Article

Autocrine secretion of Fas ligand shields tumor cells from Fas-mediated killing by cytotoxic lymphocytes.

Cancer Centrum Karolinska, Karolinska Institutet, Stockholm, Sweden.
Cancer Research (Impact Factor: 8.65). 10/2004; 64(18):6775-82. DOI: 10.1158/0008-5472.CAN-04-0508
Source: PubMed

ABSTRACT Mechanisms responsible for resistance of tumors to death receptor-mediated damage by cytotoxic lymphocytes are not well understood. Uveal melanoma cells expressed Fas but were insensitive to Fas triggering induced by bystander cytotoxic T lymphocytes or a Fas-specific agonistic antibody; this could not be ascribed to tumor counterattack against T cells or general resistance of the tumors to apoptosis. Treatment with inhibitors of metalloproteases rendered uveal melanomas sensitive to Fas-mediated cytotoxicity. Metalloprotease inhibitors did not affect the expression of Fas but increased the surface expression of Fas ligand (FasL), which correlated with the disappearance of soluble FasL from culture supernatants of tumor cells. FasL eluted from the surface of uveal melanomas specifically inhibited cytotoxic T lymphocyte lysis of tumor cells pretreated with an inhibitor of metalloproteases. In addition to uveal melanomas, a number of other tumor cell lines of various cellular origins were sensitized to Fas-mediated cytotoxicity by metalloprotease inhibitors. Our results show that autocrine secretion of FasL shields tumor cells from Fas-mediated killing by cytotoxic lymphocytes. This defines a novel mechanism of tumor escape from immune surveillance.

0 Bookmarks
 · 
102 Views
  • Source
    Current Gene Therapy - CURR GENE THER. 01/2008; 8(6):438-448.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: We have explored a gene-therapeutic approach to stimulate antitumor immunity by adenoviral-mediated transfer of CD40 ligand (CD40L) to treat metastatic liver cancer in a rat model. Rat metastatic liver cancer cells were implanted into the back of rats bilaterally. When the larger tumor reached 8.0 mm in diameter, adenovirus vector-expressing mouse CD40L was injected intratumorally as treatment group (n=5), while LacZ was injected in the control group (n=5). In the control group, the tumor gradually grew to be 20.7+/-1.6 (mean+/-SD) mm in intratumorally injected tumors and 21.8+/-3.7 mm in opposite tumors seven weeks after injection, respectively. In contrast, in the treatment group, the tumor was reduced to 3.6+/-8.2 mm and 3.7+/-8.2 mm. The tumor growth and survival rate were significantly different (p<0.001). Adenovirus vector-mediated CD40L gene therapy is an effective therapeutic method for metastatic liver cancer.
    Anticancer research 01/2008; 28(5A):2785-9. · 1.71 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: To investigate the relation of Fas and Fas ligand (FasL) protein expression with carcinogenesis and metastasis of gastric carcinoma. Immunohistochemistry was used to detect Fas and FasL protein expression in 64 gastric carcinoma tissue samples and 20 normal gastric tissue samples. Relation between FasL and Fas expression, age and gender of gastric cancer patients, and pathological subtype and lymph node metastasis of gastric cancer was analyzed. The Fas expression level was significantly higher in normal gastric tissue samples than in gastric carcinoma tissue samples (85.0% vs 25.0%, P < 0.001), while the FasL expression level was significantly lower in normal gastric tissue samples than in gastric carcinoma tissue samples (30.0% vs 81.3%, P < 0.001). The Fas expression level was significantly higher in invasive lymph nodes than in non-invasive lymph nodes (82.9% vs 56.5%, P < 0.003) and in well-differentiated gastric carcinoma tissue samples than in poorly-differentiated gastric carcinoma tissue samples (50.0% vs 18.0%, P = 0.015). The FasL expression level was significantly lower in well-differentiated gastric carcinoma tissue samples than in poorly- differentiated gastric carcinoma tissue samples (42.9% vs 84.0%, P = 0.021). The Fas and FasL expression levels (25.0% and 81.3%) were significantly different in gastric carcinoma tissue samples (P < 0.001), but had a non-linear correlation (P = 0.575). Abnormal Fas and FasL expressions in gastric carcinoma and lymph node tissues are involved in carcinogenesis and metastasis of gastric cancer.
    World Journal of Gastroenterology 03/2010; 16(10):1274-8. · 2.55 Impact Factor

Full-text (2 Sources)

View
3 Downloads
Available from
Jul 4, 2014