ENHANCEMENT OF EXPERIMENTAL METASTASIS BY TUMOR-NECROSIS-FACTOR

The influence of endogenous and exogenous tumor necrosis factor (TNF) on metastasis was investigated in an experimental fibrosarcoma metasta sis model. A single intraperitoneal injection of recombinant human (rh ) TNF or recombinant mouse (rm) TNF into mice 5 h before intravenous i noculation of methylcholanthrene-induced fibrosarcoma cells (CFS1) ind uced 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 a fter tumor cell inoculation caused an increase of tumor cell colony fo rmation on the lung surface, suggesting an influence of TNF on the vas cular adhesion and diapedesis of tumor cells. Since tumor-bearing mice showed an enhanced ability to produce TNF after endotoxin injection c ompared to control mice, tumor-bearing mice were treated with anti-mTN F antibodies. Neutralization of endogenous tumor-induced TNF led to a significant decrease of the number of pulmonary metastases. Histologic al analysis of micrometastases in the lung on day 5 by silver staining of proteins associated with nucleolar organizer regions revealed more metastatic foci and augmented proliferative activity of the tumor cel ls after rmTNF pretreatment of mice. However, no direct effect of rmTN F on the proliferation rate of tumor cells was seen in vitro. These fi ndings suggest that low doses of endogenous TNF or administered TNF du ring cytokine therapy might enhance the metastatic potential of circul ating tumor cells.