Published online before print September 4, 2008, doi: 10.1161/ATVBAHA.108.175083
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© 2008 American Heart Association, Inc.
Integrative Physiology/Experimental Medicine |
Contribution of Host-Derived Tissue Factor to Tumor Neovascularization
From the Henderson Research Centre (J.Y., L.M., C.M., J.I.W., J.R.), McMaster University, Hamilton, ON, Canada; the University of Toronto (J.Y.), ON, Canada; Centocor Inc (G.M.A.) Radnor, Pa; the Department of Pharmacology, Toxicology and Therapeutics (J.P.L.) University of Kansas Medical Center, Kansas City, Kansas; the Department of Hematology (G.B.), Washington University School of Medicine, St. Louis, Mo; the Department of Medicine (N.M.), University of North Carolina- Chapel Hill; and the Montreal Children’s Hospital (J.R.), McGill University, QC, Canada.
Correspondence to Janusz Rak, Montreal Children’s Hospital Research Institute, Place Toulon, 4060 Ste Catherine West, PT-232, Montreal, Quebec, H3Z 2Z3, Canada. E-mail janusz.rak{at}mcgill.ca
Objective— The role of host-derived tissue factor (TF) in tumor growth, angiogenesis, and metastasis has hitherto been unclear and was investigated in this study.
Methods and Results— We compared tumor growth, vascularity, and responses to cyclophosphamide (CTX) of tumors in wild-type (wt) mice, or in animals with TF levels reduced by 99% (low-TF mice). Global growth rate of 3 different types of transplantable tumors (LLC, B16F1, and ES teratoma) or metastasis were unchanged in low-TF mice. However, several unexpected tumor/context-specific alterations were observed in these mice, including: (1) reduced tumor blood vessel size in B16F1 tumors; (2) larger spleen size and greater tolerance to CTX toxicity in the LLC model; (3) aborted tumor growth after inoculation of TF-deficient tumor cells (ES TF–/–) in low-TF mice. TF-deficient tumor cells grew readily in mice with normal TF levels and attracted exclusively host-related blood vessels (without vasculogenic mimicry). We postulate that this complementarity may result from tumor-vascular transfer of TF-containing microvesicles, as we observed such transfer using human cancer cells (A431) and mouse endothelial cells, both in vitro and in vivo.
Conclusions— Our study points to an important but context-dependent role of host TF in tumor formation, angiogenesis and therapy.
Tumor angiogenesis in animals with low levels of TF (low-TF mice) has not been studied. We report that reduced levels of host-related TF impaired growth of TF-deficient teratomas, but not TF-proficient tumors. We suggest that TF can be shared between tumor and host cells via microvesicles.
Key Words: angiogenesis • tissue factor • tumor • microvesicles • cyclophosphamide
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