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PubMed1988

In vitro growth patterns and autocrine production of hemopoietic colony stimulating factors: analysis of leukemic populations arising in irradiated mice from cells of an injected factor-dependent continuous cell line.

Cells of the factor-dependent hemopoietic cell line FDC-P1 become leukemic when injected intravenously to irradiated syngeneic mice. An analysis of 117 cell lines derived from 17 such leukemic mice showed that they displayed different patterns of growth in vitro ranging from full autonomy to absolute dependency on stimulation by granulocyte-macrophage colony stimulating factor (GM-CSF) or multipotential colony stimulating factor (multi-CSF). In contrast to parental FDC-P1 cells, even the factor-dependent variant cell lines were tumorigenic in vivo. The behavior of these latter cell lines could not be explained by hyperresponsiveness to CSFs or prolonged survival in the absence of CSFs. Conditioned media and cell lysates from leukemic cell lines from 8 animals contained variable levels of GM-CSF or multi-CSF. Proliferation of a GM-CSF-producing cell line was inhibited by anti-GM-CSF antibody, while both the parental FDC-P1 line and a leukemic line secreting multi-CSF remained unaffected. The patterns of growth in vitro of the leukemic cells tended to correlate with the amounts of CSFs produced. The observations show that leukemic transformation of FDC-P1 cells in vivo is frequently linked to autogenous production of hemopoietic growth factors. The range of abnormal in vitro growth patterns observed includes those typical of human acute myeloid leukemia, and the in vivo transformation model may be useful in analyzing the mechanisms leading to the development of this human disease.

Animals↗

PubMed1985

TCGF (IL 2)-receptor inducing factor(s). I. Regulation of IL 2 receptor on a natural killer-like cell line (YT cells).

A continuous cell line (YT cells) with inducible receptor for T cell growth factor (TCGF)/interleukin 2 (IL 2) was established from a 15-yr-old boy with acute lymphoblastic lymphoma and thymoma. YT cells were tetraploid, having 4q+ chromosomal markers, and proliferated continuously in vitro without conditioned medium (CM) or IL 2. They were weakly positive for OKT9, OKT11, and Tac antigen (Ag), a determinant closely associated with the receptor for IL 2 (IL 2-R), and were negative for OKT1, OKT3, OKT4, and OKT8 Ag. YT cells also expressed HNK-1 Ag and Fc receptors for IgG, which are expressed on natural killer (NK) cells. They retained a killing activity against human cell lines, including K562 (myeloid), T, and B cell lines. Unlike Tac Ag/IL 2-R(+) cell lines derived from adult T cell leukemia (ATL), YT cells were negative for HTLV, as proved by Southern blotting with cDNA for viral DNA. The expression of Tac Ag was markedly enhanced in 18 hr, when YT cells were incubated with CM from PHA-stimulated peripheral blood leukocytes (PBL) or spleen cells, as determined by immunofluorescence by using flow cytometry and binding assay with 125I-anti-Tac antibody (Ab). The binding study with 125I-labeled recombinant IL 2 showed 3.2 X 10(4) IL 2 receptor sites on YT cells precultured with CM. PHA-P and Con A neither agglutinate nor enhance the expression of IL 2-R/Tac antigen on these non-T cell line cells. Furthermore, neither recombinant IL 2 nor gamma-interferon could induce IL 2-R on YT cells, suggesting the presence of a unique IL 2-R inducing factor in PBL or spleen CM. Unlike Tac Ag on HTLV(+), ATL-derived cell lines (Hut-102, MT-1, ATL-2), the expression of Tac Ag on YT cells was down-regulated by anti-Tac Ab. The induction of Tac Ag/IL 2-R on YT cells seemed specific, because the enhancement of Tac Ag expression was not associated with that of Ia Ag and T9/transferrin receptor.

Adolescent↗

PubMed1992

Introduction to the issues: recently developed methods for characterizing cell lines.

Cell line characterization is an integral part of establishing quality control over the manufacturing process of a biological product. Characterizing the general and unique features of the continuous cell line and the absence or presence of contaminants establishes a fundamental knowledge about the raw material from which the biological product is being derived. Such information can be used for cell line selection, design of the purification scheme and extent of ensuing validation studies. Developing the selected cell line into a cell bank system allows for a constant source of starting material and decreases the likelihood of contamination. Characterization of the cell bank system may include a) identification of the cell line species of origin, b) identification of unique reference markers, and c) pre-testing for cross-contamination and adventitious agents. This paper introduces issues surrounding present and upcoming methods used for authenticity and characterization testing of cell banks.

