Journal article
Tumoricidal activity of high-dose tumor necrosis factor-alpha is mediated by macrophage-derived nitric oxide burst and permanent blood flow shutdown
International journal of cancer, v 123(2), pp 464-475
15 Jul 2008
PMID: 18449880
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
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 flow 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 flow shutdown, resulting in tumor ulceration in the responsive tumor.
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Details
- Title
- Tumoricidal activity of high-dose tumor necrosis factor-alpha is mediated by macrophage-derived nitric oxide burst and permanent blood flow shutdown
- Creators
- Chandrakala Menon - University of PennsylvaniaTodd W Bauer - University of PennsylvaniaScott T Kelley - University of PennsylvaniaDan J Raz - University of PennsylvaniaJoshua I Bleier - University of PennsylvaniaKrina Patel - University of PennsylvaniaKirsten Steele - University of PennsylvaniaIndira Prabakaran - University of PennsylvaniaAlexander Shifrin - University of PennsylvaniaDonald G Buerk - University of PennsylvaniaChandra M Sehgal - University of PennsylvaniaDouglas L Fraker - University of Pennsylvania
- Publication Details
- International journal of cancer, v 123(2), pp 464-475
- Publisher
- Wiley
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- School of Biomedical Engineering, Science, and Health Systems
- Web of Science ID
- WOS:000256760300030
- Scopus ID
- 2-s2.0-44949091384
- Other Identifier
- 991019231751404721
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- Web of Science research areas
- Oncology