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

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

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

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

OBJECTIVETo study the interaction between transformation of human pulmonary epithelial cells and activation of fibroblasts induced by Yunnan tin mine dust.

METHODS(1) The immortalized human bronchial epithelial cell line BEAS-2B and human embryo lung fibroblast cell line WI-38 were grown in MEM medium containing 5% and 10% FBS, respectively, at 37 degrees C and 5% CO2 with saturated humidity. The cells were subcultured every 6 days. BEAS-2B cells and WI-38 cells were induced with Yunnan tin mine dust on every other generation at the concentration of 100 microg/ml. From the 11th generation, the cells were co-cultured. Epithelial cell transformation was tested using concanavalin A (ConA) agglutination and anchorage-independent growth assays. The cell cycles were analyzed through flow cytometry. The expressions of alpha-SMA in fibroblasts were determined with immunocytochemistry.

RESULTS(1) Cell morphology of mine dust-exposed epithelial cells began to transform at the 28th generation. Similar transformations were observed with mine dust-induced epithelial cells co-cultured with fibroblasts from the 20th generation and mine dust-induce epithelial cells co-cultured with mine dust-induced fibroblasts from the 16th generation. ConA agglutination assay and anchorage-independent growth assays were negative in normal BEAS-2B cells. At the 26 th generation, the agglutination test result of the mine dust-exposed epithelial cells was positive. Co-cultured with fibroblasts and mine dust-exposed fibroblasts, the agglutination time of the mine dust-exposed epithelial cells became short. Epithelial cell anchorage-independent growth assay was positive for mine dust-exposed epithelial cells co-cultured with fibroblasts at the 36th generations and for mine dust-exposed epithelial cells co-cultured with mine dust-exposed fibroblasts at the 26th generations. The clone formation rate of the 26th generation was 6.00 per thousand +/- 1.00 per thousand and 15.33 per thousand +/- 2.52 per thousand respectively, with the significant differences (P < 0.05). With generation adding, the portion of S phase increased for mine dust-exposed epithelial cells. (2) At the 26th generations, fibroblasts expressed alpha-SMA. Co-cultured with epithelial cell, the alpha-SMA expression of fibroblasts increased. Especially, positive cell numbers and intensity of staining dramatically increased with generation adding.

CONCLUSIONS(1) The tin mine dust can induce malignant transformation of human pulmonary epithelial cells BEAS-2B and activation of fibroblasts WI-38. (2) The epithelial cells are major target in carcinogenesis induced by Yunnan tin mine dust. (3) Transformation of epithelia and activation of fibroblasts co-evolve in the developing process of induced lung cancer by Yunnan tin mine dust.

Cell Cycle ; drug effects ; Cell Line ; Cell Transformation, Neoplastic ; drug effects ; Coculture Techniques ; Dust ; Epithelial Cells ; pathology ; Fibroblasts ; metabolism ; pathology ; Humans ; Tin ; toxicity

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

OBJECTIVE: To explore the effect of all-trans-retinoic acid (ATRA) on the growth inhibition and cellular differentiation of C6 glioma cells. METHODS: Human glioma C6 cells were treated with 5 mg/L ATRA,and the inhibition of cell growth was assessed by methyl thiazolyl tetrazolium assay. The differentiation of C6 cells was determined by flow cytometry, microscopy,transmission electron microscope, and immunohistochemical technique. RESULTS: Treatment of ATRA could result in the growth inhibition of C6 cells, and the cell density significantly decreased(P<0.01). The cell cycle distribution was changed, G0/G1 phase was prolonged, and cells at S phase decreased(P<0.01). The C6 glioma cells displayed normal fibroblast-like morphology under the microscope before the induction, and the ATRA-treated C6 cells became slightly long, turned into round in the middle, and had protrusions at both ends. The ATRA-treated C6 cells did not display obvious apoptosis by flow cytometry(P>0.05).Whereas, early apoptosis was observed under the transmission electron microscope, the vacuoles increased, the mitochondria and endoplasmic reticulum were abundant in the cytoplasm, and the cellular structures tended to be normal.The expression of glial fibrillaryacidic protein in C6 cells increased in the treatment group. CONCLUSION ATRA can inhibit the proliferation, and induce the differentiation of C6 glioma cells.
Animals ; Antineoplastic Agents ; pharmacology ; Brain Neoplasms ; pathology ; Cell Proliferation ; drug effects ; Cell Transformation, Neoplastic ; drug effects ; Glioma ; pathology ; Humans ; Mice ; Tretinoin ; pharmacology ; Tumor Cells, Cultured

OBJECTIVETo investigate the application value of Angelica polysaccharide (APS) on proliferation and differentiation of human erythroleukemia K562 cells.

METHODSThe effect of APS in inhibitory proliferation and inducing differentiation of human erythroleukemia K562 cells was studied by modern experimental hematologic techniques such as cell counting and culture, flowcytometry, morphology, cytochemistry and cell differential immune phenotyping.

RESULTSAPS could significantly inhibit the proliferation of K562 cells in vitro and prevent the cell from entering the active proliferative phase (P < 0.05). After being induced by APS, the differentiation of K562 cells to erythrocyte series and granulo-monocyte series increased, positive rate of benzidine, glycogen and peroxidase stain elevated, and cell surface differential antigen CD15 expression promoted significantly (P < 0.05), while C-MYC expression of K562 cells induced by APS induction lowered significantly (P < 0.05).

CONCLUSIONAPS could not only inhibit the proliferation of K562 cells in vitro, but also induce the differentiation of K562 cells toward erythrocyte and granulocyte series. It may be a natural inducer with promising prospect of development and application.

Angelica sinensis ; chemistry ; Antineoplastic Agents, Phytogenic ; pharmacology ; Cell Division ; drug effects ; Cell Transformation, Neoplastic ; drug effects ; Humans ; K562 Cells ; pathology ; Polysaccharides ; pharmacology