Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0079731 (B-cell lymphoma)
 16,671 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The present study investigated the characteristic features of cancer stem cells (CSCs) using an aggressive human osteosarcoma cell line OS-65. Hoechst 33342 dye exclusion was used to distinguish the cancer stem-like side population (SP) cells from OS-65 cells. Furthermore, the SP cells were characterized via chemoresistance and cell death assays, reverse transcription-quantitative polymerase chain reaction and immunofluorescence. The present study identified ~3.3% of cancer stem-like SP cells from OS-65 cells whose prevalence is reduced significantly (0.9%) following treatment with verapamil. It was demonstrated that osteosarcoma SP cells are highly efficient at generating additional sarcospheres as transcriptional regulation of stemness genes, including SOX2, OCT-4 and NANOG, is highly upregulated. Notably, these SP cells demonstrated high resistance against chemotherapeutic drugs and apoptosis via elevated transcriptional regulation of several ATPase binding cassette (ABC) transporter and anti-apoptotic proteins, including ABCG2, ABCB1/MDR1 ABCB5, B cell lymphoma-2 (Bcl-2) and Bcl-2 associated X protein, respectively. The results of the present study suggested that CSCs may be a novel therapeutic target for the prevention of tumor relapse.
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PMID:Increased multi-drug resistance and reduced apoptosis in osteosarcoma side population cells are crucial factors for tumor recurrence. 2734 20

Cancer stem cells are proposed to be responsible for resistance to chemotherapeutic agents, including doxorubicin. As phenylbutyrate enhances cancer stem cell properties, we analyzed surviving lymphoma cells after treatment with doxorubicin and phenylbutyrate. Human B-cell lymphoma cell lines, including Toledo, BJAB, Daudi, and Raji were incubated with IC90 concentrations of doxorubicin (300 nM) or phenylbutyrate (8 mM). After 48 h, live cells were sorted and analyzed for their resistance to treatment by examining gene expression profiles using cDNA microarray and biological characteristics. A small fraction of lymphoma cells that survived after drug application showed higher expression of stem cell markers (NANOG, and SOX2) and superior ability of self-renewal and sphere formation, compared to untreated control cells (P < 0.05). Gene expression analysis disclosed elevated expression of 41 genes, including FOXO4, in the four lymphoma cell lines that survived drug treatment. Overexpression of FOXO4 was evident in lymphoma cells surviving after phenylbutyrate treatment and refractory patient-derived lymphoma cells. Induction of FOXO4 expression promoted self-renewal whereas its knockdown led to diminished expression of stem cell markers and colony-forming ability of lymphoma cells. Immunohistochemical staining for FOXO4 in tumor tissue of diffuse large B-cell lymphoma revealed nuclear localization and significant association with poor prognosis. In conclusion, lymphoma cells resistant to treatment exhibit stem cell-like properties and enhanced FOXO4 expression. The presence of FOXO4-expressing cells in tumor tissue and their association with poor survival supports a role of FOXO4 in promoting stem cell properties resulting in poor outcomes.
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PMID:FOXO4 expression is related to stem cell-like properties and resistance to treatment in diffuse large B-cell lymphoma. 2791 Dec 72

Heat shock factor 1 (HSF1), a transcription factor activated by various stressors, regulates proliferation and apoptosis by inducing expression of target genes, such as heat shock proteins and Bcl-2 (B-cell lymphoma 2) interacting cell death suppressor (BIS). HSF1 also directly interacts with BIS, although it is still unclear whether this interaction is critical in the regulation of glioblastoma stem cells (GSCs). In this study, we examined whether small interfering RNA-mediated BIS knockdown decreased protein levels of HSF1 and subsequent nuclear localization under GSC-like sphere (SP)-forming conditions. Consistent with BIS depletion, HSF1 knockdown also reduced sex determining region Y (SRY)-box 2 (SOX2) expression, a marker of stemness, accompanying the decrease in SP-forming ability and matrix metalloprotease 2 (MMP2) activity. When HSF1 or BIS knockdown was combined with temozolomide (TMZ) treatment, a standard drug used in glioblastoma therapy, apoptosis increased, as measured by an increase in poly (ADP-ribose) polymerase (PARP) cleavage, whereas cancer stem-like properties, such as colony-forming activity and SOX2 protein expression, decreased. Taken together, our findings suggest that targeting BIS or HSF1 could be a viable therapeutic strategy for GSCs resistant to conventional TMZ treatment.
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PMID:Heat Shock Factor 1 Depletion Sensitizes A172 Glioblastoma Cells to Temozolomide via Suppression of Cancer Stem Cell-Like Properties. 2824 25

