FasL:Fas ratio - A prognostic factor in breast carcinomas

Department of Obstetrics and Gynecology, University of Rostock, Germany.
Cancer Research (Impact Factor: 9.28). 02/2000; 60(4):822-8.
Source: PubMed

ABSTRACT Programmed cell death (apoptosis) is primarily mediated by Fas ligand (FasL; CD95L) and the Fas receptor (Fas; CD95). In this study, FasL was detected by immunohistochemical analysis in 85% of breast carcinomas and 14% of fibroadenomas randomly chosen, indicating that high expression of FasL might play a role in tumor pathology. FasL and Fas levels as well as FasL:Fas ratios were further ascertained in 215 human breast tumors, including 199 invasive ductal carcinomas, by real-time quantitative reverse transcription-PCR and compared with expression levels and ratios found in 25 normal human tissues, in 37 fibroadenomas, and in 5 normal breast tissues. Among breast carcinomas, high FasL mRNA expression seems to be positively correlated with histological grading (n = 212; P<0.0001). A ratio of FasL:Fas mRNA transcripts >1 is found to be significantly associated with decreased patient's disease-free survival (n = 211; P<0.03) and increased mortality (n = 211; P = 0.19). A FasL:Fas ratio >1 is related to tumor progression scored by histological grading (n = 212; P<0.02). The selection process leading to highly aggressive breast tumor variants might be enhanced by FasL-mediated tumor fratricide, eventually a possible target for novel therapeutic strategies.

