Thrombospondin1 selectively inhibits early-stage carcinogenesis and angiogenesis but not tumor lymphangiogenesis and lymphatic metastasis in transgenic mice (original) (raw)
Related papers
The American Journal of Pathology, 1999
The function of the endogenous angiogenesis inhibitor thrombospondin-1 (TSP-1) in epithelial tumor development has remained controversial. We studied the in vitro growth characteristics and the in vivo tumor xenograft growth of the human squamous cell carcinoma cell lines A431 and SCC-13 , stably transfected to overexpress human TSP-1. Overexpression of TSP-1 inhibited tumor growth of A431 xenotransplants , and completely abolished tumor formation by SCC-13 cells. TSP-1 overexpressing A431 tumors were characterized by extensive areas of necrosis and by decreased tumor vessel number and size. The effects of TSP-1 on tumor cell growth were indirect since tumor cell proliferation rates in vivo and in vitro , anchorage-dependent and -independent growth in vitro, and susceptibility to induction of apoptosis by serum withdrawal were unchanged in TSP-1 overexpressing tumor cells. However , TSP-1 overexpression up-regulated the TSP-1 receptor CD36 , leading to enhanced adhesion of A431 cells to TSP-1. These findings establish TSP-1 as a potent inhibitor of angiogenesis and tumor growth in carcinomas of the skin.
The EMBO Journal, 2001
The angiogenic switch during tumorigenesis is thought to be induced by a change in the balance of proangiogenic and anti-angiogenic factors. To elucidate the biological role of the endogenous angiogenesis inhibitor thrombospondin-2 (TSP-2) during multistep carcinogenesis, we subjected TSP-2-de®cient and wildtype mice to a chemical skin carcinogenesis regimen. Surprisingly, TSP-2 expression was strongly upregulated in the mesenchymal stroma of wild-type mice throughout the consecutive stages of tumorigenesis whereas the angiogenesis factor, vascular endothelial growth factor, was induced predominantly in tumor cells. TSP-2 de®ciency dramatically enhanced susceptibility to skin carcinogenesis and resulted in accelerated and increased tumor formation. The angiogenic switch occurred in early stages of pre-malignant tumor formation, and tumor angiogenesis was sig-ni®cantly enhanced in TSP-2-de®cient mice. While TSP-2 de®ciency did not affect tumor differentiation or proliferation, tumor cell apoptosis was signi®cantly reduced. These results reveal upregulation of an endogenous angiogenesis inhibitor during multistep tumorigenesis and identify enhanced stromal TSP-2 expression as a novel host anti-tumor defense mechanism.
Regulation of tumor angiogenesis by thrombospondin-1
Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, 2006
Angiogenesis plays a critical role in the growth and metastasis of tumors. Thrombospondin-1 (TSP-1) is a potent angiogenesis inhibitor, and down-regulation of TSP-1 has been suggested to alter tumor growth by modulating angiogenesis in a variety of tumor types. Expression of TSP-1 is up-regulated by the tumor suppressor gene, p53, and down-regulated by oncogenes such as Myc and Ras. TSP-1 inhibits angiogenesis by inhibiting endothelial cell migration and proliferation and by inducing apoptosis. In addition, activation of transforming growth factor beta (TGFβ) by TSP-1 plays a crucial role in the regulation of tumor progression. An understanding of the molecular basis of TSP-1-mediated inhibition of angiogenesis and tumor progression will aid in the development of novel therapeutics for the treatment of cancer.
Proceedings of the National Academy of Sciences, 1999
The development of skin carcinomas presently is believed to be correlated with mutations in the p53 tumor suppressor and ras gene as well as with the loss of chromosome 9. We now demonstrate that, in addition, loss of chromosome 15 may be a relevant genetic defect. Reintroduction of an extra copy of chromosome 15, but not chromosome 4, into the human skin carcinoma SCL-I cells, lacking one copy of each chromosome, resulted in tumor suppression after s.c. injection in mice. Transfection with thrombospondin-1 (TSP-1), mapped to 15q15, induced the same tumor suppression without affecting cell proliferation in vitro or in vivo. Halted tumors remained as small cysts encapsulated by surrounding stroma and blood vessels. These cysts were characterized by increased TSP-1 matrix deposition at the tumor/stroma border and a complete lack of tumor vascularization. Coinjection of TSP-1 antisense oligonucleotides drastically reduced TSP-1 expression and almost completely abolished matrix deposition at the tumor/stroma border. As a consequence, the tumor phenotype reverted to a well vascularized, progressively expanding, solid carcinoma indistinguishable from that induced by the untransfected SCL-I cells. Thus, these data strongly suggest TSP-1 as a potential tumor suppressor on chromosome 15. The data further propose an unexpected mechanism of TSP-1-mediated tumor suppression. Instead of interfering with angiogenesis in general, in this system TSP-1 acts as a matrix barrier at the tumor/stroma border, which, by halting tumor vascularization, prevents tumor cell invasion and, thus, tumor expansion.