Although the existence of cancer stem cells (CSCs) has been suggested in diffuse large B cell lymphoma (DLBCL), there is still no definitive marker. CD45+CD19- has been regarded as a potential marker of CSCs in mantle cell lymphoma (MCL). So, we explored the role of CD45+CD19- in DLBCL. However, both CD45+CD19- cells and CD45+CD19+ cells did not generate tumors until more than 100,000 cells were inoculated in NOD/SCID mice, even CD45+CD19+ cells generated more and larger tumors, as well as the soft agar colony formation in vitro; The aldehyde dehydrogenase (ALDH) activity was also identified in this study. Only 1,500 ALDHhigh cells were enough to generate tumors in mice while the same number of ALDH- cells were not. Moreover, both groups formed tumors when more cells were inoculated, but ALDHhigh cells formed more and larger tumors. The similar result was obtained in vitro clonogenicity experiments. OCT4, SOX2, Nanog, and ABCG2 genes did not show any difference in CD45+CD19+, CD45+CD19-, ALDHhigh and ALDH- cells. Taken together, CSCs are not enriched in the CD45+CD19- cells but in the ALDHhigh cells in DLBCL cell lines.
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PMID:Cancer Stem Cells of Diffuse Large B Cell Lymphoma Are Not Enriched in the CD45+CD19- cells but in the ALDHhigh Cells. 3189 81

Up to one-third of diffuse large B cell lymphoma (DLBCL) patients eventually develop resistance to R-CHOP regimen, while the remaining therapeutic options are limited. Thus, understanding the underlying mechanisms and developing therapeutic approaches are urgently needed. Methods: We generated two germinal center B cell-like (GCB) and activated B cell-like (ABC) subtype R-CHO resistant DLBCL cell lines, of which the tumor-initiating capacity was evaluated by serial-transplantation and stemness-associated features including CD34 and CD133 expression, side population and ALDH1 activity were detected by flow cytometry or immunoblotting. Expression profiles of these resistant cells were characterized by RNA sequencing. The susceptibility of resistant cells to different treatments was evaluated by in vitro CytoTox-glo assay and in tumor-bearing mice. The expression levels of SOX2, phos-AKT, CDK6 and FGFR1/2 were detected in 12 R-CHOP-resistant DLBCL clinical specimens by IHC. Results: The stem-like CSC proportion significantly increased in both resistant DLBCL subtypes. SOX2 expression level remarkably elevated in both resistant cell lines due to its phosphorylation by activated PI3K/AKT signaling, thus preventing ubiquitin-mediated degradation. Further, multiple factors, including BCR, integrins, chemokines and FGFR1/2 signaling, regulated PI3K/AKT activation. CDK6 in GCB subtype and FGFR1/2 in ABC subtype were SOX2 targets, whose inhibition potently re-sensitized resistant cells to R-CHOP treatment. More importantly, addition of PI3K inhibitor to R-CHOP completely suppressed the tumor growth of R-CHO-resistant DLBCL cells, most likely by converting CSCs to chemo-sensitive differentiated cells. Conclusions: The PI3K/AKT/SOX2 axis plays a critical role in R-CHOP resistance development and the pro-differentiation therapy against CSCs proposed in this study warrants further study in clinical trials for the treatment of resistant DLBCL.
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PMID:PI3K/AKT inhibition reverses R-CHOP resistance by destabilizing SOX2 in diffuse large B cell lymphoma. 3219 60