Not all cancer cells are born equal. While the great majority of the cells that make up tumours are destined to differentiate, albeit aberrantly, and eventually stop dividing, a handful of cancer cells appear to possess limitless replicative potential. This review presents compelling evidence to suggest that the bulk of malignant cells of most cancers are generated by a rare fraction of stem cell-like cancer cells. These cells, dubbed cancer stem cells, are phenotypically similar to the normal stem cells of the corresponding tissue of origin, but they exhibit dysfunctional patterns of self-renewal and differentiation. Cancer stem cells that are capable of recapitulating brain tumours as xenografts in mice are characterised by defined stem cell markers. These brain tumour stem cells demonstrate enhanced chemoresistance and radioresistance mechanisms compared to non-stem cells in the heterogeneous tumour, which suggest that they may be the likely candidates for tumour progression and recurrence. Indeed, recent work has shown that such aberrant signalling pathways may be targeted in novel anti-cancer therapeutic strategies. The stem cell concept of tumour progression prompts immediate attention to a new paradigm in cancer research with a focus on this minority subset of cells, and the design of novel therapeutic strategies to target these cells that are insignificant within the population of tumour cells, but that are in fact the relevant cells to be destroyed.
Cell Transformation, Neoplastic ; Glioma ; pathology ; radiotherapy ; Humans ; Models, Biological ; Neoplastic Stem Cells ; drug effects ; pathology ; Singapore

Bronchi ; drug effects ; pathology ; Cell Line ; Cell Transformation, Neoplastic ; drug effects ; Epithelial Cells ; drug effects ; pathology ; Humans ; Mineral Fibers ; toxicity

OBJECTIVETo study the biological effects of nickel-refining dust.

METHODSThe cell phagocytosis, transformation activity, and cytotoxicity of the mouse NIH3T3 cells treated with nickel-refining dusts from two nickel-refining factories in China were observed, and the risk of carcinogenicity was studied.

RESULTS(1) Two samples of nickel-refining dusts could be phagocytosed by mouse NIH3T3 cells with different phagocytizing rates of 69.0% and 39.0% at 100.000 micro g/ml, and 78.0% and 47.0% at 200.000 micro g/ml respectively. The relative clone formation rates at 12.500 micro g/ml to 100.000 micro g/ml were 71.1% to 3.9% and 84.4% to 9.1%, respectively. The cytotoxicity expressed by clone formation rate was similar to that of Ni(2)O(3), but higher than that of TiO(2) and lower than the positive control of N-methyl-N'-nitro-N-nitroso-guanidine (MNNG). (2) MNNG, Ni(2)O(3) and the two samples of nickel-refining dusts could induce morphological transformation in NIH3T3 cells. The transformation rate at 12.500 micro g/ml to 50.000 micro g/ml were 1.9% to 3.6% and 0.9% to 2.5% respectively in a dose-dependent manner. (3) The NIH3T3 cells treated by MNNG and nickel-refining dusts could induce Con A agglutination, and may form as clone in soft agar. This finding proved the reliability of the transformed clone.

CONCLUSIONSThe present study for the first time demonstrate that nickel-refining dusts have cell transformation activity. The findings provide a new experimental evidence for the carcinogenic risk of nickel-refining dusts, and for the aetiology of lung cancer in nickel-refining workers.

Animals ; Cell Transformation, Neoplastic ; drug effects ; pathology ; Dust ; Mice ; NIH 3T3 Cells ; Nickel ; toxicity

OBJECTIVE: To determine the differentiation-inducing effects of perphenazine on K562 leukemia cells. METHODS: Differentiation-Inducing effects of a phenothiazine perphenazine were evaluated by proliferation, morphology and function of K562 cells. We evaluated the effects of perphenazine on K562 cells proliferation by cellular enumeration in liquid culture assay, MTT assay and clony formation assay, the morphology by Wight-Gimesa staining, and the function by detecting CD71 through flow cytometry. RESULTS: Perphenazine enhanced the expression of CD71 on K562 cells and increased Hb content in K562 cells, while inhibited the proliferation of K562 cells. K562 cells showed differentiation morphology after the drug treatment. CONCLUSION Perphenazine possessed differentiation-inducing effects on K562 cells.
Cell Transformation, Neoplastic ; drug effects ; Flow Cytometry ; Humans ; K562 Cells ; Perphenazine ; pharmacology

