A brief review of the evidence of the genetic regulation of tumorigenic expression in somatic cell hybrids.
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Cell Differentiation↗
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Results for “Neoplastic Stem Cells”
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[Which cells during the process of differentiation give rise to chronic B-cell lymphocytic leukemia? I].
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B-Lymphocytes↗
Analysis of treatment response in chronic lymphocytic leukemia: new approaches.
As therapeutic protocols to treat chronic lymphocytic leukemia evolve, new criteria will be required to define remission and identify early relapse. Two techniques that detect low numbers of residual monoclonal B-lymphocytes currently include immunoglobulin (Ig) gene rearrangement and clonal excess analysis. Ig-gene rearrangement studies are time consuming and expensive. Clonal excess analysis by FC may be insensitive because of minimal surface immunoglobulin (SIg) expression. Three antigens, CD5, CD11c and CD14 are expressed on B-lymphocytes of CLL. CD14 is also expressed on most normal B-lymphocytes. In contrast, CD5 and CD11c are expressed on few normal B-lymphocytes. Consequently CD5 and CD11c are useful markers for detecting residual CLL cells. Appropriate selection of the second B-cell marker such as SIg, CD19, CD20 or other, is critical. We evaluated this approach in persons with CLL receiving therapy. Preliminary results will be presented.
Biomarkers, Tumor↗
The establishment of cell lines from chronic B cell leukaemias: evidence of leukaemic origin by karyotypic abnormalities and Ig gene rearrangement.
We have studied the capacity of peripheral blood cells from 26 chronic B cell leukaemias to proliferate continuously in culture; 72 attempts to establish cell lines were made. The cells were treated in vitro with or without stimulating agents: Epstein-Barr virus (EBV) and/or phorbol-ester (TPA) were the most frequently used. Fourteen cell lines of continuous growth were established from cells from 11 patients, but only four of these were proven to be derived from the original leukaemic cells. Only in the latter four lines were the karyotypic abnormalities and the patterns of immunoglobulin (Ig)-gene rearrangements identical to those found in the patients' leukaemic cells. On the other 10 lines, five had both kappa- and lambda-producing cells, and the remaining five, despite showing light-chain restriction, were proved to be non-leukaemic clones by comparing the Ig-gene rearrangement patterns before and after culture. Three of the four leukaemic cell lines (JVM-2, JVM-3 and JVM-13) were induced by EBV + TPA and derived from prolymphocytic leukaemia (PLL) cases; the fourth (JVM-14) originated from a case of chronic lymphocytic leukaemia (CLL) with increased percentage of prolymphocytes whose cells were stimulated in vitro with EBV. The immunophenotype of the three PLL lines is more mature than that of the original prolymphocytes, as shown by a reduction in surface-Ig and FMC7 expression, enhancement of cytoplasmic-Ig and increase in CD38- and transferrin receptor-positive cells. The cells from line JVM-14 retained the CD5-antigen, a marker of CLL. This study suggests that PLL and some CLL clones are arrested at a stage of maturation ideally suited to be triggered to continuous proliferation in culture. The presence of consistent chromosomal abnormalities in PLL may offer an alternative explanation for the greater proliferative potential of these cells in vitro.
Antigens, Neoplasm↗
Gene transfer to primary normal and malignant human hemopoietic progenitors using recombinant retroviruses.
To study the feasibility of using retroviruses for gene transfer into human hemopoietic cells, various cell types were exposed to virus carrying the gene for neomycin resistance (neor). In preliminary studies using K562 cells as targets, we found that high viral titer and co-cultivation with viral producer cells rather than incubation in medium exposed to viral producer cells were important variables for achieving high frequencies of G418 resistant (G418r) colonies. The maximum frequency of G418r K562 colonies after co-cultivation with cells producing a neor virus titer of 4 X 10(6) cfu/mL was 60%. When primary human progenitors from normal marrow, fetal liver, or chronic myelogenous leukemia blood were exposed to high titer viral stocks, both with and without helper virus, under conditions optimized for K562 cells, maximum frequencies of G418r colonies were 3% to 16% for granulocyte macrophage progenitors and 2% to 6% for primitive erythroid progenitors. The presence of the neor gene in both G418r K562 and primary hemopoietic colonies was verified by Southern blot. Expression of the neor gene was shown by RNA spot blot. These data demonstrate efficient transfer and expression of the neor gene in both K562 cells and primary human hemopoietic cells from normal and leukemic individuals.