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Available from: Hans-Jürgen Thiesen, Jan 24, 2014
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    • "Perhaps the best-characterised death receptor is Fas (CD95 or APO-1), which has been implicated in the apoptotic events that drive physiological remodelling of the mammary gland after breast feeding (Song et al., 2000). Down-regulation of Fas has also been associated with poor prognosis in breast cancer patients (Reimer et al., 2000), and inhibition of Fas activity has been linked to drug resistance (Landowski et al., 1997). "
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    ABSTRACT: Cancer is a leading cause of death in developed countries, and is on the rise in developing countries due in part to a lack of prophylactic screening and non-universal access to medical care (Jemal et al., 2011). Breast cancer is initiated when breast epithelial cells escape growth arrest and form a proliferating tumour mass. Numerous cellular mechanisms are dysregulated in breast tumour cells, including modified cell fate, altered protein signalling and trafficking, and enhanced cell migratory potential. Although these events are complex and subject to regulation by multiple elements, recent evidence has suggested that specialised cell membrane domains termed lipid rafts are actively involved in each of these processes (Cary & Cooper, 2000; Nabi & Le, 2003; Simons & Toomre, 2000). This chapter will therefore focus on the contribution of lipid rafts to breast cancer initiation and progression under these headings. Lipid rafts are sub-domains of the cell membrane enriched in cholesterol and glycosphingolipids (Le Moyec et al., 1992; Nohara et al., 1998). These microdomains cluster together proteins involved in the regulation of crucial cellular processes; many of which are altered in cancer cells (Pike, 2003; de Laurentiis et al., 2007). Furthermore, lipid rafts are readily modified by diet and nutrition (Schley et al., 2007; Yaqoob, 2009), and studies have shown that fatty acid supplementation sensitises human mammary tumour cells to the cytotoxic effects of anti-cancer agents in vitro and in vivo (Germain et al., 1998; Menendez et al., 2005; Colas et al., 2006). This chapter will focus on the potential regulatory functions of lipid rafts as a novel approach towards understanding mechanisms of cancer initiation, progression and cell migration, a key event preceding metastatic progression. Finally it will discuss the potential of lipid rafts as novel therapeutic targets in breast cancer.
    Breast Cancer - Carcinogenesis, Cell Growth and Signalling Pathways, 11/2011; , ISBN: 978-953-307-714-7
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    • "Acquisition of FasL expression by tumour cells is one of the mechanisms involved in tumour immune escape. Various tumour types have been reported to express FasL, which can be negatively correlated with prognosis as described for colon and breast carcinomas (Reimer et al, 2000; Belluco et al, 2002). In our study, 89% of the GISTs expressed FasL, but no correlation was found with tumour size and mitotic index or risk groups based on these prognostic factors, which predict metastatic behaviour. "
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    ABSTRACT: Although the tyrosine kinase inhibitor imatinib has been shown to be an active agent in patients with gastrointestinal stromal tumours (GIST), complete remissions are almost never seen and most patients finally experience disease progression during their course of treatment. An alternative therapeutic option is to target death receptors such as Fas. We showed that a panel of imatinib-sensitive (GIST882) and imatinib-resistant (GIST48, GIST430 and GIST430K-) cell lines expressed Fas. MegaFasL, a recently developed hexameric form of soluble Fas ligand (FasL), appeared to be an active apoptosis-inducing agent in these cell lines. Moreover, MegaFasL potentiated the apoptotic effects of imatinib. Immunohistochemical evaluations, in 45 primary GISTs, underscored the relevance of the Fas pathway: Fas was expressed in all GISTs and was expressed strongly in 93%, whereas FasL was expressed at moderate and strong levels in 35 and 53% of GISTs, respectively. Fas and FasL expression were positively correlated in these primary GISTs, but there was no association between Fas or FasL expression and primary site, histological subtype, tumour size, mitotic index, risk classification, and KIT mutation status. The abundant immunohistochemical Fas and FasL expression were corroborated by western blot analysis. In conclusion, our data implicate Fas as a potential therapeutic target in GIST.
    British Journal of Cancer 11/2008; 99(10):1600-6. DOI:10.1038/sj.bjc.6604736 · 4.82 Impact Factor
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    • "However, high FasL expression has been consistently observed in different types of human tumours, also in melanomas. The loss of cell surface Fas expression has been described for melanomas, breast and oesophageal tumours, leukemia, lymphomas [7] [8] [9]. On the other hand, it has been reported that a variety of malignant tumours, including: carcinomas of the colon, breast, ovary, urinary bladder, lung, head and neck, melanoma, astrocytoma , show an increased FasL expression [7] [10] [11]. "
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    ABSTRACT: Fas and FasL interaction induces apoptotic cell death. In immunocompetent cells it plays a crucial role in the effector functions of the cells and in the regulation of host immune response. In tumours (e.g. melanoma), FasL expression possibly counteracts the Fas-positive effector T cells that infiltrate into tumours, and consequently the Fas/FasL interaction can contribute to the escape of tumour cells from the systemic immune response. In this study we examined differences in Fas and FasL expression on cells from the hamster melanotic melanoma line (Ma) and a more aggressive amelanotic melanoma line (Ab). We also tried to find out whether the Fas/FasL expression induces an ability to undergo spontaneous apoptosis in these two transplantable melanoma lines. Our previous studies have shown that cells of the Ma line have a higher ability to undergo spontaneous apoptosis than cells of the Ab line. Isolated transplantable melanoma cells were incubated for 4 and 24 hours and after that time the expression of Fas and FasL was estimated by flow cytometry. The results show that there was no Fas expression, although FasL was detected on both melanoma cell lines. Therefore the data reported by other authors indicate that a lack or a low level of Fas expression and an ectopic expression of FasL on melanoma cells can be an escape mechanism of the tumour, to avoid host immune responses. The content of FasL-positive melanotic melanoma cells was higher than in amelanotic melanoma cells and increased with the prolongation of the incubation time. FasL expression on amelanotic melanoma cells was detected after 24 hours at a level similar to that on melanotic melanoma cells after 4 hours incubation time. FasL expression on melanoma cells can induce apoptosis in cytotoxic T lymphocytes and NK cells which are responsible for tumour cells elimination. The results obtained suggest that the Fas/FasL system does not play any significant role in spontaneous apoptosis of two melanoma cell lines. But these results may indicate the presence of immune privilege of tumour cells with FasL expression.
    Folia Histochemica et Cytobiologica 02/2008; 46(3):337-43. DOI:10.2478/v10042-008-0041-4 · 1.00 Impact Factor
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