CD95 is a key mediator of invasion and accelerated outgrowth of mouse colorectal liver metastases following radiofrequency ablation

Background & Aims Recently, we have shown that micro-metastases, in the hypoxic transition zone surrounding lesions generated by radiofrequency ablation (RFA), display strongly accelerated outgrowth. CD95 is best known for its ability to induce apoptosis but can also promote tumorigenesis in apo...

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Bibliographic Details
Published in:Journal of hepatology 2010-12, Vol.53 (6), p.1069-1077
Main Authors: Nijkamp, Maarten W, Hoogwater, Frederik J.H, Steller, Ernst J.A, Westendorp, B. Florien, van der Meulen, Taco A, Leenders, Martijn W.H, Borel Rinkes, Inne H.M, Kranenburg, Onno
Format: Article
Language:English
Subjects:
Animals
Biological and medical sciences
Catheter Ablation
CD95
Cell Line, Tumor
Colorectal liver metastases
Colorectal Neoplasms
Fas Ligand Protein - antagonists & inhibitors
Fas Ligand Protein - deficiency
Fas Ligand Protein - genetics
fas Receptor - antagonists & inhibitors
fas Receptor - deficiency
fas Receptor - genetics
fas Receptor - physiology
Gastroenterology and Hepatology
Gastroenterology. Liver. Pancreas. Abdomen
Hypoxia
Hypoxia - immunology
Hypoxia - pathology
In Vitro Techniques
Invasion
Liver Neoplasms, Experimental - immunology
Liver Neoplasms, Experimental - pathology
Liver Neoplasms, Experimental - secondary
Liver Neoplasms, Experimental - surgery
Liver. Biliary tract. Portal circulation. Exocrine pancreas
Male
Medical sciences
Mice
Mice, Inbred BALB C
Mice, Knockout
Neoplasm Invasiveness - immunology
Other treatments
Radiofrequency ablation
RNA Interference
Signal Transduction - immunology
Treatment. General aspects
Tumors
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Summary:Background & Aims Recently, we have shown that micro-metastases, in the hypoxic transition zone surrounding lesions generated by radiofrequency ablation (RFA), display strongly accelerated outgrowth. CD95 is best known for its ability to induce apoptosis but can also promote tumorigenesis in apoptosis-resistant tumor cells. Therefore, we tested whether CD95 signaling plays a role in accelerated outgrowth of colorectal liver metastases following RFA. Methods Hypoxia-induced invasion was assessed in three-dimensional EGFP-expressing C26 tumor cell cultures by confocal microscopy. CD95 localization was tested by immunofluorescence. Invasion and outgrowth of liver metastases following RFA were analyzed by post-mortem confocal microscopy and by morphometric assessment of tumor load. Neutralization of CD95L was performed by using antibody MFL4. CD95 was suppressed by lentiviral RNA interference. The role of host CD95L was assessed using gld mice. Results Micro-metastases in the hypoxic transition zone following RFA displayed a highly invasive phenotype and increased expression of CD95 and CD95L. Hypoxia-induced tumor cell invasion in vitro increased the expression of CD95 and CD95L and induced translocation of CD95 to the invasive front. In vitro invasion, metastasis invasion, and accelerated tumor growth in the transition zone were strongly suppressed by neutralizing CD95L or by suppressing tumor cell CD95. In contrast, metastasis invasion and outgrowth were unaffected in gld mice. Conclusions Hypoxia causes autocrine activation of CD95 on colorectal tumor cells, thereby promoting local invasion and accelerated metastasis outgrowth in the hypoxic transition zone following RFA. Further pre-clinical work is needed to assess the role of CD95L neutralization, either alone or in combination with chemotherapy, in limiting aggressive recurrence of liver metastases following RFA.
ISSN:0168-8278
1600-0641
DOI:10.1016/j.jhep.2010.04.040