Dataset Information

CD117/c-kit in Cancer Stem Cell-Mediated Progression and Therapeutic Resistance.

ABSTRACT: Metastasis is the primary cause of cancer patient morbidity and mortality, but due to persisting gaps in our knowledge, it remains untreatable. Metastases often occur as patient tumors progress or recur after initial therapy. Tumor recurrence at the primary site may be driven by a cancer stem-like cell or tumor progenitor cell, while recurrence at a secondary site is driven by metastatic cancer stem cells or metastasis-initiating cells. Ongoing efforts are aimed at identifying and characterizing these stem-like cells driving recurrence and metastasis. One potential marker for the cancer stem-like cell subpopulation is CD117/c-kit, a tyrosine kinase receptor associated with cancer progression and normal stem cell maintenance. Further, activation of CD117 by its ligand stem cell factor (SCF; kit ligand) in the progenitor cell niche stimulates several signaling pathways driving proliferation, survival, and migration. This review examines evidence that the SCF/CD117 signaling axis may contribute to the control of cancer progression through the regulation of stemness and resistance to tyrosine kinase inhibitors.

SUBMITTER: Foster BM

PROVIDER: S-EPMC5874688 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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CD117/c-kit in Cancer Stem Cell-Mediated Progression and Therapeutic Resistance.

Foster Brittni M BM Zaidi Danish D Young Tyler R TR Mobley Mary E ME Kerr Bethany A BA

Biomedicines 20180308 1

Metastasis is the primary cause of cancer patient morbidity and mortality, but due to persisting gaps in our knowledge, it remains untreatable. Metastases often occur as patient tumors progress or recur after initial therapy. Tumor recurrence at the primary site may be driven by a cancer stem-like cell or tumor progenitor cell, while recurrence at a secondary site is driven by metastatic cancer stem cells or metastasis-initiating cells. Ongoing efforts are aimed at identifying and characterizing ...[more]

PMID: 29518044

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Project description:Major trauma-induced tissue injury causes a dysregulation of the immune system. Severe systemic inflammation occurs early after the insult. Later on, an enhanced risk for life-threatening opportunistic infections develops that culminates at the end of the first week after trauma. CD56bright Natural killer (NK) cells play a key role in the defense against infection due to their rapid release of Interferon (IFN) ? in response to Interleukin (IL) 12. NK cells are impaired in IFN-? synthesis after severe injury due to a disturbed IL-12/IFN-? axis. Thereby, a circulating factor mediates extrinsic suppression of NK cells. Yet unknown cell-intrinsic mechanisms manifest by day 8 after trauma and render NK cells unresponsive to stimulatory cytokines. In the present study, we investigated the origin of such late NK cell-intrinsic suppression after major trauma. Peripheral blood mononuclear cells (PBMC) were isolated from patients 8 day after severe injury and from healthy control subjects and were stimulated with inactivated Staphylococcus aureus. The expression of diverse cytokine receptors, intracellular signaling molecules, and the secretion of IFN-? by CD56bright NK cells were examined. After stimulation with S. aureus, NK cells from patients expressed enhanced levels of c-kit/CD117 that inversely correlated with IFN-? synthesis and IL-12 receptor (IL-12R) ?2 expression. Supplementation with IL-15 and inhibition of the transforming growth factor receptor (TGF-?R) I reduced CD117 expression and increased the level of IL-12R?2 and IFN-?. NK cells from patients showed reduced phosphorylation of mammalian target of rapamycin (mTOR). Addition of IL-15 at least partly restored mTOR phosphorylation and increased IL-12R?2 expression. The reduced mTOR phosphorylation after severe injury was cell-intrinsic as it was not induced by serum factors. Inhibition of mTOR in purified NK cells from healthy donors by rapamycin decreased the synthesis of IFN-?. Thus, impaired mTOR phosphorylation in response to a microbial challenge contributes to the cell-intrinsic mechanisms that underlie NK cell dysregulation after trauma. Restoration of the mTOR phosphorylation capacity along with inhibition of the TGF-?RI signaling in NK cells after severe injury might improve the immune defense against opportunistic infections.

Dataset Information

CD117/c-kit in Cancer Stem Cell-Mediated Progression and Therapeutic Resistance.

Publications

CD117/c-kit in Cancer Stem Cell-Mediated Progression and Therapeutic Resistance.

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