| Thrombospondin-1 associated with tumor microenvironment contributes to low-dose cyclophosphamide-mediated endothelial cell apoptosis and tumor growth suppression. | |
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MedLine Citation:
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PMID: 14996710 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Low-dose cyclophosphamide (LDC) induces selective apoptosis of endothelial cells within the vascular bed of tumors. Here, we investigated a hypothesis that the effect of LDC is mediated by the pro-apoptotic action of endogenous inhibitors of angiogenesis. Tumors treated with LDC demonstrate similar expression of matrix metalloproteinases and also basement membrane-derived angiogenesis inhibitors when compared with wild-type tumors, whereas the expression of thrombospondin-1 (TSP-1) is significantly elevated in LDC-treated tumors. We used mice with an absence of type XVIII collagen (endostatin) or type IV collagen alpha3 chain (tumstatin) or TSP-1 to assess the contribution of these endogenous inhibitors of angiogenesis on LDC-mediated tumor suppression. Lack of TSP-1 in the host in addition to tumor cells leads to diminished capacity of LDC to suppress tumor growth, whereas the absence of endostatin and tumstatin did not alter the effect of LDC. LDC treatment predominantly induces selective expression of TSP-1 in tumor cells and peri-vascular cells and facilitates apoptosis of proliferating endothelial cells, with minimal direct effect on tumor cells and peri-vascular cells. These studies indicate that TSP-1 contributes to tumor growth suppression induced by LDC and suggest that tumors that express high basal level of TSP-1 may be more susceptible to tumor suppression by such a regimen. This study also makes a strong case for TSP-1 expression levels as a potential predictive marker for the successful use of LDC in cancer patients. |
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Authors:
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Yuki Hamano; Hikaru Sugimoto; Mary A Soubasakos; Mark Kieran; Bjorn R Olsen; Jack Lawler; Akulapalli Sudhakar; Raghu Kalluri |
Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S. |
Journal Detail:
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Title: Cancer research Volume: 64 ISSN: 0008-5472 ISO Abbreviation: Cancer Res. Publication Date: 2004 Mar |
Date Detail:
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Created Date: 2004-03-03 Completed Date: 2004-03-31 Revised Date: 2007-11-14 |
Medline Journal Info:
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Nlm Unique ID: 2984705R Medline TA: Cancer Res Country: United States |
Other Details:
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Languages: eng Pagination: 1570-4 Citation Subset: IM |
Affiliation:
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Center for Matrix Biology, Department of Medicine and the Cancer Center, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Angiogenesis Inhibitors
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pharmacology* Animals Apoptosis / drug effects* Autoantigens / physiology Cell Division / drug effects Cell Survival / drug effects Collagen Type IV / physiology Cyclophosphamide / pharmacology*, therapeutic use Endostatins / physiology Endothelial Cells / drug effects*, pathology Matrix Metalloproteinases / analysis Mice Mice, Inbred C57BL NIH 3T3 Cells Neoplasms, Experimental / drug therapy* Thrombospondin 1 / analysis, physiology* |
| Grant Support | |
ID/Acronym/Agency:
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DK 55001/DK/NIDDK NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Angiogenesis Inhibitors; 0/Autoantigens; 0/Collagen Type IV; 0/Endostatins; 0/Thrombospondin 1; 0/type IV collagen alpha3 chain; 50-18-0/Cyclophosphamide; EC 3.4.24.-/Matrix Metalloproteinases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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