The cell biology of thrombospondin-1

Chen, Hui; Herndon, Mary E.; Lawler, Jack

doi:10.1016/s0945-053x(00)00107-4

Cited by 365 publications

(278 citation statements)

References 151 publications

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“…The thrombospondins comprise a family of homologous proteins that serve to regulate cellular phenotype and extracellular matrix structure during tissue genesis and remodeling [1]. Thrombospondin-1 (TSP-1), the first member identified, has been shown to be a potent inhibitor of angiogenesis and tumor progression [2].…”

Section: Introductionmentioning

confidence: 99%

The effect of thrombospondin-1 on breast cancer metastasis

Yee

Connolly

Duquette

et al. 2008

Breast Cancer Res Treat

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111

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Thrombospondin-1 (TSP-1) has been proposed to have both pro-metastatic and anti-metastatic properties. To elucidate its role in breast cancer metastasis, we compared tumor progression in the polyomavirus middle T antigen (Pyt) transgenic mouse and the TSP-1-null Pyt transgenic mouse. We characterized the tumors in these mice at 45, 60 and 90 days of age. Tumor size, areas of necrosis, macrophage infiltration, levels of active and total TGF-β, vessel morphology, and lung and blood metastasis were measured in these mice. Mammary tumors were larger in the TSP-1-null mouse, and vessels were larger, but fewer in number in these tumors. The level of total TGF-β was significantly higher in the Pyt tumors at 90 days of age. Importantly, significantly fewer metastases were observed in the lungs of the TSP-1-null/Pyt mouse. Primary Pyt tumor cells were more migratory than TSP-1-null Pyt tumor cells on collagen. Treatment of Pyt mice with recombinant proteins that contain the type-1 repeats of TSP-1 resulted in decreased primary tumor growth and metastasis. Sequences that are involved in CD36 binding and those required for TGF-β activation mediated the inhibition of primary tumor growth. Thus, TSP-1 in the mammary tumor microenvironment inhibits angiogenesis and tumor growth, but promotes metastasis to the lung in the Pyt transgenic mouse. The ability of TSP-1 to support metastasis correlates with its ability to promote tumor cell migration.

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Section: Introductionmentioning

confidence: 99%

The effect of thrombospondin-1 on breast cancer metastasis

Yee

Connolly

Duquette

et al. 2008

Breast Cancer Res Treat

Self Cite

111

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“…4 TSP1 blocks angiogenesis via CD36, a receptor constitutively expressed in a subset of endothelial cells. [5][6][7] The ability to bind multiple receptors complicates the therapeutic use of nascent TSP1.…”

Section: Introductionmentioning

confidence: 99%

In vivo upregulation of CD95 and CD95L causes synergistic inhibition of angiogenesis by TSP1 peptide and metronomic doxorubicin treatment

et al. 2005

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Antiangiogenic thrombospondin-1 (TSP1) induces endothelial cell death via a CD95-mediated cascade. We used this signaling pathway, where CD95/Fas is a rate-limiting intermediate, as a target to optimize the efficacy of TSP1 active peptide, DI-TSP. Like TSP1, DI-TSP upregulated endothelial CD95L in vivo. To modulate CD95 levels, we chose chemotherapy agent doxorubicin (DXR). DXR caused sustained upregulation of CD95 in the activated endothelium at 1/ 100 of the maximal tolerated dose. DI-TSP and DXR synergistically induced endothelial apoptosis in vitro, and in vivo, in developing murine vessels. Fas decoy, TSP1 receptor antibody and Pifithrin, a p53 inhibitor, severely decreased apoptosis and restored angiogenesis by DXR-DI-TSP combination, evidencing critical roles of CD95 and TSP1. Combined therapy synergistically blocked neovascularization and progression of the bladder and prostate carcinoma. Such informed design of a complex antiangiogenic therapy based on the rate-limiting molecular targets is a novel concept, which may yield new approaches to cancer treatment.

