This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hamano, Y. Articles by Kalluri, R. Search for Related Content PubMed PubMed Citation Articles by Hamano, Y. Articles by Kalluri, R.

Thrombospondin-1 Associated with Tumor Microenvironment Contributes to Low-Dose Cyclophosphamide-Mediated Endothelial Cell Apoptosis and Tumor Growth Suppression

¹ Center for Matrix Biology, Department of Medicine and the Cancer Center, and ² Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School; ³ Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School; and ⁴ Department of Cell Biology, Harvard Medical School, Boston, Massachusetts

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 3 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.

This article has been cited by other articles:

				J. CORONELLA, L. LI, K. JOHNSON, S. PIRIE-SHEPHERD, G. ROXAS, and N. LEVIN Selective Activity Against Proliferating Tumor Endothelial Cells by CVX-22, A Thrombospondin-1 Mimetic CovX-BodyTM Anticancer Res, June 1, 2009; 29(6): 2243 - 2252. [Abstract] [Full Text] [PDF]

				J. Ma and D. J. Waxman Combination of antiangiogenesis with chemotherapy for more effective cancer treatment Mol. Cancer Ther., December 1, 2008; 7(12): 3670 - 3684. [Abstract] [Full Text] [PDF]

				B. Laquente, C. Lacasa, M. M. Ginesta, O. Casanovas, A. Figueras, M. Galan, I. G. Ribas, J. R. Germa, G. Capella, and F. Vinals Antiangiogenic effect of gemcitabine following metronomic administration in a pancreas cancer model Mol. Cancer Ther., March 1, 2008; 7(3): 638 - 647. [Abstract] [Full Text] [PDF]

				A. A. Garcia, H. Hirte, G. Fleming, D. Yang, D. D. Tsao-Wei, L. Roman, S. Groshen, S. Swenson, F. Markland, D. Gandara, et al. Phase II Clinical Trial of Bevacizumab and Low-Dose Metronomic Oral Cyclophosphamide in Recurrent Ovarian Cancer: A Trial of the California, Chicago, and Princess Margaret Hospital Phase II Consortia J. Clin. Oncol., January 1, 2008; 26(1): 76 - 82. [Abstract] [Full Text] [PDF]

				J. Ma and D. J. Waxman Modulation of the antitumor activity of metronomic cyclophosphamide by the angiogenesis inhibitor axitinib Mol. Cancer Ther., January 1, 2008; 7(1): 79 - 89. [Abstract] [Full Text] [PDF]

				J. Ma and D. J. Waxman Collaboration between hepatic and intratumoral prodrug activation in a P450 prodrug-activation gene therapy model for cancer treatment Mol. Cancer Ther., November 1, 2007; 6(11): 2879 - 2890. [Abstract] [Full Text] [PDF]

				D. D. Roberts, J. S. Isenberg, L. A. Ridnour, and D. A. Wink Nitric Oxide and Its Gatekeeper Thrombospondin-1 in Tumor Angiogenesis Clin. Cancer Res., February 1, 2007; 13(3): 795 - 798. [Abstract] [Full Text] [PDF]

				M. F. McCarty and K. I. Block Preadministration of High-Dose Salicylates, Suppressors of NF-{kappa}B Activation, May Increase the Chemosensitivity of Many Cancers: An Example of Proapoptotic Signal Modulation Therapy Integr Cancer Ther, September 1, 2006; 5(3): 252 - 268. [Abstract] [PDF]

				R. Buckstein, R. S. Kerbel, Y. Shaked, R. Nayar, C. Foden, R. Turner, C. R. Lee, D. Taylor, L. Zhang, S. Man, et al. High-Dose Celecoxib and Metronomic "Low-dose" Cyclophosphamide Is an Effective and Safe Therapy in Patients with Relapsed and Refractory Aggressive Histology Non-Hodgkin's Lymphoma Clin. Cancer Res., September 1, 2006; 12(17): 5190 - 5198. [Abstract] [Full Text] [PDF]

				J. Beltinger, M. Haschke, P. Kaufmann, M. Michot, L. Terracciano, and S. Krahenbuhl Hepatic Veno-Occlusive Disease Associated with Immunosuppressive Cyclophosphamide Dosing and Roxithromycin Ann. Pharmacother., April 1, 2006; 40(4): 767 - 770. [Abstract] [Full Text] [PDF]

				R. Yap, D. Veliceasa, U. Emmenegger, R. S. Kerbel, L. M. McKay, J. Henkin, and O. V. Volpert Metronomic Low-Dose Chemotherapy Boosts CD95-Dependent Antiangiogenic Effect of the Thrombospondin Peptide ABT-510: A Complementation Antiangiogenic Strategy Clin. Cancer Res., September 15, 2005; 11(18): 6678 - 6685. [Abstract] [Full Text] [PDF]

				L. A. Ridnour, J. S. Isenberg, M. G. Espey, D. D. Thomas, D. D. Roberts, and D. A. Wink Nitric oxide regulates angiogenesis through a functional switch involving thrombospondin-1 PNAS, September 13, 2005; 102(37): 13147 - 13152. [Abstract] [Full Text] [PDF]

				M. Sund, Y. Hamano, H. Sugimoto, A. Sudhakar, M. Soubasakos, U. Yerramalla, L. E. Benjamin, J. Lawler, M. Kieran, A. Shah, et al. Function of endogenous inhibitors of angiogenesis as endothelium-specific tumor suppressors PNAS, February 22, 2005; 102(8): 2934 - 2939. [Abstract] [Full Text] [PDF]

				Z. Qiuping, X. Jei, J. Youxin, J. Wei, L. Chun, W. Jin, W. Qun, L. Yan, H. Chunsong, Y. Mingzhen, et al. CC Chemokine Ligand 25 Enhances Resistance to Apoptosis in CD4+ T Cells from Patients with T-Cell Lineage Acute and Chronic Lymphocytic Leukemia by Means of Livin Activation Cancer Res., October 15, 2004; 64(20): 7579 - 7587. [Abstract] [Full Text] [PDF]