Thrombospondin-1 associated with tumor microenvironment contributes to low-dose cyclophosphamide-mediated endothelial cell apoptosis and tumor growth suppression.
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.
Center for Matrix Biology, Department of Medicine and the Cancer Center, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
Yuki
Y
Hamano
Hikaru
H
Sugimoto
Mary A
MA
Soubasakos
Mark
M
Kieran
Bjorn R
BR
Olsen
Jack
J
Lawler
Akulapalli
A
Sudhakar
Raghu
R
Kalluri
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001324:Autoantigens / Q000502:physiology; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D024141:Collagen Type IV / Q000502:physiology; D003520:Cyclophosphamide / Q000494:pharmacology* / Q000627:therapeutic use; D043169:Endostatins / Q000502:physiology; D042783:Endothelial Cells / Q000187:drug effects* / Q000473:pathology; D020782:Matrix Metalloproteinases / Q000032:analysis; D051379:Mice; D008810:Mice, Inbred C57BL; D041681:NIH 3T3 Cells; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D019700:Thrombospondin 1 / Q000032:analysis / Q000502:physiology*
D020533:Angiogenesis Inhibitors; D001324:Autoantigens; D024141:Collagen Type IV; D043169:Endostatins; D019700:Thrombospondin 1; C057112:type IV collagen alpha3 chain; D003520:Cyclophosphamide; D020782:Matrix Metalloproteinases