Thrombospondin-2: A potent endogenous inhibitor of tumor growth and angiogenesis
Proceedings of the National Academy of Sciences, 1999
Recent evidence suggests a potential role for thrombospondin-2 (TSP-2), a matricellular glycoprotein, in the regulation of primary angiogenesis. To directly examine the biological effect of TSP-2 expression on tumor growth and angiogenesis, human A431 squamous cell carcinoma cells, which do not express TSP-2, were stably transfected with a murine TSP-2 expression vector or with vector alone. A431 cells expressing TSP-2 did not show an altered growth rate, colony-forming ability, or susceptibility to induction of apoptosis in vitro. However, injection of TSP-2-transfected clones into the dermis of nude mice resulted in pronounced inhibition of tumor growth that was significantly stronger than the inhibition observed in A431 clones stably transfected with a thrombospondin-1 (TSP-1) expression vector, and combined overexpression of TSP-1 and TSP-2 completely prevented tumor formation. Extensive areas of necrosis were observed in TSP-2-expressing tumors, and both the density and the siz...
In vivo mechanisms by which tumors producing thrombospondin 1 bypass its inhibitory effects
Genes & Development, 2001
Thrombospondin 1 (TSP1) is a multifunctional protein able to activate TGFβ and to inhibit angiogenesis in vivo. Although usually thought of as an inhibitor of tumor growth, TSP1 may sometimes be present at high levels during tumor progression, suggesting that tumors can eventually overcome their anti-tumor effects. Using a tet-repressible expression system, we demonstrate that murine TSP1 delayed the onset of tumor growth when produced in the tumor bed by rat fibrosarcoma tumor cells or by stromal fibroblasts coinjected with unmodified C6 glioma tumor cells. Yet upon prolonged exposure to TSP1, tumors came to grow at the same rate in the presence as in the absence of TSP1 and transplantation experiments showed that they had become insensitive to inhibition by TSP1 in both syngeneic and immune compromised hosts. Tumor resistance to TSP1 developed as a result of the in vivo outgrowth of pre-existing tumor cell variants that (1) secreted increased amounts of angiogenic factors that cou...
THE ANTIANGIOGENIC EFFECTS OF THROMBOSPONDIN1 AND -2 IN TUMORS
2000
Angiogenesis, the formation of new vessels, is a multistage process and is critical for the growth and proliferation of tumors. The identification of natural modulators of angiogenesis is essential to the understanding of this complex process. All five TSP family members are multimeric and modular heparin-and calcium-binding proteins, but two subfamilies from thrombospondins family (TSP-1 and TSP-2) have antiangiogenic activity.
Carcinogenesis, 2008
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, a-smooth muscle actin (a-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 a-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 a-SMA and desmin but significantly inhibited matrix metalloprotease-2 activity. Transforming growth factor-b (TGF-b), a major factor in the activation of fibroblasts, increased a-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-b-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.
Gynecology and Minimally Invasive Therapy, 2016
Tumor growth is angiogenesis dependent. Angiogenic switch (the acquisition of an angiogenic phenotype) is essential for cervical carcinogenesis. Thrombospondin-1 (TSP-1) is an endogenous angiogenic inhibitor with multiple functional domains and interacting receptors. The disruption of TSP-1 fence (the expression in basal epithelia) occurred concordantly during the transition from low-grade squamous intraepithelial lesion into high-grade squamous intraepithelial lesion. This concordance suggests that TSP-1 plays a role in the regulation of angiogenic switch during cervical carcinogenesis. Tumor vasculature as a therapeutic target offers a paradigm shift for anticancer therapy. Endothelial cells do not appear to acquire resistance during antiangiogenic therapy. Low-and-frequent dose "metronic" chemotherapy is found to be antiangiogenic, which is more effective in targeting tumor endothelia than traditional large, single bolus doses. Meanwhile, the invasion process of cancers is associated with stroma reaction, which is characterized by fibroblasts' activation. In addition to the well-known angiogenesis inhibitor, TSP-1 also has a novel role of blocking activated fibroblasts (myofibroblasts) from invading cancer. Activated fibroblasts during stroma reaction could be used as an efficient drug delivery system to prevent or slow the local growth of cancer cells. Elucidation of the mechanism by which fibroblasts are recruited into cancer stroma could lead to new insights into not only the mechanisms of cancer progression but also strategies for cancer treatment. A better understanding of stromal contributions to cancer progression will likely result in the identification of new therapeutics targeting the stroma.