A role for CD95 signaling in ischemia/reperfusion‐induced invasion and outgrowth of colorectal micrometastases in mouse liver

Nijkamp, Maarten W.; Hoogwater, Frederik J.H.; Govaert, Klaas M.; Steller, Ernst J.A.; Verheem, André; Kranenburg, Onno; Rinkes, Inne H.M. Borel

doi:10.1002/jso.21915

Cited by 12 publications

(7 citation statements)

References 27 publications

(54 reference statements)

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“…Enhanced in vitro invasion after CD95L stimulation was also observed for oncogenic KRAS‐expressing DLD1 cells and was found to be independent from caspase‐8 activation . Moreover, accelerated CD95‐mediated outgrowth of C26 micrometastases in the liver has also been observed after radiofrequency ablation and induction of ischemia‐reperfusion ischemia . The underlying CD95 signaling mechanisms have not been addressed in these studies but a follow‐up in vitro study demonstrated that CD95 signals tumor cell invasion in a transwell assay by Src kinase family‐independent activation of the PDGFRβ and subsequent PDGFRβ‐dependent PLCγ1 stimulation (Fig.…”

Section: Cell Migration and Invasion Can Be Induced By Several Cd95‐ mentioning

confidence: 99%

Cell death‐independent activities of the death receptors CD95, TRAILR1, and TRAILR2

2016

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Since their identification more than 20 years ago, the death receptors CD95, TRAILR1, and TRAILR2 have been intensively studied with respect to their cell death-inducing activities. These receptors, however, can also trigger a variety of cell death-independent cellular responses reaching from the activation of proinflammatory gene transcription programs over the stimulation of proliferation and differentiation to induction of cell migration. The cell death-inducing signaling mechanisms of CD95 and the TRAIL death receptors are well understood. In contrast, despite the increasing recognition of the biological and pathophysiological relevance of the cell death-independent activities of CD95, TRAILR1, and TRAILR2, the corresponding signaling mechanisms are less understood and give no fully coherent picture. This review is focused on the cell death-independent activities of CD95 and the TRAIL death receptors and addresses mainly three questions: (a) how are these receptors linked to noncell death pathways at the molecular level, (b) which factors determine the balance of cell death and cell death-independent activities of CD95 and the TRAIL death receptors at the cellular level, and (c) what are the consequences of the cell death-independent functions of these receptors for their role in cancer and inflammatory diseases.

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Section: Cell Migration and Invasion Can Be Induced By Several Cd95‐ mentioning

confidence: 99%

Cell death‐independent activities of the death receptors CD95, TRAILR1, and TRAILR2

2016

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“…5 However, under certain conditions, Fas signaling can exert non-apoptotic effects, including inflammatory responses, liver regeneration, increased branching of developing neurons, migration of cells, angiogenesis, fibrosis, proliferation and differentiation of cells and advancement of the cell cycle. [6][7][8][9][10][11] Therefore, although almost all tumor cells express the Fas receptor, the Fas pathway may also be beneficial to tumor cell survival rather than apoptosis. 6,[8][9][10] Activation of Fas signaling in the Lewis lung cancer cell line (3LL cells) does not cause apoptosis but induces 3LL cells to secrete more prostaglandin E2(PGE2).…”

Section: Introductionmentioning

confidence: 99%

“…[6][7][8][9][10][11] Therefore, although almost all tumor cells express the Fas receptor, the Fas pathway may also be beneficial to tumor cell survival rather than apoptosis. 6,[8][9][10] Activation of Fas signaling in the Lewis lung cancer cell line (3LL cells) does not cause apoptosis but induces 3LL cells to secrete more prostaglandin E2(PGE2). 12 High levels of PGE2 aid 3LL cells in recruiting myeloid-derived suppressor cells (MDSCs), leading to tumor cell escape.…”

