Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P10721 (c-kit)
 6,575 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tumor immune tolerance can derive from the recruitment of suppressor cell populations, including myeloid-derived suppressor cells (MDSCs). In cancer patients, increased MDSCs correlate with more aggressive disease and a poor prognosis. Expression of 15 immune factors (TGFbeta, IL-1beta, IL-4, IL-6, IL-10, GM-CSF, M-CSF, IDO, fms-related tyrosine kinase 3 ligand, c-kit ligand, inducible NO synthase, arginase-1, TNF-alpha, cyclo-oxygenase 2, vascular endothelial growth factor [VEGF]) by MDSC-inducing human solid tumor cell lines was evaluated by RT-PCR. Based upon these data, cytokine mixtures were then tested for their ability to generate suppressive CD33(+) cells from healthy donor PBMCs in vitro by measuring their ability to inhibit the proliferation of, and IFN-gamma production by, fresh autologous human T cells after CD3/CD28 stimulation. Induced MDSCs were characterized with respect to their morphology, surface phenotype, and gene expression profile. MDSC-inducing cancer cell lines demonstrated multiple pathways for MDSC generation, including overexpression of IL-6, IL-1beta, cyclo-oxygenase 2, M-CSF, and IDO. CD33(+) cells with potent suppressive capacity were best generated in vitro by GM-CSF and IL-6, and secondarily by GM-CSF + IL-1beta, PGE(2), TNF-alpha, or VEGF. Characterization studies of cytokine-induced suppressive cells revealed CD33(+)CD11b(+)CD66b(+)HLA-DR(low)IL-13R alpha2(int) large mononuclear cells with abundant basophilic cytoplasm. Expression of inducible NO synthase, TGFbeta, NADPH oxidase, VEGF, and/or arginase-1 was also upregulated, and Transwell studies showed suppression of autologous T cells to be contact dependent. Suppressive CD33(+) cells generated from PBMCs by GM-CSF and IL-6 were consistent with human MDSCs. This study suggests that these cytokines are potential therapeutic targets for the inhibition of MDSC induction in cancer patients.
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PMID:Characterization of cytokine-induced myeloid-derived suppressor cells from normal human peripheral blood mononuclear cells. 2064 62

The purpose of this study was to evaluate the influence of bone marrow-mesenchymal stem cells (BM-MSC) and exogenously added cytokines on the proliferation, primitive cell subpopulation maintenance (including the c-kit+ marker) and clonogenic capacity of hematopoietic stem cells (HSC). BM-MSC were collected from volunteer donors, isolated and characterized. Umbilical cord blood (UCB) samples were collected from healthy full-term deliveries. UCB-CD34+ cells were cultured in the presence or absence of BM-MSC and/or cytokines for 3 and 7 days. CD34+ cell proliferation was evaluated using the CSFE method and cell phenotype was determined by CD34, c-kit, CD33, CD38, HLA-DR, cyCD22 and cyCD3 detection. Cell clonogenic ability was also assessed. Exogenously added SCF, TPO and FLT3L increased CD34+ cell proliferation in the presence or absence of BM-MSC, but with concomitant cell differentiation. Without any added cytokines, BM-MSC are able to increase the percentage of primitive progenitors as evaluated by c-kit expression and CFU-GEMM increase. Interestingly, this latter effect was dependent on both cell-cell interactions and secreted factors. A 7-day co-culture period will be optimal for obtaining an increased primitive HSC level. Including c-kit as a marker for primitive phenotype evaluation has shown the relevance of BM-MSC and their secreted factors on UCB-HSC stemness function. This effect could be dissociated from that of the addition of exogenous cytokines, which induced cellular differentiation instead.
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PMID:Mesenchymal stem cells promote a primitive phenotype CD34+c-kit+ in human cord blood-derived hematopoietic stem cells during ex vivo expansion. 2310 53

Cancer is associated with immune dysfunction characterized by the presence of proinflammatory and immunosuppressive cells and factors that contribute to tumor growth and progression. Here we show that mammary tumor growth is associated with defects in hematopoiesis, leading to myeloproliferative-like disease (leukemoid reaction), anemia, and disruption of the bone marrow stem/progenitor compartment. The defects we characterized included impaired erythropoiesis, leukocytosis, loss of early progenitor cells in the bone marrow, and splenic extramedullary hematopoiesis. We established an in vitro model to dissect interactions between mammary cancers and the hematopoietic system. Investigations in this model revealed that granulocyte colony-stimulating factor (G-CSF) produced by mammary tumors can synergize with FLT3L and granulocyte macrophage CSF (GM-CSF) to expand myeloid progenitors and their progeny in culture. Mammary tumor growth was associated with histone methylation changes within lineage-negative c-Kit-positive hematopoietic cells within the bone marrow of tumor-bearing mice. Similarly, parallel histone methylation patterns occurred in cultured bone marrow cells exposed to mammary tumor-conditioned cell culture media. Notably, changes in histone methylation in these cell populations correlated with dysregulated expression of genes controlling hematopoietic lineage commitment and differentiation, including Hox family genes and members of the Polycomb repressive complex 2 (PRC2) chromatin-remodeling complex. Together, our results show that mammary tumor-secreted factors induce profound perturbations in hematopoiesis and expression of key hematopoietic regulatory genes.
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PMID:Dysregulated hematopoiesis caused by mammary cancer is associated with epigenetic changes and hox gene expression in hematopoietic cells. 2391 28