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Clinical & Experimental Metastasis

, Volume 25, Issue 5, pp 497–508 | Cite as

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

  • Edward W. Howard
  • Steve C. L. Leung
  • H. F. Yuen
  • Chee Wai Chua
  • Davy T. Lee
  • K. W. Chan
  • Xianghong WangEmail author
  • Yong Chuan WongEmail author
Research Paper

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.

Keywords

Circulating tumor cell Metastasis Anoikis Adhesiveness GRP94 

Abbreviations

CTC

Circulating tumor cells

HRPC

Hormone Refractory Prostate Cancer

IEF

Isoelectric focusing

ER

Endoplasmic reticulum

Notes

Acknowledgment

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

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Copyright information

© Springer Science+Business Media B.V. 2008

Authors and Affiliations

  • Edward W. Howard
    • 1
  • Steve C. L. Leung
    • 2
  • H. F. Yuen
    • 2
  • Chee Wai Chua
    • 2
  • Davy T. Lee
    • 2
  • K. W. Chan
    • 2
  • Xianghong Wang
    • 2
    • 3
    Email author
  • Yong Chuan Wong
    • 2
    • 3
    Email author
  1. 1.Department of Internal MedicineGeorgetown University HospitalWashingtonUSA
  2. 2.Cancer Biology Group, Departments of Anatomy and Pathology, Faculty of MedicineUniversity of Hong KongHong KongHong Kong
  3. 3.Department of AnatomyThe University of Hong KongHong KongHong Kong

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