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“…In particular, the ability of thrombospondin 1 (TSP1) to inhibit angiogenesis in cultured cells and in vivo has been well documented (reviewed in Armstrong et al, 1998;Dawson and Bouck, 1999;Chen et al, 2000). Studies with cultured cells indicate that TSP2 also contains antiangiogenic activity (Volpert et al, 1995;Panetti et al, 1997;Bornstein et al, 2000a).…”

Section: Introductionmentioning

confidence: 99%

Thrombospondin 2 Inhibits Microvascular Endothelial Cell Proliferation by a Caspase-independent Mechanism

Armstrong¹,

Björkblom²,

Hankenson³

et al. 2002

MBoC

101

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The matricellular protein thrombospondin 2 (TSP2) regulates a variety of cell-matrix interactions. A prominent feature of TSP2-null mice is increased microvascular density, particularly in connective tissues synthesized after injury. We investigated the cellular basis for the regulation of angiogenesis by TSP2 in cultures of murine and human fibroblasts and endothelial cells. Fibroblasts isolated from murine and human dermis synthesize TSP2 mRNA and secrete significant amounts of immunoreactive TSP2, whereas endothelial cells from mouse lung and human dermis did not synthesize TSP2 mRNA or protein. Recombinant mouse TSP2 inhibited growth of human microvascular endothelial cells (HMVECs) mediated by basic fibroblast growth factor, insulin-like growth factor-1, epidermal growth factor, and vascular endothelial growth factor (VEGF). HMVECs exposed to TSP2 in the presence of these growth factors had a decreased proportion of cells in S and G 2 /M phases. HMVECs cultured with a combination of basic fibroblast growth factor, insulin-like growth factor-1, and epidermal growth factor displayed an increased proportion of nonviable cells in the presence of TSP2, but the addition of VEGF blocked this TSP2-mediated impairment of cell viability. TSP2-mediated inhibition of DNA synthesis by HMVECs in the presence of VEGF was not affected by the broadspectrum caspase inhibitor zVAD-fmk. Similar findings were obtained with TSP1. Taken together, these observations indicate that either TSP2 or TSP1 can inhibit HMVEC proliferation by inhibition of cell cycle progression and induction of cell death, but the mechanisms responsible for TSP2-mediated inhibition of cell cycle progression are independent from those leading to cell death. INTRODUCTIONThe process of wound healing is highly dependent on angiogenesis to provide a vascular network for the regenerating tissue. The study of mechanisms governing vascularization of healing connective tissues has primarily focused on proangiogenic factors occurring early in the wound-healing process. Degranulating platelets and a fibrin clot provide growth and chemotactic factors and an adhesive substrate for initial influx of endothelial cells (ECs) (Singer and Clark, 1999;Tonnesen et al., 2000). Infiltrating inflammatory cells, such as macrophages, appear at the wound site shortly after the wounding event and are also potent sources of proangiogenic factors such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) (Sunderkö tter et al., 1994). A number of these factors also induce migration of fibroblasts into the wound area and stimulate fibroblasts to deposit extracellular matrix (Kalluri and Sukhatme, 2000). The direct influence of fibroblasts on ECs in determining the vascularity of the healing wound is less clear. Regression of blood vessels seen in the resolution phase of a wound, in which fibroblasts become the predominant cell type, suggests an inhibitory role for fibroblasts in the angiogenic process (Kyriakides et al., 1999b).A large number of factors...

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The cell biology of thrombospondin-1

Cited by 365 publications

References 151 publications

The effect of thrombospondin-1 on breast cancer metastasis

The effect of thrombospondin-1 on breast cancer metastasis

In vivo upregulation of CD95 and CD95L causes synergistic inhibition of angiogenesis by TSP1 peptide and metronomic doxorubicin treatment

Thrombospondin 2 Inhibits Microvascular Endothelial Cell Proliferation by a Caspase-independent Mechanism

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