CCL23 is a human CC chemokine with potential suppression effects on both human and murine myeloid progenitor cells both in vitro and in vivo, and only expressed and released by dendritic cells differentiated from monocytes in blood cells. However, recent study has shown that CCL23 was over-expressed in bone marrow and peripheral blood cells from pediatric patients with acute myeloid leukemia (AML). In order to investigate the effects of CCL23 on the development, therapy and prognosis of leukemia, the U937 cells, a leukemic cell strain, were adopted and cultured with rhCCL23 for 72 hours. The cell proliferation and apoptosis rate were detected by Cell Counting Kit-8 and FITC-AnnexinV/PI respectively; the morphologic changes and the expression of CCR1 (the only receptor of CCL23 known by now) were observed during the differentiation process. The results showed that no obvious effect on the proliferation, apoptosis and differentiation of U937 was found by using CCL23 alone (P > 0.05), but cultured in combination with CCL23 and PMA, the differentiation of U937 cells were promoted remarkably, during which the CCR1 expression increased (P < 0.05). It is concluded that CCL23 alone did not inhibit the proliferation and differentiation of U937, while its use in combination with PMA may possess synergistic effect on inducting differentiation of U937 through the increase of receptor CCR1 expression.
Apoptosis ; physiology ; Cell Proliferation ; drug effects ; Cell Transformation, Neoplastic ; drug effects ; Chemokines, CC ; pharmacology ; Humans ; U937 Cells

Carcinoma, Hepatocellular ; pathology ; Cell Transformation, Neoplastic ; drug effects ; Ginsenosides ; pharmacology ; Humans ; Liver Neoplasms ; pathology ; Signal Transduction ; drug effects

Basal autophagy plays a critical role in maintaining cellular homeostasis and genomic integrity by degrading aged or malfunctioning organelles and damaged or misfolded proteins. However, autophagy also plays a complicated role in tumorigenesis and treatment responsiveness. It can be tumor-suppressing during the early stages of tumorigenesis (i.e., it is an anti-tumor mechanism), as reduced autophagy is found in tumor cells and may be associated with malignant transformation. In this case, induction of autophagy would seem to be beneficial for cancer prevention. In established tumors, however, autophagy can be tumor-promoting (i.e., it is a pro-tumor mechanism), and cancer cells can use enhanced autophagy to survive under metabolic and therapeutic stress. The pharmacological and/or genetic inhibition of autophagy was recently shown to sensitize cancer cells to the lethal effects of various cancer therapies, including chemotherapy, radiotherapy and targeted therapies, suggesting that suppression of the autophagic pathway may represent a valuable sensitizing strategy for cancer treatments. In contrast, excessive stimulation of autophagy may also provide a therapeutic strategy for treating resistant cancer cells having high apoptotic thresholds. In order for us to develop successful autophagy-modulating strategies against cancer, we need to better understand how the roles of autophagy differ depending on the tumor stage, cell type and/or genetic factors, and we need to determine how specific pathways of autophagy are activated or inhibited by the various anti-cancer therapies.
Anticarcinogenic Agents/therapeutic use ; Autophagy/*physiology ; Cell Transformation, Neoplastic/drug effects ; Humans ; Neoplasms/*drug therapy/metabolism/*pathology

