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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have previously described a murine mammary tumor cell line (SP1) that metastasizes when transplanted into the mammary gland, but not when injected into the subcutaneous site. We used cytogenetic markers to assess genetic heterogeneity, and to monitor the selection and evolution of karyotypically distinct cell types during primary tumor growth and in metastases. The SP1 tumor cells are hypotetraploid (mean chromosome number = 72), and have at least four karyotypically distinct cell types. We found no consistent pattern of selection of tumor cell types in primary tumors. However, metastases were derived from a cell type that was present in the corresponding primary tumor. In addition, novel, karyotypically distinct cell types also appeared in the metastatic nodules. Markers that appeared in metastases included two translocations, t(10;18) and t(1;19). By injecting a mixture of cells from a metastatic nodule with a non-metastatic clone into mice, we showed that the new cell types in metastases displayed a stable increased growth and metastatic potential when compared to the non-metastatic clone, or when compared to the initial cell type from which the metastases derived. These results indicate that metastases are derived from a distinct cell type in the primary tumor, but that additional chromosome and cell evolution occurs, resulting in new cell types that are selected in metastases.
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PMID:Karyotypic evolution of a murine mammary adenocarcinoma in vitro and during progression from primary to metastatic growth in vivo. 137 34

Experiments were undertaken to explore whether in vitro exposure of a nonmetastatic murine tumor to chemotherapeutic drugs would affect the ability of this tumor to metastasize spontaneously. The tumor chosen was an aneuploid (near-tetraploid) spontaneously arising intraductal mammary adenocarcinoma (CBA-SP1), which normally fails to give rise to microscopic or macroscopic metastases after s.c. inoculation of cells. The drugs tested were 5-aza-2'-deoxycytidine (5-aza-dCyd) and hydroxyurea. We found that the injection of 1 X 10(5) uncloned drug-treated cells s.c. resulted in the emergence of gross and/or microscopically detectable metastases in the lungs of CBA mice. Individual clones derived from hydroxyurea-treated cells all produced metastases in a manner similar to the bulk culture injections. Clones of 5-aza-dCyd-treated cells also produced metastases, but fewer of these produced macroscopic metastases. In addition, only 9 of 15 5-aza-dCyd-treated clones produced tumor takes because of the ability of 5-Aza-dCyd to engender Imm+ variants in CBA-SP1 cells. Lung metastases obtained after the injection of uncloned cells retained their metastatic phenotype for three generations, indicating that the phenotypic change was a heritable characteristic. Although the genetic or epigenetic mechanism for this change is unknown, we observed karyotypic changes of a similar nature in the drug-treated cell lines established from micrometastases. These involved the detection of extra copies of chromosome 8. It is possible that exposure of tumors to therapeutic agents may in some cases increase their aggressiveness through genetic or epigenetic mechanisms that lead to high frequency heritable phenotypic alterations associated with distinguishable chromosomal changes.
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PMID:Selection of metastatic variants with identifiable karyotypic changes from a nonmetastatic murine tumor after treatment with 2'-deoxy-5-azacytidine or hydroxyurea: implications for the mechanisms of tumor progression. 243 55

Evidence is provided to show that two secondary cell-signaling pathways, Ca2+ mobilization and the activation of protein kinase C (PKC), are involved in the induction of spontaneous metastasis in mouse adenocarcinoma cell line SP1. Unlike the parental cells, which were found to be tumorigenic but unable to metastasize from a s.c. site, SP1 cells treated with ionophore A23187 (to mobilize Ca2+) or phorbol 12-myristate 13-acetate (to activate PKC) were able to metastasize spontaneously. Analysis of SP1 cells treated with either agent separately or with both agents simultaneously revealed that both pathways contributed to the final response in a separate and nonsynergistic way. The induced metastatic phenotype in most cases appeared to be heritable. Examination of Ca2+ sources during cell activation by ionophore A23187 suggested that internal Ca2+ was sufficient for the process of induction. Examination of PKC activity and its intracellular distribution during and after treatment of SP1 cells with ionophore A23187 and phorbol 12-myristate 13-acetate were also evaluated. The results suggested that the basal levels of PKC and the activation of the enzyme appear to be involved in the induction of spontaneous metastasis. Taken together, these observations are consistent with the hypothesis that cell-signaling pathways exist which can induce the metastatic phenotype and that this may be related to phosphatidylinositol turnover.
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PMID:Possible involvement of Ca2+ mobilization and protein kinase C activation in the induction of spontaneous metastasis by mouse mammary adenocarcinoma cells. 249 16

