Enhancement of experimental metastasis by tumor necrosis factor.

Abstract

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.

Association of tumour necrosis factor alpha and its receptors with thymidine phosphorylase expression in invasive breast carcinoma

“…Our finding that increased TNF-ax staining of tumour cells was correlated with the presence of nodal metastases accords well with previous reports showing the enhanced metastatic potential of tumour cells in vivo, following exposure to TNF-ox (Malik et al, 1990;Orosz et al, 1993). Moreover, TNF-ox is known to induce expression of adhesion molecules thought to be involved in the increased motility and invasive/metastatic behaviour of tumour cells (loculano et al, 1995).…”

Enhancement of active MMP release and invasive activity of lymph node metastatic tongue cancer cells by elevated signaling via the TNF-α-TNFR1-NF-κB pathway and a possible involvement of angiopoietin-like 4 in lung metastasis

“…In contrast, TNF-α at low doses exerted angiogenic activity in both the rabbit cornea and chick chorioallantoic membrane models (23,24). By treating tumor cells or mice TNF-α augmented the metastatic activity of transplanted tumor cells (25,26). These reports suggest TNF-α activity for cancer progression.…”

Selective inhibition of TNF-α-induced activation of mitogen-activated protein kinases and metastatic activities by gefitinib

“…These processes require tumour cell attachment, migration, and invasion. In several tumour cell lines, TNF-a induced the expression of several different adhesive molecules including several integrin subunits, ICAM-1 and VCAM-1 (Orosz et al, 1993;Qin et al, 1993;Choo et al, 2005). Tumour necrosis factor-a also induced the activation of MAPKs, which has been shown to be involved in MMP-9 expression and invasion.…”

“…However, extensive research during past years has made it apparent that TNF-a enhances the incidence of metastasis in several tumour models (Orosz et al, 1993;Qin et al, 1993;Kitakata et al, 2002;Mochizuki et al, 2004;Tomita et al, 2004). The role of endogenous TNF-a in the metastatic process remains to be clarified; however, TNF-a has been found to increase the expression of adhesion molecules and invasive molecules, including intracellular adhesion molecule-1 (ICAM-1) and matrix metalloproteinase-9 (MMP-9) (Aggarwal et al, 2002).…”