Tumor Necrosis Factor Receptor 2-Mediated Tumor Suppression Is Nitric Oxide Dependent and Involves Angiostasis

X. Zhao, M. Mohaupt, J. Jiang, S. Liu, B. Li, Z. Qin
2007 Cancer Research  
Tumor necrosis factor (TNF) binds to two different receptors. Although most of its functions are attributed to TNF receptor 1 (TNFR1), the independent role of TNFR2 is still largely unknown. Using TNFR single or double knock-out mice, we show here that the expression of TNFR2 alone on host cells was sufficient to suppress the growth of TNF-secreting tumors in both immune competent and T/B lymphocyte-deficient severe combined immunodeficiency (SCID) mice. Histologic studies showed that TNF
more » ... ted, via TNFR2, large numbers of macrophages and efficiently inhibited angiogenesis in the tumor. In vitro, TNF activated TNFR1-deficient macrophages to produce nitric oxide (NO). Treatment of TNFR1 knock-out mice with L-NAME, a specific NO synthase inhibitor, almost completely eliminated TNF-induced angiostasis and tumor suppression. Moreover, L-NAME acted only during the first few days of tumor growth. Our results show for the first time that TNFR2 expressed on host innate immune cells is sufficient to mediate the antitumor effect of TNF, and NO is necessary for this process, possibly by inhibition of angiogenesis in the tumor. [Cancer Res 2007;67(9):4443-50] Materials and Methods Animals. BALB/c mice were purchased from Charles River and Vital River. CB17 SCID mice were purchased from Bomholtgard. TNFR1 À/À mice with a mixed genetic background of 129/Sv/Ev and C57BL/6 were kindly provided by Dr. ). TNFR2 À/À mice were obtained from The Jackson Laboratory. Both strains of mice were backcrossed for 12 generations onto the BALB/c background. To obtain TNFR1 À/À /R2 À/À mice, TNFR1 À/À mice were paired with TNFR2 À/À mice, and subsequent intercross of their offspring led to the Requests for reprints: Zhihai Qin,
doi:10.1158/0008-5472.can-07-0185 pmid:17483359 fatcat:gfcjppvoavd5tmdvybo6dpr2uu