Animals↗

PubMed1979

Feeder layer and nutritional requirements for the establishment and cloning of human malignant lymphoma cell lines.

Cell lines were successfully established in continuous suspension culture from 10 patients with a histopathological diagnosis of diffuse histiocytic lymphoma (SU-DHL-1 to SU-DHL-10), two with North American Burkitt's lymphoma (SU-AmB-1 and SU-AmB-2), and one with acute lymphoblastic leukemia (SU-ALL-1). By screening a variety of parameters, including media, sera, effusion fluids, feeder layers, and chemical supplements, the nutritive growth requirements of lymphoma cells obtained from malignant effusions and lymph node biopsies were determined for each tumor. Most of these cell lines initially required human skin fibroblast or epithelial cell feeder layers from which they could be weaned after one to six weeks in culture and maintained in Roswell Park Memorial Institute Tissue Culture Medium 1640 containing 20% fetal calf serum and 10% pooled human serum. Several of these cell lines were successfully cloned on 0.5% Noble agar substrates. In the presence of human serum and selected feeder monolayers, cloning efficiencies increased significantly from less than 1% to 15 to 25%. In addition, the cloning efficiencies of certain cell lines showed a concentration-dependent increase with specific chemical supplements including L-cysteine and dithiothreitol. Placental colony-stimulating factor, nerve growth factor, epithelial growth factor, and fibroblastic growth factor were ineffective in augmenting the cloning efficiencies of the human lymphoma cell lines. After a single passage on agar, cells subpassaged from visible colonies showed markedly increased cloning efficiencies to levels as high as 50%. Such cloning efficiencies, coupled with the use of replica plating, make this technique applicable to genetic and quantitative radiobiological, immunological, and chemotherapeutic studies. Although these methods have thus far been used only with lymphoreticular tumors, they may also be applicable to the cell culture of other human neoplasms and normal tissues.

Burkitt Lymphoma↗

PubMed1977

Search for inhibitors against herpes simplex virus type-I in cell extracts derived from human lymphoblastoid cell lines.

Cell extracts obtained from KB cells and 5 human lymphoblastoid cell lines including 2 from Burkitt's lymphoma (P3HR-1 and Raji), one each from nasopharyngeal carcinoma (no.223), acute lymphatic leukemia (MOLT-4) and a healthy person (NC-37) were tested for their inhibitory effects on the growth of herpes simplex virus type-1 (HSV-1) in green monkey kidney (GMK) cells by the plaque titration method. The relationship between the production of HSV-1 inhibitors and the degree of Epstein-Barr virus (EBV) genome repression in lymphoblastoid cells were also examined. Among the cell lines used P3HR-1 and no.223 cells produced a few EBV particles, Raji and NC-37 cells contained EBV genomes only, and MOLT-4 as well as KB cells were EBV genome-negative. The results revealed that P3HR-1 cell extract showed a tendency to inhibit HSV-1 growth in GMK cells but the other 4 lymphoblastoid cell lines and KB cells did not produce HSV-1 inhibitors, indicating that EBV genomes governing the formation of EBV structural antigens were not related to the production of HSV-1 growth inhibitors. The extracts from MOLT-4 cells, which are only a T lymphocyte cell line used in this study, stimulated HSV-1 growth in GMK cells significantly.

Antiviral Agents↗

PubMed1976

The effect of pH on incorporation of galactose by a normal human cell line and cell lines from patients with defective galactose metabolism.

