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Carcinogenesis Advance Access published online on April 15, 2008
Carcinogenesis, doi:10.1093/carcin/bgn077
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

A novel role of thrombospondin-1 in cervical carcinogenesis: Inhibit stroma reaction by inhibiting activated fibroblasts from invading cancer

Ming-Ping Wu1,2,3, Ming-Jer Young1,2, Ching-Cherng Tzeng4, Chii-Ruey Tzeng3, Kuo-Feng Huang1, Li-Wha Wu2,5,* and Cheng-Yang Chou2,6

1 Department of Obstetrics and Gynecology, Chi Mei Foundation Hospital, Tainan, Taiwan
2 Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
3 Department of Obstetrics and Gynecology, College of Medicine, Taipei Medical University, Taipei, Taiwan
4 Department of Pathology, Chi Mei Foundation Hospital, Tainan, Taiwan
5 Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
6 Department of Obstetrics and Gynecology, College of Medicine, National Cheng Kung University, Tainan, Taiwan

To whom correspondence should be addressed: Dr. Cheng-Yang Chou, Department of Obstetrics and Gynecology, College of Medicine, National Cheng Kung University, 138 Sheng-Li Rd. 704, Tainan, Taiwan Tel: 886 6 2353535 ext 5608; Fax: 886 6 2766185 e-mail: chougyn{at}mail.ncku.edu.tw

Thrombospondin-1 (TSP-1), a potent angiogenesis inhibitor, has been shown to exert different biological functions on various cell types. Here we investigate the role of TSP-1 in tumor stroma reaction, which is mainly characterized by fibroblast activation to create a permissive microenvironment for tumor progression. Immunohistochemistry examinations in the human surgical specimens have shown a downregulation of TSP-1 during the progression of cervical carcinogenesis was accompanied by an emergence in the upregulation of stroma markers, {alpha}-SMA and desmin. Transfection of SiHa cervical cancer cells with a plasmid expressing the TSP-1 protein exhibited anti-angiogenic activity in vitro, and resulted in reduced tumor growth in SCID mice, which was accompanied by a decrease in tumor vascularization and lower expressions of {alpha}-SMA and desmin than those in the vector controls. Transfection with TSP-1 and purified TSP-1 added to NIH3T3 cells did not alter the protein levels of {alpha}-SMA and desmin, but significantly inhibited matrix metalloprotease-2 (MMP-2) activity. Transforming growth factor β (TGF-β), a major factor in the activation of fibroblasts, increased {alpha}-SMA and desmin expression, and the ability of cell migration and invasion in NIH3T3 cells. The increased migration ability and the invasive ability into tumor cluster of TGF-β-treated-NIH3T3 cells were dose-dependently inhibited by TSP-1. In contrast, ectopic TSP-1 expression in SiHa cells has little effect on the invasive ability of the NIH3T3 cells. Together, our findings demonstrate a novel role of TSP-1 to inhibit tumor stroma reaction that could be attributed to the blockage of activated fibroblasts from invading cancer cells.

Key Words: thrombospondin-1 • stromal reaction • cervical neoplasms • angiogenesis • activated fibroblasts

* Wu LW is a co-corresponding author.

Received October 2, 2007; revised March 11, 2008; accepted March 15, 2008.


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