Cell Line↗
Dye-mediated photolysis of human neuroblastoma cells: implications for autologous bone marrow transplantation.
Cells from three different human neuroblastoma cell lines and normal human bone marrow cells were exposed to the lipophilic fluorescent dye, merocyanine 540 (MC 540), and white light. In vitro clonogenic tumor cells were inactivated up to 25,000 times more rapidly than multipotent hematopoietic progenitor cells (CFU-GEMM). It is conceivable that this pronounced difference in sensitivity to MC 540-mediated photolysis can be exploited for the selective killing of residual neuroblastoma cells in autologous remission marrow grafts.
Bone Marrow↗
Phorbol ester-induced alteration of differentiation and proliferation in human hematopoietic tumor cell lines: relationship to the presence and subcellular distribution of protein kinase C.
The intracellular translocation of protein kinase C (PKC) from the soluble to the membranous fraction has been shown previously to correlate with biological activity of phorbol esters in several systems. In this paper, we describe that PKC translocation was a general phenomenon in all PKC containing cell types when five 12-O-tetradecanoylphorbol-13-acetate (TPA) responsive and nonresponsive hematopoietic tumor cell lines were investigated. The nonresponsive cell line U-266 contained undetectable levels of PKC. The dose of TPA required for translocation was similar to the TPA concentration necessary to suppress erythroid differentiation in K-562 cells and to induce macrophage differentiation in U-937 cells, but 100-fold higher than that required for suppression of proliferation in K-562 and U-937 cells. By contrast, PKC translocation and TPA induced proliferation inhibition exhibited a similar dose dependence in a subline of U-937 (U-937 RES) adapted to growth in the presence of 10(-9) M TPA. It is suggested that U-937 RES is deficient in a TPA dependent but PKC independent signal pathway.
Biological Transport↗
The preleukemic syndrome.
While the preleukemic syndrome (PLS) is not a homogeneous entity, its spectrum of clinical and laboratory findings has been sufficiently characterized to allow increasing certainty in its recognition. Approximately 25 percent of these patients can be expected to develop overt acute nonlymphocytic leukemia (ANLL) within an average of two to three years, and another 40 percent will die of non-leukemic complications usually related to their cytopenias within a similar time period. The remaining patients may be stable and survive for prolonged periods. Accumulating evidence indicates that in the PLS, a stem cell neoplastic clonal proliferation has already been established and may frequently be demonstrated by cytogenic analysis or culture of marrow hematopoietic cells.
Anemia↗
Antiblastic chemotherapy drugs up-modulate interferon-gamma receptor expression on human malignant T cells.
We have previously shown that the contrasting ability of interferon-gamma (IFN-gamma) either to stimulate the proliferation of malignant T cells or to induce their apoptosis is determined by the low and high intensity of IFN-gamma receptor (IFN-gamma R) expression, respectively. High IFN-gamma R expression is a marker for the T cell stress that precedes apoptosis. In this paper, we show that a 12- to 24-h culture of three human malignant T-cell lines displaying distinct differentiation stages (ST4, PF382, and Jurkat) in medium supplemented with four chemotherapy drugs (etoposide, cisplatin, cytarabine, and daunomycin) up-modulates their IFN-gamma R expression followed by their apoptosis after 24-48 h later. Increased IFN-gamma R expression (by at least an order of magnitude) was observed in 30 to 90% of cells during exposure to pharmacologic drug concentrations. Timely combination of chemotherapy drugs with IFN-gamma may thus provide a more effective way of inhibiting the progress of human malignant T cells through synergistic induction of their apoptosis.
Antineoplastic Agents↗
Chlorambucil synergizes with purine analogs in inducing in vitro cytotoxicity in B-cell chronic lymphocytic leukemia.
Combinations of different drug concentrations of CLB + FAMP and CLB + 2-CDA were synergistic in, respectively, 42.9% and 34.8%. At leukemic cell survival < or = 50%, 16.4% and 23.4% of all combinations were synergistic in the 2-CDA and FAMP groups, respectively. A significantly higher mean value of antagonistic interactions was observed in the 2-CDA group (p = 0.037).
Antimetabolites, Antineoplastic↗
Production of skeletal muscle elements by cell lines derived from neoplastic rat mammary epithelial stem cells.