Incorporation of radioactive galactose into TCA-insoluble material of galactosemic fibroblasts is more sensitive to low pH than is the incorporation by normal human fibroblasts. This study was undertaken to determine (1) whether there was any pH which could correct or counteract the galactosemic defect relative to galactose incorporation, and (2) whether the low pH effect was specific for galactose metabolism or whether general cellular metabolism in galactosemic cells was more sensitive to low pH than that in normal cells. The pH dependencies of incorporation of radioactive galactose and glucose into cellular macromolecules were investigated in galactosemic and normal cells. Normal cells have a biphasic curve with respect to galactose incorporation with peaks at pH 7.0 and 8.5. Galactosemic cells have only the high pH peak. The maximum incorporation by galactosemic cells was never more than about 30% that seen by normal cells under the conditions of these experiments. Thus manipulation of the pH alone cannot correct the galactosemic defect. The rate of incorporation of radioactive galactose was studied in normal, galactosemic and galactokinase deficient cells, at pH 7.2 and at pH 6.3. At pH 7.2, galactosemic cells incorporate galactose at a linear rate which is 30 to 40% that of normal cells while incorporation by kinase-deficient cells is between 5 and 10% of normal. At pH 6.3, the incorporation is also linear. However, galactosemic cells now exhibit the same rate as kinase-deficient cells in which the low level of incorporation is unaffected by pH. These results suggest that incorporation of galactose by galactosemic cells at low pH is not due to metabolic death of the cells, but may be due to the inhibition of some specific step or steps along a metabolic route of galactose metabolism other than the Leloir pathway.

Cell Line↗

PubMed1986

Sodium cotransport processes in renal epithelial cell lines.

Cell growth and synchronization, gene expression and regulation, maintenance of epithelial cell polarization are major functional aspects of the nephron which have been difficult to approach with conventional preparations. Certainly, without the introduction of tissue culture techniques, the opportunity to analyze these issues could not have been afforded. Several renal epithelial cell lines with differentiated characteristics of proximal and distal segments of the nephron are already available. LLC-PK1, derived from a normal Hampshire pig kidney, shows multiple differentiated characteristics of in vivo epithelia. Specifically, this cell line has Na+-dependent sugar, amino acid, and phosphate cotransport systems with similar characteristics as those present in the renal proximal tubule. The expression of the Na+-dependent sugar transport system in LLC-PK1 cells depends on the growing conditions of the cells. For instance, isolated cells obtained by trypsin-EDTA treatment of confluent monolayers or exponentially growing cells do not express the Na+-dependent sugar transport system. Full expression occurs after the monolayer reaches confluency. Expression of the transporter can also be modified by agents that affect the differentiation of other cellular systems, such as the Friend erythroleukemia cells. The expression of the Na-sugar cotransport system is also regulated by the concentration of glucose in the growth medium. Low glucose concentration increases the sugar influx through the Na+-coupled apical membrane transporter by increasing the number rather than the affinity of the transporter. This effect appears to be mediated through the sugar metabolism of the cell. The expression of the Na+-amino acid cotransport system in LLC-PK1 cells and the epithelial cell line MDCK derived from a normal dog kidney also responds to regulatory signals associated with cell growth or amino acid deprivation. LLC-PK1 cells and the cell line OK derived from an opposum kidney, shows a Na+-dependent phosphate cotransport system modulated by parathyroid hormone and cyclic nucleotides that will prove to be an excellent model not only to study the mechanisms of the action of the hormone, but to study the mechanisms involved in the expression and modulation of the Na+-dependent phosphate cotransport system.

Amino Acids↗

PubMed1992

Repair of damaged DNA by extracts from a xeroderma pigmentosum complementation group A revertant and expression of a protein absent in its parental cell line.

Cells derived from individuals with mutations in the xeroderma pigmentosum complementation group A gene (XP-A gene) are hypersensitive to UV light and have a severe defect in nucleotide excision repair of damaged DNA. UV-resistant revertant cell lines can arise from XP-A cells in culture. Cells of one such revertant, XP129, were previously shown to remove (6-4) photoproducts from irradiated DNA, but to have poor repair of cyclobutane pyrimidine dimers. To analyze the biochemical nature of the reversion, whole cell extracts were prepared from the SV40-immortalized fibroblast cell lines XP12RO (an XP-A cell line), the revertant XP129 (derived from XP12RO), and 1BR.3N (from a normal individual). The ability of extracts to carry out repair synthesis in UV-irradiated DNA was examined, and immunoblots were performed using antiserum that recognizes XP-A protein. XP12RO extracts exhibited a very low level of repair and no detectable XP-A protein, but repair activity could be conferred by adding purified XP-A protein to the reaction mixture. XP129 extracts have essentially normal repair synthesis consistent with the observation that most repair of UV-irradiated DNA by extracts appears to occur at (6-4) photoproducts. An XP-A polypeptide of normal size was present in XP129, but in reduced amounts. The results indicate that in XP129 a mutational event has converted the inactive XP12RO XP-A gene into a form which expresses an active XP-A protein.