In previous studies we have shown that the ability of murine tumor cells to metastasize in situ is directly linked to expression of -GlcNAc beta 1-6Man alpha 1-6Man beta 1-branched complex-type Asn-linked oligosaccharides in tumor-cell glycoproteins. Here we demonstrate that cell-surface expression of beta 1-6 branched oligosaccharides in metastatic tumor cells is specifically associated with increased invasion of human amnion basement membranes in vitro. Compared to nonmetastatic SP1 murine mammary carcinoma cells, 2 metastatic sublines expressed higher levels of beta 1-6 branched oligosaccharides and were found to be invasive but poorly adhesive on the amnion basement membrane. Swainsonine, a non-toxic inhibitor of Asn-linked oligosaccharide processing which blocks the pathway prior to initiation of the beta 1-6 linked antenna, blocked metastatic tumor-cell invasion and increased adhesiveness. Swainsonine and the metalloprotease inhibitor O-phenanthroline inhibited invasion, apparently via independent mechanisms. O-phenanthroline did not affect tumor-cell adhesion to the amnion basement membrane and swainsonine did not block secretion of metalloproteases, beta-hexosaminadase or tissue plasminogen activator activity by the tumor cells. These results suggest that tumor-cell invasion of basement membranes requires both secretion of hydrolase activities and expression of beta 1-6 branched complex-type oligosaccharides at the tumor cell surface, such oligosaccharides being associated with reduced tumor-cell adhesion to extracellular matrix.
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PMID:Evidence that beta 1-6 branched Asn-linked oligosaccharides on metastatic tumor cells facilitate invasion of basement membranes. 250 55

We have exploited random integrations of foreign DNA as a means of genetically tagging tumour cell populations with which to analyse the clonal evolution of tumour growth in vivo. Transfection of a non-metastatic mouse mammary carcinoma called SP1 (or a metastatic variant, SP1HU9L) with the pSV2neo plasmid or retrovirus vector infection with a "clipped-wing' vector (delta p delta eMoTN) was used to generate large numbers of uniquely marked tumour cell clones in single-step selections. The basic approach was to pool large numbers of independently marked transfectants or infectants, inject these cells into mice and analyse the resulting primary tumours and/or metastases later. Overgrowth or derivation of tumour masses by a limited number of clones could be detected by Southern gel analysis. The main findings were: (i) injection of pooled populations containing large numbers of uniquely marked cell clones (up to several thousand) invariably resulted in advanced primary tumours that contained a very limited number of clones, and in some cases only one easily detectable clone; (ii) primary tumours could be overgrown within six weeks by the progeny of the same single metastatic clone when the inoculum contained 1-10% metastatic cells, which suggests that metastatic SP1 cells have a selective growth advantage in primary tumours as well as for metastatic spread; and (iii) spontaneous lung metastases were clonal or biclonal at the time of analysis. The results show that spontaneous metastases can develop from a genetically distinct subpopulation of cells in a non-random (i.e. selective) manner. Because primary tumours can become overgrown by the progeny of a metastatic clone, results of any comparison of the properties of a primary tumour with a distant metastasis could be affected by the stage at which the primary tumour is removed and analysed.
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PMID:Clonal changes in tumours during growth and progression evaluated by southern gel analysis of random integrations of foreign DNA. 285 13

We have exploited random insertions of transfected DNA as unique clonotypic markers to follow cell lineages during primary and metastatic tumor growth of a mouse mammary adenocarcinoma, SP1. Southern analysis was undertaken of primary solid tumors and metastases obtained after injection of a pooled population of individual SP1 transfectants, or reconstituted mixtures of genetically marked metastatic and unmarked nonmetastatic cells. Here we provide evidence for the reproducible selection and eventual overgrowth of primary tumors by genotypically distinct metastatic clones, thereby illustrating that late-state, advanced primary tumors can evolve to become biologically similar, or even identical, to distant metastases. The selective growth advantage of metastatic cells within primary tumors was shown to occur despite the fact that tumors generated by both metastatic and nonmetastatic SP1 cell populations grew at comparable growth rates when injected and analyzed separately. The extent of the local growth advantage manifested by individual metastatic clones varied considerably, from 5- to 50-fold. Clonal overgrowth was also observed whether the tumor cells were injected ectopically, or orthotopically (i.e., into the mammary fat). This type of experimental approach should provide new insights into the dynamics of tumor progression and metastasis, the lineage relationship of primary tumors to metastases, the influence of clonal interactions on tumor behavior, and the physiological changes which are causative of malignant disease.
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PMID:Genetic evidence for progressive selection and overgrowth of primary tumors by metastatic cell subpopulations. 316 57

