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Decreased adhesiveness, resistance to anoikis and suppression of GRP94 are integral to the survival of circulating tumor cells in prostate cancer

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Abstract

The presence of circulating tumor cells (CTC) is common in prostate cancer patients, however until recently their clinical significance was unknown. The CTC stage is essential for the formation of distant metastases, and their continuing presence after radical prostatectomy has been shown to predict recurrent or latent disease. Despite their mechanistic and prognostic importance, due both to their scarcity and difficulties in their isolation, little is known about the characteristics that enable their production and survival. The aim of this study was to investigate the molecular mechanisms underlying the survival of CTC cells. A novel CTC cell line from the bloodstream of an orthotopic mouse model of castration-resistant prostate cancer was established and compared with the primary tumor using attachment assays, detachment culture, Western blot, flow cytometry and 2D gel electrophoresis. Decreased adhesiveness and expression of adhesion molecules E-cadherin, β4-integrin and γ-catenin, together with resistance to detachment and drug-induced apoptosis and upregulation of Bcl-2 were integral to the development of CTC and their survival. Using proteomic studies, we observed that the GRP94 glycoprotein was suppressed in CTC. GRP94 was also shown to be suppressed in a tissue microarray study of 79 prostate cancer patients, indicating its possible role in prostate cancer progression. Overall, this study suggests molecular alterations accounting for the release and survival of CTC, which may be used as drug targets for either anti-metastatic therapy or the suppression of latent disease. We also indicate the novel involvement of GRP94 suppression in prostate cancer metastasis.

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Abbreviations

CTC:

Circulating tumor cells

HRPC:

Hormone Refractory Prostate Cancer

IEF:

Isoelectric focusing

ER:

Endoplasmic reticulum

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Acknowledgment

The work was supported by American Association for Cancer Research to X. Wang.

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Authors and Affiliations

  1. Department of Internal Medicine, Georgetown University Hospital, 3800 Reservoir Road, NW, Washington, DC, 20007, USA

    Edward W. Howard

  2. Cancer Biology Group, Departments of Anatomy and Pathology, Faculty of Medicine, University of Hong Kong, Hong Kong, Hong Kong

    Steve C. L. Leung, H. F. Yuen, Chee Wai Chua, Davy T. Lee, K. W. Chan, Xianghong Wang & Yong Chuan Wong

  3. Department of Anatomy, The University of Hong Kong, 1/F, Faculty of Medicine Building, 21 Sassoon Road, Hong Kong, Hong Kong

    Xianghong Wang & Yong Chuan Wong

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  1. Edward W. Howard
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Correspondence to Xianghong Wang or Yong Chuan Wong.

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Howard, E.W., Leung, S.C.L., Yuen, H.F. et al. Decreased adhesiveness, resistance to anoikis and suppression of GRP94 are integral to the survival of circulating tumor cells in prostate cancer. Clin Exp Metastasis 25, 497–508 (2008). https://doi.org/10.1007/s10585-008-9157-3

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