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Loss of functional Fas ligand enhances intestinal tumorigenesis in the Min mouse model.

Fingleton B, Carter KJ, Matrisian LM
Cancer Res. 2007 67 (10): 4800-6

PMID: 17510409 · DOI:10.1158/0008-5472.CAN-06-4473

Fas ligand (FasL/CD95L), a member of the tumor necrosis factor family, interacts with a specific receptor Fas, ultimately leading to cell death. Tumor expression of FasL has been proposed to aid in immune evasion through a "Fas counterattack" mechanism but has also been described as a proinflammatory factor. Here, we tested the role of FasL in a mouse model of spontaneous tumor development. We used the Min mouse in which multiple benign polyps develop in the intestine due to a mutation in the Apc tumor suppressor gene. Mutant mice deficient in functional FasL, termed gld/gld, were crossed to Min mice to generate tumor-prone animals lacking functional FasL. Comparison of FasL-deficient versus proficient Min mice revealed a significant increase in polyp number in the gld/gld mice. We next assessed immune cell infiltration into adenomas. There was no difference in the number of either lymphocytes or macrophages; however, the number of tumor-infiltrating neutrophils was 3-fold lower in the gld/gld specimens compared with controls. Neutrophil migration in vitro was stimulated by wild-type but not mutant FasL. In a nontumor-bearing colitis model in vivo, neutrophil recruitment to the intestine was also reduced in gld/gld mice. Although the Fas counterattack hypothesis suggests that the absence of FasL would result in increased immune-mediated tumor elimination, the opposite is true in the Min model with lack of functional FasL associated with reduced neutrophil influx and increased tumor development. Thus, the proinflammatory rather than counterattack role of tumor FasL is more relevant.

MeSH Terms (17)

Adenoma Animals Cell Movement Cell Transformation, Neoplastic Disease Models, Animal Fas Ligand Protein Genes, APC Humans Inflammation Intestinal Neoplasms Intestinal Polyps Lymphocytes Male Mice Mice, Inbred C57BL Mice, Mutant Strains Mutation

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