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Review
, 22 (4), 549-59

The Role of CD95 and CD95 Ligand in Cancer

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Review

The Role of CD95 and CD95 Ligand in Cancer

M E Peter et al. Cell Death Differ.

Erratum in

Abstract

CD95 (Fas/APO-1) and its ligand, CD95L, have long been viewed as a death receptor/death ligand system that mediates apoptosis induction to maintain immune homeostasis. In addition, these molecules are important in the immune elimination of virus-infected cells and cancer cells. CD95L was, therefore, considered to be useful for cancer therapy. However, major side effects have precluded its systemic use. During the last 10 years, it has been recognized that CD95 and CD95L have multiple cancer-relevant nonapoptotic and tumor-promoting activities. CD95 and CD95L were discovered to be critical survival factors for cancer cells, and were found to protect and promote cancer stem cells. We now discuss five different ways in which inhibiting or eliminating CD95L, rather than augmenting, may be beneficial for cancer therapy alone or in combination with standard chemotherapy or immune therapy.

Figures

Figure 1
Figure 1
The canonical apoptosis-inducing function of the CD95/CD95L system in killing cancer cells. Cancer cells that are recognized by CTLs in an antigen-specific way are being attacked by direct mechanisms: release of perforin/granzyme (shown as GrB) or use of CD95L to engage CD95 on the surface of cancer cells. Alternatively, indirect mechanisms are activated that result in upregulation of cytokines such as TNFα and INFγ, which in turn cause upregulation of CD95 and MHC-I (by IFNγ) or induction of cell death through cancer-expressed TNF receptors (by TNFα). Ag, antigen; CTL, cytotoxic lymphocyte; GrB, granzyme B; IFNγ, interferon γ; MHC-I, major histocompatibility complex I; TCR, T-cell receptor; TNFα, tumor necrosis factor α
Figure 2
Figure 2
Graphical summary of the role of CD95/CD95L in cancer. Together with the tumor-suppressing ability to trigger apoptosis in (apoptosis sensitive) cancer cells (1), CD95L has a range of tumor-promoting activities, some of which are indirect, such as the suppression of the immune response in the cancer micro-environment by either tumor-generated CD95L (2) or by CD95L expressed by endothelial cells (3), and some of which are direct, such as the promotion of tumor growth and invasiveness (4) or the acquisition of a CSC phenotype (5). Importantly, a low-baseline level of CD95/CD95L signaling is required for survival of cancer cells. Elimination of CD95/CD95L signaling leads to an irreversible and effective type of cell death, DICE, which predominantly affects CSCs (6). CSC, cancer stem cell, CTL; cytotoxic T lymphocyte; IL-10, interleukin 10; EMT, epithelial-to-mesenchymal transition; PGE2, prostaglandin E2; TIL, tumor-infiltrating lymphocyte; VEGF-A, vascular endothelial growth factor A. Stippled arrows indicate hypothetical interactions

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