Expression of Fas and Fas ligand in human gastric adenomas and intestinal-type carcinomas: Correlation with proliferation and apoptosis

Gastric Cancer (Impact Factor: 3.72). 11/2001; 4(4):198-205. DOI: 10.1007/s10120-001-8010-z


Background. Fas (APO-1/CD95), a member of the tumor necrosis factor/nerve growth factor receptor superfamily, mediates apoptosis in response to agonistic antibodies or Fas ligand (FasL) binding. Previous reports indicated an upregulation of FasL in gastric carcinomas to evade host immune attack. Fas/FasL expression, however, has not been analyzed in terms of apoptosis and proliferation in gastric adenoma and carcinoma.
Methods. This study was conducted on seven human gastric carcinoma cell lines, 47 gastric adenomas, and 75 intestinal-type adenocarcinomas (48 early and 27 advanced carcinomas). Fas/FasL expression was examined by immunohistochemistry, apoptosis by the terminal deoxynucleotidyl transferase-mediated dUTP-digoxigenin nick-end labeling (TUNEL) method, and Fas gene mutation by a reverse transcriptase (RT) polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) and sequencing method.
Results. Fas and FasL expressions were noted in 18 (38.3%) and 17 (36.2%) adenomas, in 21 (43.8%) and 33 (68.8%) early carcinomas, and in 10 (37.0%) and 19 (70.4%) advanced carcinomas, respectively. The frequency of FasL expression was significantly higher in advanced carcinomas than in the early carcinomas and adenomas; in contrast, there was no significant difference in Fas expression among the three groups. The mean apoptotic index (AI) was 4.96 ± 0.51 in the adenomas, 2.96 ± 0.23 in the early carcinomas, and 1.67 ± 0.17 in the advanced carcinomas. A significantly higher AI was noted in the lesions with Fas expression than in those without Fas expression in all three groups. No missense mutations of the Fas gene were detected in any of the gastric carcinoma cell lines, or in the gastric adenomas or carcinomas.
Conclusions. Upregulation of FasL may correlate with the progression of gastric carcinoma. Apoptosis in gastric adenoma and carcinoma cells may occur via Fas-dependent and -independent pathways, but further clarification is needed.

Full-text preview

Available from:
  • [Show abstract] [Hide abstract]
    ABSTRACT: Fas (CD95, APO-1), a member of the TNF superfamily, is a prototypical "death receptor" which transduces apoptotic signals in a variety of cell types. However, cell death is not the only possible outcome of Fas signalling. Fas engagement by Fas Ligand can also trigger proliferation or differentiation, promote tumour progression and angiogenesis, and induce cytokine secretion and integrin expression. Recently, we have reported that Fas engagement induces a potent regenerative response in sensory neurons in vitro, and enhances peripheral nerve regeneration in vivo. In contrast, other types of neurons, notably motoneurons, are acutely sensitive to Fas-induced apoptosis. Here, we review the literature on non-apoptotic Fas signalling pathways, and discuss the potential roles, molecular mechanisms, and regulators of Fas signalling in the nervous system.
    No preview · Article · Jan 2004 · APOPTOSIS
  • [Show abstract] [Hide abstract]
    ABSTRACT: It is well known that Fas ligand and anti-Fas antibodies can induce apoptosis, although some cancer cells are resistant to their stimuli. On the other hand, phosphatidylinositol 3'-kinase (PI3 K) and Akt mediate the survival signal and allow the cells to escape from apoptosis in various human cancers. Thus, we postulated that LY294002, a PI3 K inhibitor, should inactivate Akt, consequently inhibiting cell proliferation and increase apoptosis in the human gastric carcinoma cell line, MKN-45. Previously, we reported that MKN-45 was resistant against the anti-Fas antibody, CH-11, without interferon-gamma pretreatment in vitro. LY294002 caused a decrease of phosphorylated-Akt and an inhibition of cell proliferation via cell cycle arrest in the G0/G1 phase by P27/Kip1 accumulation, but there was no obvious induction of apoptosis. The simultaneous treatment of LY294002 and CH-11 significantly induced apoptosis confirmed by morphology and DNA ladder formation. Decreased phosphorylated-Akt by LY294002 treatment led to a down-regulation of Mcl-2 and phosphorylated Bad proteins, which are anti-apoptotic factors and belong to the Bcl-2 family. On the other hand, expression levels of the other anti-apoptotic factors, such as FLICE-inhibitory protein (FLIP), Bcl-2 and Bcl-XL, which are associated with the Fas-mediated apoptotic signal pathway, did not change after LY294002 treatment. We concluded that: 1) the PI3K-Akt pathway plays an important role in preventing Fas-mediated apoptosis; and 2) a PI3 K inhibitor, such as LY294002, might be a useful anti-tumoral agent for gastric carcinoma.
    No preview · Article · Feb 2004 · Journal of Cancer Research and Clinical Oncology
  • [Show abstract] [Hide abstract]
    ABSTRACT: The progression from precancerous (adenomatous) colon polyps to malignant colorectal cancer involves the complex actions of various cytokines on T cell proliferation, cell-cell adhesion, apoptosis and host immunity. A broad spectrum of new treatments, including innovative molecular therapies such as gene therapy and treatment with cytokines, is under experimental and preclinical investigation. Nonsteroidal anti-inflammatory drugs and selective cyclooxygenase-2 inhibitors have traditionally been used as inflammation-reducing agents in cases of colon adenoma. Currently, adjuvant immunotherapies such as recombinant gene therapy and antibody-cytokine fusion proteins are assuming a more significant role in the management of colorectal neoplasia. Furthermore, advances in antitumour necrosis factor antibodies for the treatment of ulcerative colitis and Crohn's disease may have potential as chemoprotective agents for the treatment of colon polyposis. The present review aims to discuss the immunological mechanisms underlying colon tumour progression and the molecular and immune-based therapies that are leading to new methods of prognosis and treatment.
    No preview · Article · May 2004 · Canadian journal of gastroenterology = Journal canadien de gastroenterologie
Show more