FasDR (CD95)
in many cancers, in particular
Non-Hodgkin’s Lymphoma
Benjamin Badger
Fas activates by binding to Fas ligand,
causing apoptosis—Thymic Education
Fas would logically be a tumor
suppressor: if it is lost, cells cannot
be instructed to undergo apoptosis
as easily
(1996)
Loss of Fas in mice leads to
death from lymphoma
In people, Fas loss-of-function mutations
are found in non-Hodgkin’s Lymphomas
RT-PCR of leukemia cells shows
defective splicing of Fas
compared to the
control (PBL).
(1998)
But wait! FasR=CD95. What gives?
2010
Clue: Fas activation via mAbs causes
monocytes to express
proinflammatory genes.
Human monocytes,
grown in culture
Possible mechanisms by which death
receptors could cause inflammation
Inflammation is the enemy of effective
apoptosis: why would an apoptosis
receptor also lead to inflammation?
Is Fas an oncogene or tumor
suppressor in humans?
“FAS is not significantly focally amplified across
the entire dataset of 3131 tumors…(or) any of
the 14 individual subtypes”
but “FAS is significantly focally deleted across
the entire dataset of 3131 tumors…(and) in 2 of
14 independent subtypes”
So Fas appears to be a tumor
suppressor after all in humans. But
“FASLG is significantly focally amplified across
the entire dataset of 3131 tumors”.
(Tumorscape)
Why?? One reason may be so that cancer cells
can activate Fas more easily (the oncogene
hypothesis), but the reason could also be…
FasL is expressed by cancer cells to kill
lymphocytes
The Return of
Thymic Eduction
References
Abusamra et al. Blood Cells, Molecules and Diseases 35 (2005) 169-173
Bronbaek et al. (1998) Somatic Fas Mutations in Non-Hodgkin’s Lymphoma:
Association With Extranodal Disease and Autoimmunity. Blood 92: 3018-3024
Chen et al, 2010. CD95 promotes tumour growth. Nature 465:492-496 with
corrigendum (475:254, 2011).
Cullen SP, Martin SJ. Fas and TRAIL ‘death receptors’ as initiators of inflammation:
Implications for cancer. Semin Cell Dev Biol (2015)
Douglas R. Green & Thomas A. Ferguson 2001. The role of fas ligand in immune
privilege Nature Reviews Molecular Cell Biology 2, 917-924
Park et al, 2003. Fas (CD95) Induces Proinflammatory Cytokine Responses by Human
Monocytes and Monocyte-Derived Macrophages. J Immunology 170: 6209-6216
Peng et al. (1996). A tumor-suppressor Function for Fas (CD95) Revealed in T Celldeficient Mice. Journal of Experimental Medicine 184: 1149-1154
Tumorscape (2011). The Broad Institute, data retrieved 3/15/15. Published form:
Beroukhim, et al. The landscape of somatic copy-number alteration across human
cancers. Nature. 2010 Feb 18;463(7283):899-905.