Table 2 Tumor promoting activities of CD95 and CD95L in vitro and in mouse models
Cancer type | Observation | Reference |
|---|---|---|
Multiple cancers | Stimulation of 22 breast, ovarian, lung, colon, renal, melanoma, or glioblastoma cancer cell lines through CD95 causes them to increase in motility and invasiveness, and by activating NF-kB and MAP kinase pathways and upregulation of uPA | Barnhart et al.64 |
Knockdown of either CD95 or CD95L resulted in reduced growth of ovarian, liver, colon, breast cancer cell lines in vitro and of ovarian cancer cell lines in xenografted mice | Chen et al.44 | |
In lung cancer, GBM, and hepatocellular carcinoma cell lines CD95L increased motility and cell growth through binding to c-Met | Lin et al.177 | |
Knockdown of either CD95 or CD95L resulted in induction of cell death in 12 cancer cell lines representing ovarian, liver, breast, cervical, colon, renal cancer, neuroblastoma, or glioblastoma | Hadji et al. 119 | |
Stimulation of CD95 on breast, ovarian, renal, colon cancer, and glioblastoma cell lines increases cancer stemness | Ceppi et al. 115 | |
Breast cancer | Stimulation of CD95 on triple negative breast cancer cells by soluble CD95L resulted in Yes/Orai1/EGFR/PI3K mediated migration | Malleter et al. 82 |
Blockade of CD95 signaling in 4T1 cancer cells markedly reduced tumor growth, inhibited tumor metastasis in vivo, and prolonged survival of tumor-bearing mice | Liu et al.178 | |
Colon cancer | Expression of CD95L on colon cancer cells greatly increased their local growth and ability to metastasize to the liver | Li et al.150 |
CD95 driven liver metastasis of CD95 stimulated colon cancer cells is dependent on oncogenic Kras | Hoogwater et al.70 | |
Radiofrequency ablation of colorectal liver metastases induces hypoxia that causes autocrine activation of CD95 promoting local invasion and accelerated metastasis outgrowth | Nijkamp et al.75 | |
CD95 triggering resulted in an increased metastatic ability and activation of EMT in cells resistant to oxaliplatin | Ametller et al.125 | |
CD95 stimulation induced phosphorylation of phospholipase C-g1 through the platelet-derived growth factor receptor-b, resulting in phosphatidylinositol (4,5)-bisphosphate (PIP2) hydrolysis, liberating cofilin from the plasma membrane to initiate cortical actin remodeling in turn increasing tumor cell invasion | Steller et al.81 | |
Gastrointestinal cancer | CD95 stimulation induced ERK1/2 driven EMT and motility | Zheng et al.112 |
Glioblastoma | Stimulation of CD95 by CD95L induced invasiveness through recruitment of the Yes src kinase and the p85 subunit of phosphatidylinositol 3-kinase to CD95, resulting in activation of GSK3β and subsequent expression of matrix metalloproteinases | Kleber et al.74 |
Hepatocellular carcinoma | Neutralizing CD95L in a transgenic model of hepatocellular carcinogenesis reduced both inflammation and tumor formation | Nakamoto et al.179 |
Mice with a point mutation in the CD95 DD expressed only on nonhematopoietic cells developed spontaneous liver cancer independent of the lack of apoptosis induction through CD95 | Park et al.180 | |
Mice with tissue specific deletion of CD95 in hepatocytes showed a 50% reduced occurrence of DEN induced liver cancer | Chen et al.44 | |
Histiocytic sarcoma | Cancer formed in the liver of mice engineered to express only soluble and lacking expression of membrane bound CD95L | La et al.78 |
Lung cancer | CD95 overexpressing Lewis lung carcinoma (3LL) cells grew faster in vivo in syngeneic mice when compared with control transfected cells | Lee et al.68 |
CD95 ligation-induced 3LL cells to produce the proinflammatory factor PGE2 by activating p38 contributing to CD95 ligation-induced chemoattraction of myeloid-derived suppressor cells | Zhang et al.69 | |
CD95 mediated activation of NF-kB was found to contribute to the resistance of lung cancer to a EGFR tyrosine kinase inhibitor | Bivona et al.79 | |
Melanoma | Stimulation of B16 cells by exosome-derived CD95L in vitro activates NF-kB and ERK, and in vivo increases migration to the lung | Cai et al.181 |
Ovarian cancer | Mice lacking expression of CD95 in the surface epithelial cells of the ovaries barely developed cancer in a mouse model of endometrioid ovarian cancer driven by oncogenic Kras and deletion of pten | Chen et al.44 |
Tissue specific deletion of CD95 in the ovaries resulted in an increase in inflammation in the ovaries and reduced tumor development in a model of low grade ovarian cancer driven by oncogenic Kras and deletion of pten. All outgrowing cancer cells still expressed at least one allele of wt CD95 | Hadji et al.119 | |
Pancreatic cancer | Stimulation of TRAF2 overexpressing cells resulted in increased invasiveness by activating NF-kB and AP-1 resulting in upregulated uPA | Trauzold et al.73 |
Stimulation of CD95 on FADD knockdown cell lines mediates cell survival by recruiting calmodulin and Src resulting in activation of ERK | Yuan et al.72 | |
CD95 was identified as upregulated on cancer stem cells driving cell cycle progression by using Sck. Invasiveness and tumor growth could be inhibited in vivo by blocking CD95L | Teodorczyk et al.83 | |
Thyroid cancer | Stimulation of CD95 induced cell growth through ERK, NF-kB, and AP-1 | Mitsiades et al.182 |
