Interactions among clonal subpopulations affect stability of the metastatic phenotype in polyclonal populations of B16 melanoma cells.

Poste, George; Doll, John; Fidler, Isaiah J.

doi:10.1073/pnas.78.10.6226

Cited by 260 publications

(134 citation statements)

References 21 publications

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“…When HPRT-subclones of Melgo-1 were isolated and examined, although the take incidences remained 100%, the incidence of metastases varied from 0-77%. This type of variation in subclones has been described by Poste et al (1981), who argue that heterogeneity of the cell population innoculated is required for the production of metastases. An equally plausible explanation is that the cells capable of generating metastases form only a small minority of the cell population injected so that individual subclones would be expected to show large variations in metastatic potential.…”

Section: Resultsmentioning

confidence: 71%

Cell fusion segregates progressive growth from metastasis

Sidebottom¹,

Clark²

1983

Br J Cancer

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Summary Cell fusion has been used to analyse the genetic determinants of metastasis at the cellular level. Highly metastatic mouse melanoma cells were fused with diploid mouse lymphocytes and a range of hybrid clones isolated and tested for tumorigenicity and metastatic potential by s.c. injection into newborn, histocompatible, sublethally-irradiated mice. Although almost all clones tested were tumorigenic, most had considerably reduced metastatic potential. This suggests that tumorigenicity and metastasis are determined by different genetic elements. Histological examination of primary tumours produced by metastatic and nonmetastatic hybrid cell lines showed that an essential step in the production of metastases is the separation of tumour cells from the main tumour mass and their movement into the surrounding tissues. The primary tumours of a metastatic hybrid cell line showed local invasiveness whereas those of a non-metastatic cell line did not.

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Section: Resultsmentioning

confidence: 71%

Cell fusion segregates progressive growth from metastasis

Sidebottom¹,

Clark²

1983

Br J Cancer

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“…Intratumoral phenotypic diversity is known to be expressed in malignant cell populations in respect to a number of biological features, including growth rate and clonability (25)(26)(27)(28)(29)(30) and onc-gene expression (31). The biological basis for this diversity is unknown, but involves probably both genetic and epigenetic factors.…”

Section: Discussionmentioning

confidence: 99%

Treatment of human cell lines with 5-azacytidine may result in profound alterations in clonogenicity and growth rate.

Olsson¹,

Due²,

Diamant³

1985

The Journal of Cell Biology

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Liquid medium cultures of three human cell lines (B-lymphoma, myeloma, and squamous lung carcinoma) with population-doubling times (PDT) and cloning efficiencies (CE) in the range of 32-43 h and 0.01-5.6%, respectively, were exposed to 5-azacytidine (5-azaC) for 3 d. The doses used (1-3/zM) were found to be nontoxic as measured by cell growth in liquid and semisolid agar medium and to be nonmutagenic as measured by the rate of generation of ouabain-and 6-thioguanine-resistant cell variants. After 5-azaC treatment, cell samples were subsequently harvested every day and assayed for their CE in semisolid agar medium. For each cell line, 30 to 42 individual clones were harvested at the day of maximal CE and expanded in liquid culture medium. PDT and CE were determined for each subclone about every 6 wk for 12 too. The majority of the subclones had unaltered PDT and CE compared to the original lines. However, several clones had profoundly changed proliferative activity with PDT on ~12-14 h and/or CE 5 to >50%. Some of the clones with altered growth properties reverted to PDT and/or CE values of untreated clones. However, a few clones of each line had stable alterations with PDT on 12-14 h and CE 5 to >50%; these clones were all significantly hypomethylated. It is concluded that the human gene repertoire does contain genes that appropriately activated can result in growth properties with very short PDT and high CE (and comparable to animal cell lines), and that this activation may be obtained by 5-azaC treatment. It is conceivable that the procedure here described to alter growth properties of human cell lines may be applied to experimental situations, where alterations of cell growth properties are desired.Many reports in recent years on regulation of both cellular 0-6) and viral~ genes (7-11) have provided experimental support to the hypothesis (12-15) that 5-methylcytosine (mSCyt) t may be important in the regulation of gene expression. Moreover, a number of experiments have shown that exposure of cells to 5-azacytidine (5-azaC) may result in hypomethylation of DNA and cause expression of otherwise silent genes of both cellular and viral origin (for review, cf. references 16, 17) to the extent that it mimics mutation induced genetic alterations, e.g., reversion frequency of thyAbbreviations used in this paper." 5-azaC, 5-azacytidine; CE, cloning efficiency; mSCyt, 5-methylcytosine; Oua r, ouabin resistant; PDT, population-doubling time; RPMI/FCS, RPMI-1640 medium SUlSplemerited with 0.3% L-glutamine and 10-15% fetal calf serum; 6-TG ~, 6-thioguanine resistant. midine kinase negative cells to thymidine kinase positive cells (18).The growth properties of malignant tumor cell lines are at least in part reflected in the growth rate and CE. However, it has hitherto not been possible by exogenous factors to alter profoundly these biological features, despite numerous attempts that mainly have been based on alterations in the growth medium conditions such as addition of growth factors like insulin and transferr...

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“…The variation in expressed metastatic potential between individual mice may thus be due to variations in host response against different cell subpopulations. In our experiments the use of heterogeneous sublines, possibly stabilised by clonal interactions (Poste et al, 1981), may have been advantageous, since although phenotypic drift may occur this instability is often much greater in clonally derived sublines . The existence of metastatic heterogeneity and evidence for stabilisation of heterogeneous cell populations by clonal interactions support the use of well characterised cellular subpopulations with defined stable metastatic capabilities isolated from the original heterogeneous tumour cell population .…”

Section: Discussionmentioning

confidence: 99%

Heterogeneity in a spontaneous mouse lung carcinoma: Selection and characterisation of stable metastatic variants

Layton¹,

Franks²

1984

Br J Cancer

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Summary The development and characterisation of a new epithelial model for the experimental investigation of metastasis is described. A tissue culture cell line CMT64 was established from a spontaneous alveolar lung carcinoma of a 17 month old female C57BL/ICRF a' mouse . Subcutaneous inoculation of cells produces local tumours which give rise to a small number of lung metastases within three weeks. Four different tissue culture sublines CMT167, 170, 175 and 181 with increased metastatic ability were selected from pooled lung metastases by culture, mouse inoculation and reselection from lung metastases through four culture/inoculation cycles. These sublines are themselves heterogeneous and clones derived from them display marked differences in metastatic behaviour. Both CMT64 and its sublines have remained relatively stable in morphology and behavior since their origin, are fairly well differentiated, produce basal lamina even in metastases, and metastasise rapidly and preferentially to the lung after subcutaneous and intravenous inoculation in both syngeneic C57 and Nu/Nu mice (Franks & Layton, 1984). The expression of the metastatic potential of these cells is strongly influenced by the age and immune status of the host. The CMT64 system is a particularly useful model for experimental metastasis studies.

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Interactions among clonal subpopulations affect stability of the metastatic phenotype in polyclonal populations of B16 melanoma cells.

Cited by 260 publications

References 21 publications

Cell fusion segregates progressive growth from metastasis

Cell fusion segregates progressive growth from metastasis

Treatment of human cell lines with 5-azacytidine may result in profound alterations in clonogenicity and growth rate.

Heterogeneity in a spontaneous mouse lung carcinoma: Selection and characterisation of stable metastatic variants

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