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 ofThymic Eduction

ReferencesAbusamra 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 Cell-deficient 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.