SummaryThe influence of endogenous and exogenous tumor necrosis factor (TNF) on metastasis was investigated in an experimental fibrosarcoma metastasis model. A single intraperitoneal injection of recombinant human (rh) TNF or recombinant mouse (rm) TNF into mice 5 h before intravenous inoculation of methylcholanthrene-induced fibrosarcoma cells (CFS1) induced a significant enhancement of the number of metastases in the lung. Dose responses of rmTNF and rhTNF demonstrated a stronger metastasis-augmenting effect by rmTNF compared with rhTNF. This effect was time dependent, as administration of rmTNF 5 h before or 1 h but not 24 h after tumor cell inoculation caused an increase of tumor cell colony formation on the lung surface, suggesting an influence of TNF on the vascular adhesion and diapedesis of tumor cells. Since tumor-bearing mice showed an enhanced ability to produce TNF after endotoxin injection compared to control mice, tumor-bearing mice were treated with anti-mTNF antibodies. Neutralization of endogenous tumor-induced TNF led to a significant decrease of the number of pulmonary metastases. Histological analysis of micrometastases in the lung on day 5 by silver staining of proteins associated with nucleolar organizer regions revealed more metastatic loci and augmented proliferative activity of the tumor cells after rmTNF pretreatment of mice. However, no direct effect of rmTNF on the proliferation rate of tumor cells was seen in vitro. These findings suggest that low doses of endogenous TNF or administered TNF during cytokine therapy might enhance the metastatic potential of circulating tumor cells.

Models for experimental metastasis were established to investigate the influence of rmTNF on tumor-colony formation in the liver. Highly metastatic lymphoma tumor cells were either injected i.v. or inoculated s.c. to form spontaneous metastases. In both systems, administration of rmTNF to the animals led to significant enhancement of the number of liver metastases in comparison with control groups. The number of metastatic tumor-cell colonies at an early stage of metastasis was increased, as well as the number of surface metastases in a late stage. Consequently, TNF-treated animals revealed a higher mortality. The optimal time for TNF to exert this metastasis-enhancing effect was found to be 7 days after tumor inoculation. In vitro adhesion of the lymphoma tumor cells to a mouse endothelioma cell line was strongly inhibited by monoclonal antibodies interfering with the interaction of VCAM-1 with VLA-4. These results support and extend earlier results with a fibrosarcoma lung colonization model. In addition, they show that stimulation of the immune system in tumor-bearing hosts activates tumor-promoting pathways, in addition to having possible beneficial effects.

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Inflammatory mediators such as tumor necrosis factor (TNF)and interleukin-I enhance tumor colony formation in different models of experimental and spontaneous metastasis. The involvement of the natural killer (NK) cell system in this process was investigated. Tumor necrosis factor does not appear to act directly on tumor cells by reducing their susceptibility to the cytotoxic action of NK cells but rather impairs NK activity in tumor-bearing mice. Such impairment of the natural killer system might be one means by which TNF supports tumor colony formation. Even though the metastasis-enhancing effect of TNF remained detectable in mice which have a greatly reduced NK cell cytotoxic activity due to a defect in the bg locus, normal mice which were depleted of NK cells by antibody treatment did not show enhanced metastasis after TNF injection. Therefore, the TNF-enhanced metastasis can only be seen as long as some NK cell function is operating in the animals.o 1996 Wiley-Liss, Inc.Besides the well-known anti-tumoral activity of tumor necrosis factor (TNF) in certain experimental systems, a metastasispromoting effect has been described (Malik et at., 1990;Orosz et al., 1993Orosz et al., , 1995Qin et al., 1993;Okahara et al., 1994), demonstrating a dual role of this cytokine depending on site, time and dose of administration. The enhancement of numbers of tumor lung colonies found after injection of recombinant mouse (rm)TNF or IL-1 in experimental metastasis models has been seen with different types of tumor cells. Due to the pleiotropism of these pro-inflammatory cytokines, different molecular mechanisms for this metastasis-enhancing effect can be envisaged. Several possible explanations have been discussed e.g., direct effects on the tumor cells by enhancing their proliferative capacity (Orosz et al., 1993), facilitated extravasation via enhanced expression of adhesion molecules (Miyata et al., 1992;Okahara et al., 1994) and inhibition of the host natural killer (NK) system by TNF (Palrnieri et al., 1992).We found that rmTNF inhibits NK activity in normal mice. When beige mice which have a reduced cytolytic NK activity due to a defect of the bg locus were tested, rmTNF-enhanced experimental metastasis was still observed. Depletion of NK cells in normal mice by treatment with monoclonal antibodies (MAbs) to the IL-2 receptor p chain (Tanaka et al., 1993) strongly increased metastasis compared with the bg mutation and completely abolished the TNF-induced enhancement of metastasis. Therefore, TNF seems to exert its enhancing effect on tumor colonization seen in inflammation by impairing NK functions. MATERIAL AND METHODS AnimalsSpecific pathogen-free female C3H mice 5-7 weeks of age were obtained from the Institut fur Versuchstierforschung, Hannover, Germany, or from Charles River, Sulzfeld, Germany. DBA/2 bg/bg and DBA/2 +/bg mice were a kind gift of Dr. I. Gresser (Villejuif, France). C57BI/6 beige mice were kindly provided by Dr. H. Mossmann, (Freiburg, Germany). Tumor cellsCFSl is a methylcholanthrene-induced fibros...

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Background and purpose: Brain arteriovenous malformations (AVM) are uncommon vascular lesions with the risk of hemorrhage, epileptic seizures, neurological deficits, and headache. Comparing the risks of the natural history and that of preventive treatment, a recent study has found observation more beneficial than treatment for unruptured AVMs. This study, however, did not consider the long-term impact of carrying a brain AVM on everyday activities. In this study we analyzed the Quality Of Life (QOL) of patients with untreated AVMs, a measure increasingly used in clinical trials to asses this kind of impact.Methods: We enrolled 36 patients with unruptured, untreated brain AVM from our hospital database and measured their QOL retrospectively using the EQ-5D-5L questionnaire. As a control group we used the results of the Research Report, a nationwide study based on the quality of life of 5534 healthy Hungarians in 2002. Due to the low number of cases, statistical analysis could not be made.Results: Headache proved to be the most common AVM-related sign in our cohort (40%, n = 17), with a female predominance; neurological deficit was detected in 33% (n = 14), while epileptic seizures occurred in 26% (n = 11), more commonly affecting male subjects. Anxiety and discomfort seemed to be the most prevalent influencing factors on QOL, especially in the youngest age group (18–34 years). Female subjects showed a greater dependence than men in all age groups, though males had a more significant impairment in their usual activities. Older patients were affected more significantly in their self-care and usual activities compared with the younger population.Conclusions: Untreated AVMs have a significant negative impact on patients carrying unruptured brain AVMs, as proved by QOL assessment. Beside neurological deficits, this impact should also be considered in the therapeutic decision.

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