Influence of TNFA on the formation of liver metastases in a syngenic mouse model

• Published in: International journal of cancer Vol. 107; no. 1; pp. 11 - 21
• Main Authors: Sturm, Jörg W., Magdeburg, Richard, Berger, Kristine, Petruch, Beate, Samel, Stefan, Bönninghoff, Roderich, Keese, Michael, Hafner, Mattias, Post, Stefan
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 20-10-2003; Wiley-Liss
• Subjects: Adenocarcinoma - metabolism; Adenocarcinoma - pathology; Animal tumors. Experimental tumors; Animals; Anti-Inflammatory Agents - pharmacology; Biological and medical sciences; Colonic Neoplasms - metabolism; Colonic Neoplasms - pathology; Disease Models, Animal; E-Selectin - metabolism; EGFP; Experimental digestive system and abdominal tumors; Fluorescent Dyes; Gadolinium - pharmacology; Green Fluorescent Proteins; Indicators and Reagents - metabolism; Injections, Intravenous; Intercellular Adhesion Molecule-1 - metabolism; intravital microscopy; Liver Neoplasms - metabolism; Liver Neoplasms - secondary; Luminescent Proteins - metabolism; Male; Medical sciences; Mice; Mice, Inbred BALB C; Rhodamines; RNA, Messenger - metabolism; syngenic, metastases; TNFα; transfected tumor cells; Tumor Cells, Cultured - transplantation; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - metabolism; Tumors; Vascular Cell Adhesion Molecule-1 - metabolism; Liver; Cytokine; Rodentia; Hepatic disease; Malignant tumor; Metastasis; Anatomic pathology; Vertebrata; Mammalia; Microscopy; Mouse; Animal; Digestive diseases; Tumor necrosis factor α
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.11320

The level of TNFα expression is increased after partial hepatectomy, and experimental evidence exists that TNFα plays a key role in liver regeneration. Contradictory results are reported about the influence of TNFα on tumor growth: on the one hand, stimulation of tumor growth in various animal models and, on the other hand, intraperitoneally administered TNFα leads to reduced metastasis formation. TNFα may be one responsible factor for increased metastasis formation after surgical trauma. The objective of our study was to clarify the influence of TNFα on the formation of liver metastases in a syngenic mouse model in vivo. We used a novel marker system, EGFP transfected C26 tumor cells for in vivo observation of metastasis formation by intravital microscopy. We analyzed the effect of intraperitoneal TNFα‐injection on tumor cell adhesion, extravasation and tumor development. The expression of ICAM‐1, VCAM‐1 and E‐Selectin was measured by Western blot and immunohistochemical staining. Tumor load was assessed by determining EGFP in Western blots. GdCl3 was employed 24 and 48 hr before tumor cell injection to selectively deplete the liver of functioning Kupffer cells. We observed significantly more extravasated tumor cells in the TNFα‐pre‐treated animals at early time points with increased expression of adhesion molecules. Measurement of the EGFP levels showed fewer liver metastases in the TNFα‐pretreated animals at day 8. After GdCl3 pretreatment even lower levels of EGFP, i.e., fewer metastases and also lower expression levels of ICAM‐1, VCAM‐1 and E‐Selectin could be observed. TNFα, acts in a bidirectional manner: whereas TNFα facilitates tumor cell adhesion and extravasation of C26 tumor cells by inducing the expression of adhesion molecules, at later time points, TNFα seems to hinder the formation of liver metastases. © 2003 Wiley‐Liss, Inc.