Tumoricidal activity of high-dose tumor necrosis factor-α is mediated by macrophage-derived nitric oxide burst and permanent blood flow shutdown

被引:9
|
作者
Menon, Chandrakala [1 ]
Bauer, Todd W. [1 ]
Kelley, Scott T. [1 ]
Raz, Dan J. [1 ]
Bleier, Joshua I. [1 ]
Patel, Krina [1 ]
Steele, Kirsten [1 ]
Prabakaran, Indira [1 ]
Shifrin, Alexander [1 ]
Buerk, Donald G. [2 ]
Sehgal, Chandra M. [1 ,3 ]
Fraker, Douglas L. [1 ]
机构
[1] Univ Penn, Dept Surg, Philadelphia, PA 19104 USA
[2] Univ Penn, Dept Physiol, Philadelphia, PA 19104 USA
[3] Univ Penn, Dept Radiol, Philadelphia, PA 19104 USA
关键词
high-dose TNF; nitric oxide; blood flow; macrophage; tumor;
D O I
10.1002/ijc.23499
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
This study investigates the role of tumor nitric oxide (NO) and vascular regulation in tumor ulceration following high-dose tumor necrosis factor-alpha (TNF) treatment. Using TNF-responsive (MethA) and nonresponsive (LL2) mouse tumors, tumor NO concentration was measured with an electrochemical sensor and tumor blood flow by Doppler ultrasound. Mice were also pretreated with a selective inducible nitric oxide synthase (iNOS) inhibitor, 1400 W. Tumors harvested from TNF-treated mice were cryosectioned and immunostained for murine macrophages, or/and iNOS. MethA tumor-bearing mice were depleted of macrophages. Pre- and post-TNF tumor NO levels were measured continuously, and mice were followed for gross tumor response. In MethA tumors, TNF caused a 96% response rate, and tumor NO concentration doubled. Tumor blood flow decreased to 3% of baseline by 4 hr and was sustained at 24 hr and 10 days post-TNF. Selective NO inhibition with 1400 W blocked NO rise and decreased response rate to 38%. MethA tumors showed tumor infiltration by macrophages post-TNF and the pattern of macrophage immunostaining overlapped with iNOS immunostaining. Depletion of macrophages inhibited tumor NO increase and response to TNF. LL2 tumors had a 0% response rate to TNF and exhibited no change in NO concentration. Blood How decreased to 2% of baseline by 4 hr, recovered to 56% by 24 hr and increased to 232% by 10 days. LL2 tumors showed no infiltration by macrophages post-TNF. We conclude that TNF causes tumor infiltrating, macrophage-derived iNOS-mediated tumor NO rise and sustained tumor blood How shutdown, resulting in tumor ulceration in the responsive tumor. (C) 2008 Wiley-Liss, Inc.
引用
收藏
页码:464 / 475
页数:12
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