The purpose of this study was to explore the effect of N, N'-di-(m-methylphenyi)-3, 6-dimethyl-1, 4-dihydro-1, 2, 4, 5-tetrazine-1, 4-dicarboamide (ZGDHu-1) on proliferation, differentiation and apoptosis in NB4 human leukemia cell line and its possible mechanism. Different concentrations of ZGDHu-1 and the different time of cultivation were used to treat NB4 cells. The proliferation inhibition of NB4 cells was analysed by cell counting, alive cell count, MTT assay. Cell apoptosis was determined by cell morphology, DNA agarose gel electrophoresis, DNA content, Annexin-V/PI and Hoechst 33258 labeling method. The analysis of cell morphological change, expression of CD11b, CD13 and NBT reduction were performed to evaluate the differentiation of NB4 cells. The expressions of bcl-2, bax and phosphorylated p38MAPK or STAT3 were detected by flow cytometry. While the expression of hTERT mRNA in transcriptional level was measured by fluorescence quantitative RT-PCR. The results showed that ZGDHu-1 could inhibit NB4 cell proliferation viability within a certain range of treating time and does, IC(50) values at 48 and 72 hours were 450 ng/ml and 200 ng/ml respectively. A majority of NB4 cells were arrested in G(2/M) phase and a progressive decline of cells was seen in G(0/1). The NB4 cells apoptosis was confirmed by cell typical cell morphology, DNA fragments and sub-G(1) phase peak as well as Hoechst33258 and Annexin-V/PI labeling method with a time-dose-related manner. The morphology of NB4 cells cultured in the presence of 2 - 100 ng/ml ZGDHu-1 for three days was more mature with higher NBT positivity and expressions of CD11b and CD13 than those in control. The expression of phosphor-p38MAPK and bax was increased while phosphor-STAT3 and bcl-2 were unchanged by the treatment of ZGDHu-1. ZGDHu-1 could decrease the expression of hTERT-mRNA in a dose-dependent manner. It is concluded that ZGDHu-1 can inhibit proliferation, induce differentiation and apoptosis of NB4 cells. The mechanism may be associated with up-regulation of bax expression, enhancement of phosphor-p38MAPK activation and inhibition of hTERT-mRNA.
Antineoplastic Agents ; pharmacology ; Apoptosis ; drug effects ; Cell Proliferation ; drug effects ; Cell Transformation, Neoplastic ; drug effects ; Heterocyclic Compounds, 1-Ring ; pharmacology ; Humans ; Leukemia, Promyelocytic, Acute ; pathology ; Tumor Cells, Cultured

Bronchi ; drug effects ; pathology ; Cell Line ; Cell Transformation, Neoplastic ; drug effects ; genetics ; Dust ; Epithelial Cells ; drug effects ; pathology ; Gene Library ; Humans ; Minerals ; toxicity

OBJECTIVETo observe the effect of crystalline NiS on genome DNA methylation profile in in vitro cultured cells.

METHODS16HBE Cells were treated with crystalline NiS at 0.25, 0.50, 1.00 and 2.00 µg/cm(2) for 24 h and three times at total. DAC treatment was given at 3 µmol/L for 72 h.5-mC immunofluorescence and SssI methyltransferase assay methods were applied to investigate if the hypomethylation of genome DNA involved.

RESULTSThe results of 5-mC immunofluorescence showed that the fluorescence intensity of NiS-treated cells were decreased in some degree, and transformed cells were decreased dramatically. By the SssI methylase assay, an average of (81.9 ± 7.3)% methylated CpG were found in negative control cells. By contrast, (77.9 ± 6.2)%, (75.3 ± 6.8)%, (59.5 ± 4.9)%, (67.4 ± 5.1)% methylated CpG were observed in cells treated with NiS for three times at dosage of 0.25, 0.50, 1.00 and 2.00 µg/cm(2) which were abbreviated as NiS0.25, NiS0.50, NiS1.00, NiS2.00 respectively. The ANOVA analysis results showed that there was a significant difference in the 5 groups above (F = 124.95, P < 0.01). The results of Dunnett-t test showed that the methylated CpG of both group NiS1.00 and NiS2.00 were significantly decreased compared with the negative control group (t values were 7.64, 4.89 respectively, P < 0.01). For methylated CpG, (46.2 ± 4.1)% and (43.6% ± 4.3)% were observed in NiS-transformed cells (NSTC1 and NSTC2) which were dramatically decreased compared with the negative control group (t values were 12.79, 13.56 respectively, P < 0.01).

CONCLUSIONGenomic DNA methylation levels were decreased during NiS induced malignant transformation.

Bronchi ; cytology ; Cell Line ; Cell Transformation, Neoplastic ; chemically induced ; DNA Methylation ; drug effects ; Epithelial Cells ; drug effects ; Genome ; Humans ; Nickel ; adverse effects ; chemistry