Thrombospondin-based antiangiogenic therapy

Zhang, Xuefeng; Lawler, Jack

doi:10.1016/j.mvr.2007.04.007

Cited by 127 publications

(106 citation statements)

References 88 publications

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“…Multiple therapeutic strategies for the inhibition of tumor angiogenesis by increasing the level of TSP-1 have been proposed [43]. In addition, the anti-angiogenic compound ABT-510 is currently in clinical trials for the treatment of cancer [44,45].…”

Section: Tsr2 ± Rfk Inhibits Tumor Growth and Metastasismentioning

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: Tsr2 ± Rfk Inhibits Tumor Growth and Metastasismentioning

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 (TSP1) is a trimeric glycoprotein composed of three identical (∼145-kDa) polypeptide chains that contain multiple structural elements (31). In physiological conditions, high expression is restricted to megakaryocytes and platelets, being stored in α-granules, and TSP1 is secreted on platelet activation.…”

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confidence: 99%

Thrombospondin-1 acts as a ligand for CD148 tyrosine phosphatase

Takahashi¹,

Mernaugh²,

Friedman³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

109

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CD148 is a receptor-type protein tyrosine phosphatase that is expressed in several cell types, including vascular endothelial cells and duct epithelial cells. Growing evidence demonstrates a prominent role for CD148 in negative regulation of growth factor signals, suppressing cell proliferation and transformation. However, its extracellular ligand(s) remain unknown. To identify the ligand(s) of CD148, we introduced HA-tagged CD148 into cultured endothelial cells and then isolated its interacting extracellular protein(s) by biotin surface labeling and subsequent affinity purifications. The binding proteins were identified by mass spectrometry. Here we report that soluble thrombospondin-1 (TSP1) binds to the extracellular part of CD148 with high affinity and specificity, and its binding increases CD148 catalytic activity, leading to dephosphorylation of the substrate proteins. Consistent with these findings, introduction of CD148 conferred TSP1-mediated inhibition of cell growth to cells which lack CD148 and TSP1 inhibition of growth. Further, we demonstrate that TSP1-mediated inhibition of endothelial cell growth is antagonized by soluble CD148 ectodomain as well as by CD148 gene silencing. These findings provide evidence that CD148 functions as a receptor for TSP1 and mediates its inhibition of cell growth.growth factor signaling | EGF receptor | VEGF receptor | ERK

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confidence: 99%

“…TSPs directly bind and clear growth factors (such as vascular endothelial growth factor, VEGF) and metalloproteinases. [7][8][9] Interactions with matrix metalloproteinases 2 and 9 are thought to alter extracellular matrix integrity and modulate the ability of the endothelial cells to proliferate. 10 As well, the TSP2 homolog TSP1 induces endothelial cell apoptosis through the CD36 receptor and blocks nitric oxide stimulated endothelial cell proliferation through interactions with the CD36 and/or CD47 receptors.…”

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confidence: 99%

Disruption of thrombospondin‐2 accelerates ischemic fracture healing

Miedel

Dishowitz

Myers

et al. 2012

Journal Orthopaedic Research

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Thrombospondin-2 (TSP2) is a matricellular protein that is highly up-regulated during fracture healing. TSP2 negatively regulates vascularity, vascular reperfusion following ischemia, and cutaneous wound healing. As well, TSP2-null mice show increased endocortical bone formation due to an enhanced number of mesenchymal progenitor cells and show increased cortical thickness. Mice deficient in TSP2 (TSP2-null) show an alteration in fracture healing, that is unrelated to their cortical bone phenotype, which is characterized by enhanced vascularization with a shift towards an intramembranous healing phenotype; thus, we hypothesized that there would be enhanced ischemic fracture healing in the absence of TSP2. We investigated whether an absence of TSP2 would enhance ischemic fracture healing utilizing Laser doppler, mCT and histological analysis. Ischemic tibial fractures were created in wildtype (WT) and TSP2-null mice and harvested 10, 20, or 40 days post-fracture. TSP2-null mice show enhanced vascular perfusion following ischemic fracture. At day 10 post-fracture, TSP2-null mice have 115% greater bone volume than WT mice. This is associated with a 122% increase in vessel density, 20% increase in cell proliferation, and 15% decrease in apoptosis compared to WT. At day 20, TSP2-null mice have 34% more bone volume, 51% greater bone volume fraction, and 37% more bone tissue mineral density than WT. By 40 days after fracture the TSP2-null mice have a 24% increase in bone volume fraction, but other parameters show no significant differences. These findings indicate TSP2 is a negative regulator of ischemic fracture healing and that in the absence of TSP2 bone regeneration is enhanced. Keywords: thrombospondin-2; ischemia; bone fracture healing Blood supply during fracture healing is crucial for proper bone repair. Vasodilation following fracture promotes edema and inflammation at the site of injury, and contributes to the development of the fracture hematoma. Inflammatory cells that occupy the hematoma produce cytokines and growth factors that then drive neovascularization which is essential for the next phases of repair. Intact vessels are required for new vessel formation to occur during the normal healing process.1,2 However, with a fracture injury there is almost always some disruption of established blood vessels. Thus, fractures with severely disrupted vascularization (ischemia) present a complex medical challenge. Up to 46% of patients with impaired vascular flow have complications during fracture repair, leading to delayed healing or nonunion that necessitates multiple surgeries that typically include staged bone grafting or possibly even amputation. [3][4][5] An important, yet largely untapped, therapeutic strategy to improve ischemic bone regeneration is to enhance vascularization at the fracture site. This can be achieved by either activating angiogenic pathways or by blocking angiogenesis inhibitors. Blocking angiogenic inhibitors has received relatively little attention as a therapeutic target in f...

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Thrombospondin-based antiangiogenic therapy

Cited by 127 publications

References 88 publications

The effect of thrombospondin-1 on breast cancer metastasis

The effect of thrombospondin-1 on breast cancer metastasis

Thrombospondin-1 acts as a ligand for CD148 tyrosine phosphatase

Disruption of thrombospondin‐2 accelerates ischemic fracture healing

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