Amino Acid Sequence↗

PubMed1991

Characterisation of adriamycin- and amsacrine-resistant human leukaemic T cell lines.

Cell lines resistant to adriamycin and amsacrine were derived from cloned sublines of the human T cell line Jurkat. Most of the lines resemble atypical MDR cells (Danks et al., 1987; Beck et al., 1987). Thus, resistant Jurkat sublines were cross resistant to several topoisomerase II inhibiting drugs but had low or no resistance to other classes of drugs, resistance was not reversed by verapamil, Pgp was not overexpressed, and drug accumulation was unaltered in resistant compared to parental (control) sublines. Other findings were that anthracycline metabolism differed between resistant and parental sublines, and that resistant sublines displayed altered expression of small polypeptides (less than 20K MW) and an 85K MW protein. Drug resistant cells showed resistance to the production of drug induced cytogenetic aberrations, DNA breaks, and protein-DNA complexes. Resistance was not mediated by altered binding of drugs to DNA or by increased repair of DNA damage. Indirect evidence suggests that the resistant cells had an altered drug-DNA-topoisomerase II association. The study highlights the complex relationships between DNA breaks, cytogenetic aberrations, protein-DNA complexes and drug cytotoxicity, and shows that the relationships differ for adriamycin and amsacrine, suggesting some differences in the modes of action and/or resistance for the drugs and cell lines.

Amsacrine↗

PubMed1991

Effects of the PAF-analog and -antagonist CV-6209 on cultured human glioma cell lines.

Cell lines of human glioma (U-343 MGa and U-251 MG) and human glia (U-533 CG) origin were cultured as monolayers and exposed to CV-6209, an alkyl-phospholipid analog and antagonist of platelet activating factor. This drug had very potent antiproliferative effects on the studied human glioma cell lines; IC50 was 0.9 microM after 48 h treatment and 0.2 microM after 2 weeks treatment. At these doses no growth inhibitory effect was noted on the normal glia cells. The effects on the glioma cells were reversible in the dose intervals, where cell proliferation, 3H-thymidine and 14C-methionine uptakes were greatly inhibited. The simultaneous administration of platelet activating factor [(R)PAF] did not influence the antiproliferative effects of CV-6209 on the cells cultured as monolayers. The structurally similar analog CV-3988 also had antiproliferative effects, although at 10 times higher concentration than CV-6209. Two other, structurally unrelated, PAF-antagonists (WEB-2086 and TCV-309) gave effects only at very high concentrations. The U-343 MGa cell line was also exposed to CV-6209 when growing as multicellular spheroids. The studies on the spheroid cultures also demonstrated good antitumoral effects with decreases of both the volume growth and the thymidine uptake. The simultaneous administration of (R)PAF reversed the inhibitory effect of CV-6209 on thymidine incorporation. This study demonstrates a strong antitumoral effect at low concentrations of CV-6209. The antiproliferative effects were probably primarily related to the ether-lipid structure and not to the PAF-antagonistic properties. The good antitumoral effect of CV-6209 on both monolayer and spheroid cultures and the possible PAF-antagonistic properties are discussed.

Cell Division↗

PubMed1989

SV-40 large-T immortalization of embryonic bone cells: establishment of osteoblastic clonal cell lines.

Cells derived from embryonic rat calvariae were immortalized by retroviral delivery of cDNA for the SV-40 large T antigen and the bacterial neomycin resistance gene. After selection with G418, cells were cloned by limiting dilution and screened for expression of osteoblast characteristics. One clone (RCT-3), derived from cells collected during the third period of enzymatic digestion, showed high constitutive expression of alkaline phosphatase (ALP), synthesized type I collagen in the virtual absence of type III and exhibited a parathyroid hormone (PTH)-responsive adenylate cyclase (EC50, 10 nM). Messenger RNAs for osteonectin and osteopontin were present in RCT-3 cells and osteopontin mRNA was enhanced by 1,25 (OH)2 vitamin D3 treatment. The other cell line (RCT-1), derived from cells released during the first 10 min of digestion, expressed osteoblast features only after 3 d treatment with 1 microM retinoic acid (RA). ALP activity increased from 0.003 to 0.25 mumole/min/mg protein, there was a substantial increase in the steady-state level of type I collagen mRNA and a dose-dependent and saturable response to PTH was induced (EC50, 10 nM). Osteopontin mRNA was induced by 1,25 (OH)2D3. This study has provided two new cell lines which may be useful models for studies of differentiation-related gene expression in bone cells.