Section: Introductionmentioning

confidence: 99%

Activated cytotoxic lymphocytes promote tumor progression by increasing the ability of 3LL tumor cells to mediate MDSC chemoattraction via Fas signaling

et al. 2014

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The Fas/FasL system transmits intracellular apoptotic signaling, inducing cell apoptosis. However, Fas signaling also exerts non-apoptotic functions in addition to inducing tumor cell apoptosis. For example, Fas signaling induces lung cancer tumor cells to produce prostaglandin E2 (PGE2) and recruit myeloid-derived suppressor cells (MDSCs). Activated cytotoxic T lymphocytes (CTLs) induce and express high levels of FasL, but the effects of Fas activation initiated by FasL in CTLs on apoptosis-resistant tumor cells remain largely unclear. We purified activated CD81 T cells from OT-1 mice, evaluated the regulatory effects of Fas activation on tumor cell escape and investigated the relevant mechanisms. We found that CTLs induced tumor cells to secrete PGE2 and increase tumor cell-mediated chemoattraction of MDSCs via Fas signaling, which was favorable to tumor growth. Our results indicate that CTLs may participate in the tumor immune evasion process. To the best of our knowledge, this is a novel mechanism by which CTLs play a role in tumor escape. Our findings implicate a strategy to enhance the antitumor immune response via reduction of negative immune responses to tumors promoted by CTLs through Fas signaling.

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“…For instance, we have previously shown that the presence of oncogenic KRAS in colon cancer cells causes a switch in CD95-signaling output from apoptosis to invasion, which is required for metastatic spread and tumor recurrence. 15, 20, 21 This raises the question of how to select patients for CD95-inhibitory therapy and whether there could be genetic or epigenetic traits that may determine the response to such therapy. To address this, we further explored the context dependency of CD95 signaling in human colon cancer by making use of a series of patient-derived ‘colonosphere' cultures.…”

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confidence: 99%

CD95 ligand induces senescence in mismatch repair-deficient human colon cancer via chronic caspase-mediated induction of DNA damage

et al. 2017

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CD95 is best known for its ability to induce apoptosis via a well-characterized pathway involving caspase-mediated proteolytic events. However, in apoptosis-resistant cell lines of diverse cancer types stimulation of CD95 primarily has pro-tumorigenic effects that affect many of the hallmarks of cancer. For instance, in colon cancer cells with a mutant KRAS gene CD95 primarily promotes invasion and metastasis. In the current study, we further investigated the context dependency of the consequences of CD95 activation in colon cancer. We used a series of patient-derived three-dimensional colon cancer cultures and studied their response to stimulation with CD95 ligand (CD95L). CD95L had a strong inhibitory effect on the clone-forming capacity of five out of nine cultures. In line with previous work, these cultures all had a wild-type KRAS gene and expressed high levels of CD95. Furthermore, the most sensitive cultures were characterized by microsatellite instability (MSI) and deficient mismatch repair. The reduced clonogenic growth of MSI-type colonospheres resulting from chronic CD95 stimulation was only partly due to apoptosis as many tumor cells survived treatment, yet were unable to regenerate clones. CD95 stimulation caused an irreversible cell cycle arrest, which was associated with cytokine secretion, similar to the senescence-associated secretory phenotype (SASP), and expression of senescence-associated β-galactosidase. In human colon cancer cohorts, CD95 expression was strongly correlated with the recently identified consensus molecular subtype 1 (CMS1), which mainly consists of MSI-high tumors, and with two independent SASP signatures. Mechanistically, CD95-induced senescence was caused by chronic DNA damage via caspase-activated DNAse resulting in p53 activation and p21 expression, with a minor contribution of the SASP. We conclude that induction of senescence is a hitherto unrecognized consequence of high CD95 expression, which appears to be most relevant for CMS1.

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A role for CD95 signaling in ischemia/reperfusion‐induced invasion and outgrowth of colorectal micrometastases in mouse liver

Abstract: I/R induces invasion and accelerated outgrowth of preestablished metastases in a CD95-dependent manner. Activation of the CD95 system following I/R not only contributes to liver injury, but may also promote aggressive tumor recurrence.

Cited by 12 publications

References 27 publications

Cell death‐independent activities of the death receptors CD95, TRAILR1, and TRAILR2

Cell death‐independent activities of the death receptors CD95, TRAILR1, and TRAILR2

Activated cytotoxic lymphocytes promote tumor progression by increasing the ability of 3LL tumor cells to mediate MDSC chemoattraction via Fas signaling

CD95 ligand induces senescence in mismatch repair-deficient human colon cancer via chronic caspase-mediated induction of DNA damage

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