Yu Joanne, May Linda, Milsom Chloe, Anderson G Mark, Weitz Jeffrey I, Luyendyk James P, Broze George, Mackman Nigel, Rak Janusz
Henderson Research Centre, McMaster University, Hamilton, ON, Canada.
Arterioscler Thromb Vasc Biol. 2008 Nov;28(11):1975-81. doi: 10.1161/ATVBAHA.108.175083. Epub 2008 Sep 4.
The role of host-derived tissue factor (TF) in tumor growth, angiogenesis, and metastasis has hitherto been unclear and was investigated in this study.
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.
Our study points to an important but context-dependent role of host TF in tumor formation, angiogenesis and therapy.
宿主源性组织因子（TF）在肿瘤生长、血管生成和转移中的作用迄今尚不清楚，本研究对此进行了探究。
我们比较了野生型（wt）小鼠或TF水平降低99%的动物（低TF小鼠）体内肿瘤的生长、血管形成以及对环磷酰胺（CTX）的反应。低TF小鼠体内3种不同类型可移植肿瘤（LLC、B16F1和ES畸胎瘤）的总体生长速率或转移情况未发生变化。然而，在这些小鼠中观察到了一些意外的肿瘤/背景特异性改变，包括：（1）B16F1肿瘤中肿瘤血管大小减小；（2）LLC模型中脾脏更大且对CTX毒性的耐受性更强；（3）在低TF小鼠中接种TF缺陷肿瘤细胞（ES TF(-/-)）后肿瘤生长停止。TF缺陷肿瘤细胞在TF水平正常的小鼠中易于生长，并且仅吸引宿主相关血管（无血管生成拟态）。我们推测这种互补性可能源于含TF微泡的肿瘤-血管转移，因为我们在体外和体内使用人癌细胞（A431）和小鼠内皮细胞均观察到了这种转移。
我们的研究指出宿主TF在肿瘤形成、血管生成和治疗中具有重要但依赖背景的作用。