Animals↗

PubMed1990

Differential utilization of the SV40 enhancer and early promoter in various human lung carcinoma cell lines.

Cell lines derived from the major morphological types of human lung cancer were tested for their ability to utilize the SV40 enhancer/early promoter. These cell lines were transfected with a recombinant plasmid containing a reporter gene, coding for chloramphenicol acetyltransferase (CAT), under the control of the SV40 enhancer/early promoter. The transfected cells were then assayed for CAT activity. Non-small-cell carcinomas, especially squamous carcinomas, were found to be 2-3 orders of magnitude more efficient in utilizing the SV40 enhancer/early promoter than small-cell carcinomas. The presence of different SV40 enhancer/early promoter specific DNA-binding nuclear factors in squamous and small-cell carcinomas was demonstrated in gel mobility shift experiments. These observations seem to suggest that the set of transcriptional regulatory factors associated with squamous carcinomas may be distinct from that associated with small-cell carcinomas.

Adenocarcinoma↗

PubMed1989

N-myc amplification and neuron-specific enolase production of a neuroblastoma cell line and germ cell tumor cell lines.

N-myc gene amplification of the gynecological malignant tumor cell lines and a neuroblastoma cell line was studied by the Southern hybridization method along with the production of neuron-specific enolase (NSE) by these cell lines. N-myc amplification and NSE production were observed side by side in three cell lines: neuroblastoma cell line HSNB, endodermal sinus tumor cell line HAEST, and malignant teratoma cell line HUOT. However, N-myc amplification and NSE production disappeared gradually following successive passages of the HAEST and HUOT lines. With respect to the HUOT line, these parameters disappeared along with the cells of nervous origin. N-myc amplification and NSE production were not observed in nine other cell lines.

Female↗

PubMed2026

Protocol for the isolation and characterization of extracellular vesicles and particles from human and murine cell lines.

Cells produce a heterogeneous population of extracellular vesicles and particles (EVPs). Small extracellular vesicles (sEVs or exosomes) are lipid membrane-enclosed vesicles with sizes ranging from 30 to 150 nm. Here, we present a protocol to isolate and characterize EVPs from the conditioned medium of cell lines. We describe steps for cell culture, conditioned media collection, differential ultracentrifugation, and EVP characterization. We then detail procedures for proteomic and biodistribution analyses. For complete details on the use and execution of this protocol, please refer to Yeung et al.1.

Animals↗

PubMed1976

Tumour growth and melanogenesis in hamster tumours in vivo and in vitro: growth, cytochemistry and ultrastructure of tissue cultural cell lines.

Cell lines were established from three hamster melanomas. One was a spontaneous melanotic tumour which lost its ability to produce pigment. Two were induced with DMBA (9.10 dimethyl 1,2-benz/a/anthracene). One of these was pigmented. The two amelanotic lines (CHT-1 and 2) produced highly malignant amelanotic tumours after reimplantation of tissue culture cells. Electron microscopy showed that melanin forming organelles were absent. Tyrosinase activity was also absent. The line established from the pigmented tumour (CHT-8) retained its pigment production for the first seven transfers. Cells from these cultures produced slow growing pigmented tumours. Cells from the 7th to the 35th transfer, a period of 28 weeks, failed to produce tumours but cells from the 36th and subsequent transfers produced slow growing amelanotic tumours. The change in tumorigenicity was not related to changes in the growth rate of the cells in vitro: this remained constant after the 11th transfer generation. Tyrosinase activity and a whole range of melanin forming organelles were present in cells of transfers 1 to 7 but absent from subsequent transfers. Type A and H virus particles were present in the two amelanotic cell lines, CHT-1 and 2. Although the two amelanotic lines produced highly malignant tumours the loss of a differentiated character--melanin production--was not invariably associated with increased malignancy. Three cell lines should provide a good system for studying the relationship between tumour differentiation and growth.

