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, Cheng-Yang Chou

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1115-1123
Number of pages9
JournalCarcinogenesis
Volume29
Issue number6
DOIs
Publication statusPublished - 2008 Jun 1

Fingerprint

Thrombospondin 1
Carcinogenesis
Fibroblasts
Desmin
Neoplasms
Transforming Growth Factors
Transfection
Severe Combined Immunodeficiency
Angiogenesis Inhibitors
Tumor Microenvironment
Metalloproteases
Uterine Cervical Neoplasms
Cell Movement
Smooth Muscle
Actins
Proteins
Plasmids
Up-Regulation
Down-Regulation
Immunohistochemistry

All Science Journal Classification (ASJC) codes

  • Cancer Research

Cite this

Wu, Ming Ping ; Young, Ming Jer ; Tzeng, Ching Cherng ; Tzeng, Chii Ruey ; Huang, Kuo Feng ; Wu, Li-Wha ; Chou, Cheng-Yang. / A novel role of thrombospondin-1 in cervical carcinogenesis : Inhibit stroma reaction by inhibiting activated fibroblasts from invading cancer. In: Carcinogenesis. 2008 ; Vol. 29, No. 6. pp. 1115-1123.
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abstract = "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.",
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A novel role of thrombospondin-1 in cervical carcinogenesis : Inhibit stroma reaction by inhibiting activated fibroblasts from invading cancer. / Wu, Ming Ping; Young, Ming Jer; Tzeng, Ching Cherng; Tzeng, Chii Ruey; Huang, Kuo Feng; Wu, Li-Wha; Chou, Cheng-Yang.

In: Carcinogenesis, Vol. 29, No. 6, 01.06.2008, p. 1115-1123.

Research output: Contribution to journalArticle

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AB - 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.

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