Journal Article

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

Ming-Ping Wu, Ming-Jer Young, Ching-Cherng Tzeng, Chii-Ruey Tzeng, Kuo-Feng Huang, Li-Wha Wu and Cheng-Yang Chou

in Carcinogenesis

Volume 29, issue 6, pages 1115-1123
Published in print June 2008 | ISSN: 0143-3334
Published online April 2008 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgn077
A novel role of thrombospondin-1 in cervical carcinogenesis: inhibit stroma reaction by inhibiting activated fibroblasts from invading cancer

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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, α-smooth muscle actin (α-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 α-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 α-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 α-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.

Journal Article.  5634 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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