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Carcinogenesis Advance Access published online on May 19, 2005
Carcinogenesis, doi:10.1093/carcin/bgi128
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© The Author 2005. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oupjournals.org
Received November 24, 2004
Revised May 3, 2005
Accepted May 13, 2005

CANCER BIOLOGY

Overexpression of Id-1 in prostate cancer cells promotes angiogenesis through activation of vascular endothelial growth factor (VEGF)

Ming-Tat Ling 1, Tracy C. M. Lau 1, Chun Zhou 1, Chee Wai Chua 1, Wai Kei Kwok 1, Xianghong Wang 1*, and Yong-Chuan Wong 1

1 Cancer Biology Group, Department of Anatomy, Faculty of Medicine, The University of Hong Kong, 21 Sassoon Road, Hong Kong, SAR, China

* To whom correspondence should be addressed.
Xianghong Wang, E-mail: xhwang{at}hkucc.hku.hk


  Abstract

Androgen independent metastatic prostate cancer is the main cause of cancer related death in men. One of the reasons is the lack of understanding on the molecular mechanisms leading to metastatic progression of prostate cancer. In this study, we have demonstrated that overexpression of Id-1 (inhibitor of differentiation/DNA synthesis), a member of the helix-loop-helix family proteins, is a key factor in promoting angiogenesis through activation of the Vascular Endothelial Growth Factor (VEGF) in prostate cancer cells. Using prostate cancer cells ectopically transfected with the Id-1 gene, we found that upregulation of Id-1 was able to induce VEGF secretion through activation of the VEGF gene transcription. Downregulation of Id-1, however, led to suppression of VEGF secretion and its gene promoter activity. The association of Id-1 and VEGF was also confirmed on human xenografts by immunohistochemical staining. In addition, the growth medium generated by the Id-1 expressing cells was able to promote morphological changes as well as capillary tube formation in human umbilical vein endothelial cells (HUVEC) at similar degrees to the recombinant human VEGF. Furthermore, inhibition of VEGF function by treatment with an Flk-1 inhibitor, SU1498, or with the VEGF neutralizing antibody resulted in the reverse of the angiogenic effect on HUVEC cells. Our results suggest that overexpression of Id-1 in prostate cancer cells may provide an autocrine signal to promote angiogenesis through activation of VEGF. Since increased Id-1 has been reported in many types of advanced human cancers, our results indicate that downregulation of Id-1 may be a novel target to inhibit the growth of metastatic cancers through suppression of angiogenesis.

Keywords: Id-1; VEGF; prostate cancer; angiogenesis.
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