Carcinogenesis Advance Access originally published online on April 15, 2008
Carcinogenesis 2008 29(6):1115-1123; doi:10.1093/carcin/bgn077
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A novel role of thrombospondin-1 in cervical carcinogenesis: inhibit stroma reaction by inhibiting activated fibroblasts from invading cancer
1 Department of Obstetrics and Gynecology, Chi Mei Foundation Hospital, Tainan 710, Taiwan
2 Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan
3 Department of Obstetrics and Gynecology, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
4 Department of Pathology, Chi Mei Foundation Hospital, Tainan 710, Taiwan
5 Institute of Molecular Medicine
6 Department of Obstetrics and Gynecology, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan
* To whom correspondence should be addressed. Tel: +886 6 2353535 ext. 5608; Fax: +886 6 2766185; Email: chougyn{at}mail.ncku.edu.tw Correspondence may also be addressed to Li-Wha Wu. Tel: 886 6 2353535 ext. 3618; Fax: 886 6 2095845; Email: liwhawu{at}mail.ncku.edu.tw
Thrombospondin (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 that a downregulation of TSP-1 during the progression of cervical carcinogenesis was accompanied by an emergence in the upregulation of stroma markers, 
-smooth muscle actin (-SMA) and desmin. Transfection of SiHa cervical cancer cells with a plasmid expressing the TSP-1 protein exhibited antiangiogenic activity in vitro and resulted in reduced tumor growth in severe combined immunodeficiency (SCID) mice, which was accompanied by a decrease in tumor vascularization and lower expressions of -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 -SMA and desmin but significantly inhibited matrix metalloprotease-2 activity. Transforming growth factor-β (TGF-β), a major factor in the activation of fibroblasts, increased -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.
Abbreviations: CIS, carcinoma in situ; CM, conditioned medium; HUVEC, human umbilical vein endothelial cell; MMP, matrix metalloprotease; SCC, squamous cell carcinoma; SCID, severe combined immunodeficiency; -SMA, -smooth muscle actin; SPARC, secreted protein, acidic and rich in cysteine; TGF-β, transforming growth factor-β; TSP-1, thrombospondin
Received October 2, 2007; revised March 11, 2008; accepted March 15, 2008.