Acid Phosphatase↗

PubMed1978

Human cell membrane components bound to beta2-microglobulin in T cell-type cell lines.

Cell membrane components bound to beta2-microglobulin were isolated from Renex 30 (a nonionic detergent)-solubilized membrane materials of two human T cell-type cell lines, MOLT-4 and CCRF-CEM, by gel filtration and lectin affinity chromatography. The isolation was carried out by following the beta2-microglobulin activity by radioimmune inhibition assay. The T cell membrane components bound to beta2-microblogulin had a uniform molecular size of about 200,000 daltons and most of them showed an affinity to lentil lectin. The isolated membrane components were radioiodinated and examined for identity to HLA antigens by sequential precipitation with rabbit anti-HLA antiserum (specific to HLA large components) and with rabbit anti-beta2-microblogulin antiserum. In addition to HLA antigens, the beta2-microglobulin-bound components obtained from the MOLT-4 cells were found to contain certain membrane components that are the same in molecular size as the HLA large components but that are different antigenically from the HLA large components. On the other hand, the beta2-microglobulin-bound membrane components obtained from the CCRF-CEM cells were all HLA antigens. No other membrane components were involved in the binding.

Cell Line↗

PubMed1986

Presentation of Candida albicans and purified protein derivative soluble antigens by Epstein-Barr virus-transformed human lymphoblastoid B-cell lines.

Cells other than the macrophage can function as antigen-presenting cells (APCs). These class II-bearing accessory cells include dendritic cells, epidermal Langerhans cells, B cells, murine B-cell tumors, and human Epstein-Barr virus-transformed lymphoblastoid cell lines (EBV-LCL). We investigated the ability of EBV-LCL to present two soluble antigens, Candida albicans and purified protein derivative of tuberculin (PPD). The EBV-LCL derived from B cells of two different individuals can present both antigens to bulk cultures of autologous antigen-primed peripheral blood lymphocytes. The responses of PPD-reactive T-cell clones were weaker to PPD when presented by EBV-LCL than by PBL-APCs, with some clones responding only to PPD presented by PBL-APCs. This suggests that EBV-LCL are not equivalent to PBL monocytes in APC function, and that expression of class II major histocompatibility complex antigen is not sufficient in enabling antigen-presenting capability.

Antigen-Presenting Cells↗

PubMed1992

Characterization and comparison of two newly established Epstein-Barr virus (EBV)-negative and EBV-positive Burkitt's lymphoma cell lines. EBV-negative cell line with a low level of expression of ICAM-1 molecule and EBV-positive cell line with a high level of expression of ICAM-1 molecule.

Two human Burkitt's lymphoma cell lines (HBL-4 and HBL-5) were established individually from two patients with small noncleaved cell lymphoma (Burkitt's type). The HBL-4 cell line is Epstein-Barr virus (EBV)-negative, and the HBL-5 cell line is EBV-positive. Cytogenetically, both cell lines had the same chromosomal translocation, t(8;14)(q24;q32) as those observed in the primary malignant cells from individual patients. Morphologic, immunophenotypic, cytogenetic, and molecular studies confirmed that both cell lines were derived from the primary lymphoma cells in vivo. HBL-4 cells lacked CD23(H107), CD11a(LFA-1), and latent membrane protein (LMP) but expressed CD54(ICAM-1) at low levels, whereas HBL-5 cells showed the high level of expression of CD54 and faint expression of LMP but lacked CD11a. In addition, the EBV-positive lymphoblastoid cell line (LCL) expressed CD11a, CD23, CD54, and LMP at high levels. Therefore, an HBL-5 phenotype with expression of CD54 and LMP tends toward an LCL phenotype, and the augmentation of CD54 on the HBL-5 cells in comparison with primary lymphoma cells is likely to be upregulated by LMP, probably resulting from the EBV infection. There was little difference in the BrdUrd uptake in vivo and in vitro, doubling time, tumorigenicity, and dynamics of tumor growth in athymic nude mice between both cell lines. These findings indicate that the potentiality of cell growth and tumorigenicity of these two cell lines are unlikely to be related with EBV.

Adult↗