mater Research Institute-University of Queensland, Translational Research Institute, Woolloongabba, Queensland, Australia.|Mater Health Services, South Brisbane, Queensland, Australia.
authors.forename: C M
authors.initials: CM
authors.lastname: Davies
authors.affiliation: Mater Health Services, South Brisbane, Queensland, Australia.
authors.forename: S J
authors.initials: SJ
authors.lastname: Wallace
authors.affiliation: Mater Research Institute-University of Queensland, Translational Research Institute, Woolloongabba, Queensland, Australia.
authors.forename: M N
authors.initials: MN
authors.lastname: Adams
authors.affiliation: Mater Research Institute-University of Queensland, Translational Research Institute, Woolloongabba, Queensland, Australia.
authors.forename: J S
authors.initials: JS
authors.lastname: Palmer
authors.affiliation: Mater Research Institute-University of Queensland, Translational Research Institute, Woolloongabba, Queensland, Australia.
authors.forename: D K
authors.initials: DK
authors.lastname: Roche
authors.affiliation: Institute of Health and Biomedical Innovation, Queensland University of Technology, Woolloongabba, Queensland, Australia.
authors.forename: B G
authors.initials: BG
authors.lastname: Hollier
authors.affiliation: Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX, USA.
authors.forename: T F
authors.initials: TF
authors.lastname: Westbrook
authors.affiliation: University of California, Los Angeles, CA, USA.
authors.forename: H
authors.initials: H
authors.lastname: Hamidi
authors.affiliation: University of California, Los Angeles, CA, USA.
authors.forename: G E
authors.initials: GE
authors.lastname: Konecny
authors.affiliation: Mayo Clinic, Rochester, MN, USA.
authors.forename: B
authors.initials: B
authors.lastname: Winterhoff
authors.affiliation: Mater Health Services, South Brisbane, Queensland, Australia.
authors.forename: N P
authors.initials: NP
authors.lastname: Chetty
authors.affiliation: Mater Health Services, South Brisbane, Queensland, Australia.
authors.forename: A J
authors.initials: AJ
authors.lastname: Crandon
authors.affiliation: Mater Health Services, South Brisbane, Queensland, Australia.
authors.forename: N B
authors.initials: NB
authors.lastname: Oliveira
authors.affiliation: Mater Health Services, South Brisbane, Queensland, Australia.
authors.forename: C M
authors.initials: CM
authors.lastname: Shannon
authors.affiliation: Division of Medical Oncology, Vancouver Centre, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.|Cheryl Brown Ovarian Cancer Outcomes Unit, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: A V
authors.initials: AV
authors.lastname: Tinker
authors.affiliation: Department of Pathology and Laboratory Medicine, Vancouver General Hospital, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: C B
authors.initials: CB
authors.lastname: Gilks
authors.affiliation: Mater Research Institute-University of Queensland, Translational Research Institute, Woolloongabba, Queensland, Australia.|Mater Health Services, South Brisbane, Queensland, Australia.
authors.forename: J I
authors.initials: JI
authors.lastname: Coward
authors.affiliation: Wesley Hospital, Auchenflower, Queensland, Australia.
authors.forename: J W
authors.initials: JW
authors.lastname: Lumley
authors.affiliation: Mater Health Services, South Brisbane, Queensland, Australia.
authors.forename: L C
authors.initials: LC
authors.lastname: Perrin
authors.affiliation: Mater Research Institute-University of Queensland, Translational Research Institute, Woolloongabba, Queensland, Australia.|Mater Health Services, South Brisbane, Queensland, Australia.
authors.forename: J E
authors.initials: JE
authors.lastname: Armes
authors.affiliation: Mater Research Institute-University of Queensland, Translational Research Institute, Woolloongabba, Queensland, Australia.
authors.forename: J D
authors.initials: JD
authors.lastname: Hooper
mesh_terms: D018262:Adenocarcinoma, Clear Cell / Q000378:metabolism / Q000401:mortality* / Q000473:pathology*; D000818:Animals; D015703:Antigens, CD / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D000951:Antigens, Neoplasm; D016190:Carboplatin / Q000494:pharmacology; D015815:Cell Adhesion Molecules / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor / Q000187:drug effects; D002465:Cell Movement; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D016688:Mice, Inbred NOD; D009363:Neoplasm Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000401:mortality* / Q000473:pathology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D018874:Spheroids, Cellular / Q000378:metabolism / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D015703:Antigens, CD; D000951:Antigens, Neoplasm; C432044:CDCP1 protein, human; D015815:Cell Adhesion Molecules; D009363:Neoplasm Proteins; D016190:Carboplatin; D051057:Proto-Oncogene Proteins c-akt