Spontaneous regression of lung metastasis in the absence of tumor necrosis factor receptor p55.

In order to clarify the roles of tumor necrosis factor (TNF)-alpha in lung metastasis, we injected Renca cells intravenously into TNF receptor p55-deficient (TNF-Rp55 KO) and wild-type (WT) mice. Microscopic and macroscopic metastasis foci appeared in lungs at 7 and 14 days after the tumor injection, respectively. Moreover, metastasis foci expanded at similar rates in both WT and TNF-Rp55 KO mice until 21 days, and lungs were occupied with metastasis foci. However, later than 21 days after the injection, metastasis foci spontaneously regressed in TNF-Rp55 KO mice, whereas WT mice exhibited a progressive growth of metastasis foci. Moreover, metastasis foci remained reduced sizes in TNF-Rp55 KO mice even at 26 days, when all WT mice died with lungs filled with metastasis foci. Later than 21 days after the tumor injection, the number of apoptotic tumor cells was increased in TNF-Rp55 KO mice. In contrast, neovascularization was less evident in TNF-Rp55 KO than WT mice, with depressed hepatocyte growth factor (HGF) gene in TNF-Rp55 KO mice at 21 days after the tumor injection. Thus, TNF-Rp55-mediated signals can maintain tumor neovascularization at least partly by inducing HGF expression, and eventually support lung metastasis process. (c) 2004 Wiley-Liss, Inc.