A spontaneous murine mammary carcinoma, designated SP1, grew more aggressively in the mammary gland than in the subcutis exhibiting a 10-fold lower 50% lethal tumor dose and the ability to metastasize spontaneously from the orthotopic mammary gland site. The appearance of metastasis could be abrogated by resection of the primary tumor up to 21 days postinjection, arguing against the possibility that metastasis occurred due to trauma of the injection and/or healing processes. In addition, tumor cells recovered from lung metastases exhibited an increased ability to metastasize when reinjected into either the s.c. or mammary sites. Tumor cells from lung metastases showed low levels of Class I major histocompatibility (MHC) antigens, like the parental SP1 cells, but were found to express differentiation markers typical of normal basal and luminal mammary epithelium. SP1 tumors expressed increased Class I MHC antigens, as well as high levels of basal and luminal breast epithelial markers, within 7 days of implantation into the mammary gland. On the other hand, SP1 tumors growing in the subcutis never expressed increased Class I MHC levels and expressed the epithelial marker antigens at lower levels and not until at least 21 days of growth. Removal of host epithelium by cauterization of the mammary bud at 3 weeks had no effect on the increased growth, metastasis and acquired heterogeneity of MHC and epithelial associated antigens, suggesting that the mammary gland stroma was responsible for the observed phenomenon. These findings suggest that the mammary gland either selects distinct tumor subpopulations, or induces a phenotypic change leading to tumor progression and the generation of metastatic subpopulations.
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PMID:Expression of epithelial-like markers and class I major histocompatibility antigens by a murine carcinoma growing in the mammary gland and in metastases: orthotopic site effects. 319 95

Retrovirus vector infection was used to introduce large numbers of unique genetic markers into tumor cell populations for the purpose of analyzing comparative changes in the clonal composition of metastatic versus that of nonmetastatic tumors during their progressive growth in vivo. The cell lines used were SP1, a nonmetastatic, aneuploid mouse mammary adenocarcinoma, and SP1HU9L, a metastatic variant of SP1. Cells were infected with delta e delta pMoTN, a replication-defective retrovirus vector which possesses the dominant selectable neo gene and crippled long terminal repeats. G418r colonies were obtained at a frequency of 4 x 10(-3). Southern blot analysis of a number of clones provided evidence of random and heritable integration of one or two copies of the proviral DNA. Clonal evolution of primary tumor growth and the nature of lineage relationships among spontaneous metastases and primary tumors were analyzed by subcutaneously injecting 10(5) cells from a pooled mixture of 3.6 x 10(2) G418r SP1HU9L or 10(4) G418r SP1 colonies into syngeneic CBA/J mice. The most striking finding was the relative clonal homogeneity of advanced primary tumors; they invariably consisted of a small number (less than 10) of distinct clones despite the fact that hundreds or thousands of uniquely marked clones had been injected. In the case of the metastatic SP1HU9L cells, the nature of these "dominant" clones varied from one tumor to another. Analysis of a number of lung metastases revealed that a proportion of them were derived from dominant primary tumor clones and were composed of one, and sometimes two, distinct progenitors. In some animals, all the lung metastases were derived from a common progenitor clone, whereas in others, each metastatic nodule had a different progenitor. The results show the following. (i) Retrovirus vector infection can be used to introduce large numbers of unique and stable clonal markers into tumor cell populations. (ii) The progeny of a very limited number of clones dominate in advanced primary tumors. (iii) Mammary carcinoma metastases are of mono- or biclonal origin. The significance of the results is discussed.
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PMID:Genetic tagging of tumor cells with retrovirus vectors: clonal analysis of tumor growth and metastasis in vivo. 321 Nov 40

The mouse mammary adenocarcinoma cell line SP1 was transfected with either the activated T24-H-ras or the normal c-H-ras gene and assessed for metastatic potential in syngeneic CBA/J or nude mice. Unlike the parental control cells, which were tumorigenic but unable to metastasize from a subcutaneous site, all SP1 transfectants expressing the T24-H-ras gene were able to metastasize (predominantly to the lung). In contrast, a much smaller fraction of the clones obtained following transfection with either normal c-H-ras or pSV2neo were metastatic and, significantly, elevated expression of the c-H-ras proto-oncogene did not correlate with acquisition of metastatic potential. We conclude that activated and normal forms of the c-H-ras gene differ in their ability to confer metastatic potential to SP1 mouse mammary adenocarcinoma cells.
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PMID:Metastatic potential of SP1 mouse mammary adenocarcinoma cells is differentially induced by activated and normal forms of c-H-ras. 332 79

In order to test the hypothesis that tumor cells with greater malignant potential should have an increased sensitivity to mutagens, four individual murine cell lines, each paired for their metastatic and nonmetastatic potentials, were compared with respect to the prevalence at which ouabain-resistant mutants could be obtained after treatment of the cells with the mutagen MNNG. No increase in the prevalence of induced mutation in metastatic cells was observed; and, in fact, in two cases (h-ras-transfected 3T3 and SP1 cells), nonmetastatic cells had a higher prevalence of mutations after MNNG treatment than did their metastatic counterparts. We suggest that the absolute level of genomic instability, measured by this means, is not critical to malignant potential and tumor progression.
Invasion Metastasis 1988
PMID:The prevalence of ouabain-resistant variants after mutagen treatment. Lack of correlation between the frequency of variant expression and the metastatic phenotype. 336 May 93


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