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Elevated CDCP1 predicts poor patient outcome and mediates ovarian clear cell carcinoma by promoting tumor spheroid formation, cell migration and chemoresistance

Oncogene volume 35, pages 468–478 (2016)Cite this article

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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.

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Acknowledgements

This work was supported by Cancer Council Queensland grants 614205 and 1021827 and Wesley Research Institute grant 2008/06 to JDH. MNA and BSH received Australian Post-Graduate Awards. BGH holds a Queensland Government Smart Futures Fund Fellowship. JDH holds Australian Research Council Future Fellowship FT120100917.

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Authors and Affiliations

  1. Mater Research Institute-University of Queensland, Translational Research Institute, Woolloongabba, Queensland, Australia

    Y He, A C Wu, B S Harrington, C M Davies, M N Adams, J S Palmer, D K Roche, J I Coward, J E Armes & J D Hooper

  2. Mater Health Services, South Brisbane, Queensland, Australia

    C M Davies, S J Wallace, N P Chetty, A J Crandon, N B Oliveira, C M Shannon, J I Coward, L C Perrin & J E Armes

  3. Institute of Health and Biomedical Innovation, Queensland University of Technology, Woolloongabba, Queensland, Australia

    B G Hollier

  4. Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX, USA

    T F Westbrook

  5. University of California, Los Angeles, CA, USA

    H Hamidi & G E Konecny

  6. Mayo Clinic, Rochester, MN, USA

    B Winterhoff

  7. Division of Medical Oncology, Vancouver Centre, British Columbia Cancer Agency, Vancouver, British Columbia, Canada

    A V Tinker

  8. Cheryl Brown Ovarian Cancer Outcomes Unit, British Columbia Cancer Agency, Vancouver, British Columbia, Canada

    A V Tinker

  9. Department of Pathology and Laboratory Medicine, Vancouver General Hospital, University of British Columbia, Vancouver, British Columbia, Canada

    C B Gilks

  10. Wesley Hospital, Auchenflower, Queensland, Australia

    J W Lumley

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  1. Y He
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Corresponding author

Correspondence to J D Hooper.

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Competing interests

JDH is an inventor on a patent describing CDCP1 as an anti-cancer target. All other authors declare no conflict of interest.

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He, Y., Wu, A., Harrington, B. et al. Elevated CDCP1 predicts poor patient outcome and mediates ovarian clear cell carcinoma by promoting tumor spheroid formation, cell migration and chemoresistance. Oncogene 35, 468–478 (2016). https://doi.org/10.1038/onc.2015.101

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