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

He, Y., Wu, A. C., Harrington, B. S., Davies, C. M., Wallace, S. J., Adams, M. N., Palmer, J. S., Roche, D. K., Hollier, B. G., Westbrook, T. F., Hamidi, H., Konecny, G. E., Winterhoff, B., Chetty, N. P., Crandon, A. J., Oliveira, N. B., Shannon, C. M., Tinker, A. V., Gilks, C. B., Coward, J. I., Lumley, J. W., Perrin, L. C., Armes, J. E. and Hooper, J. D. (2016) Elevated CDCP1 predicts poor patient outcome and mediates ovarian clear cell carcinoma by promoting tumor spheroid formation, cell migration and chemoresistance. Oncogene, 35 4: 468-478. doi:10.1038/onc.2015.101

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Author He, Y.
Wu, A. C.
Harrington, B. S.
Davies, C. M.
Wallace, S. J.
Adams, M. N.
Palmer, J. S.
Roche, D. K.
Hollier, B. G.
Westbrook, T. F.
Hamidi, H.
Konecny, G. E.
Winterhoff, B.
Chetty, N. P.
Crandon, A. J.
Oliveira, N. B.
Shannon, C. M.
Tinker, A. V.
Gilks, C. B.
Coward, J. I.
Lumley, J. W.
Perrin, L. C.
Armes, J. E.
Hooper, J. D.
Title Elevated CDCP1 predicts poor patient outcome and mediates ovarian clear cell carcinoma by promoting tumor spheroid formation, cell migration and chemoresistance
Journal name Oncogene   Check publisher's open access policy
ISSN 0950-9232
1476-5594
Publication date 2016
Year available 2015
Sub-type Article (original research)
DOI 10.1038/onc.2015.101
Open Access Status File (Author Post-print)
Volume 35
Issue 4
Start page 468
End page 478
Total pages 11
Place of publication London, United Kingdom
Publisher Nature Publishing Group
Collection year 2016
Language eng
Formatted 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.
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Mater Research Institute-UQ (MRI-UQ)
Official 2016 Collection
School of Medicine Publications
 
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