Single-cell-cloned cell lines intermediate in morphology between the cuboidal epithelial and fully elongated myoepithelial-like cells have been isolated from the single-cell-cloned epithelial stem cell lines Rama 25 and Rama 37 originally obtained from dimethylbenz(a)anthracene-induced mammary tumors from Sprague-Dawley and Wistar-Furth rats, respectively. These are designated Rama 25-l1, Rama 25-l2, Rama 25-l4 (Sprague-Dawley) and Rama 50-55, Rama 59, and Rama 60 (Wistar-Furth), respectively. When growing as tumors in nude mice or syngeneic Wistar-Furth rats, respectively, many of the newly cloned cell lines give rise to spindle and giant, multinucleated cells which stain immunocytochemically with antisera to myoglobin and myosin and contain longitudinal fibrils, some of which contain phosphotungstic acid-hematoxylin-staining cross-striations. Ultrastructural analysis demonstrates the presence of A-, l-, and H-bands and Z-discs and the hexagonal arrangement of thick and thin filaments characteristic of skeletal muscle. Similar results are obtained with selected cloned cell lines growing on floating collagen gels in vitro. Thus, a developmentally committed mammary epithelial cell can give rise, under suitable conditions, to a well-differentiated mesenchymal lineage, that of skeletal muscle. It is suggested that such cells may be responsible for the generation of the well-differentiated mesenchymal elements seen in the mixed (epithelial and myoepithelial) tumors of glandular origin.
Animals↗
Adult human mesenchymal stem cell as a target for neoplastic transformation.
The neoplastic process may involve a cancer stem cell. This concept has emerged largely from the careful analysis of tumour biopsy systems from haematological, breast and brain tumours. However, the experimental systems necessary to provide the cellular and molecular evidence to support this important concept have been lacking. We have used adult mesenchymal stem cells (hMSC) transduced with the telomerase hTERT gene to investigate the neoplastic potential of adult stem cells. The hTERT-transduced line, hMSC-TERT20 at population doubling level (PDL) 256 showed loss of contact inhibition, anchorage independence and formed tumours in 10/10 mice. hMSC-TERT4 showed loss of contact inhibition at PDL 95, but did not exhibit anchorage independence and did not form tumours in mice. Both lines had a normal karyotype but showed deletion of the Ink4a/ARF locus. At later passage, hMSC-TERT4 also acquired an activating mutation in KRAS. In hMSC-TERT20, expression of the cell cycle-associated gene, DBCCR1 was lost due to promoter hypermethylation. This epigenetic event correlated with acquisition of tumorigenicity. These data suggest that the adult hMSCs can be targets for neoplastic transformation and have implications for the development of novel anticancer therapeutics and for the use of hMSC in tissue engineering and transplantation protocols.
Adult↗
The cancer stem cell hypothesis: a work in progress.
There is a growing body of evidence that supports the idea that malignant tumors are initiated and maintained by a population of tumor cells that share similar biologic properties to normal adult stem cells. This model, the cancer stem cell (CSC) hypothesis, is based on the observation that tumors, like adult tissues, arise from cells that exhibit the ability to self-renew as well as give rise to differentiated tissue cells. Although the concept of the CSC is not entirely new, advances made over the past two decades in our understanding of normal stem cell biology in conjunction with the recent application of these concepts to experimentally define CSCs have resulted in the identification of CSCs in several human malignancies.
Adult Stem Cells↗
Peripheral blood mobilization of hematopoietic stem cells: cytokine-mediated regulation of adhesive interactions within the hematopoietic microenvironment.
Peripheral blood (PB) mobilization of hematopoietic progenitors, presently regarded as an alternative source of cells intended for autologous or allogeneic bone marrow (BM) transplantation, supports a role for cytokines in the regulated adhesion of hematopoietic compartments to the BM microenvironment. Two major consequences might result from cytokine-induced rearrangements of adhesive interactions within the hematopoietic tissue, both potentially relevant for clinical purposes of PB grafts. The first one, arising from abrogated adhesion of hematopoietic stem cells to their microenvironmental 'niche', which is critical for the maintenance of cell cycle quiescence and endurability, might result in some impairment of the long-term repopulating potential of PB grafts. The second and possibly more harmful one is due to the inability of the cytokine to distinguish between normal and transformed cells, and would likely result in graft contamination by tumor cells, increasing the metastasizing potential of hematological malignancies and solid tumors.
Blood Cells↗
[Hybrids between F9 "nullipotent" teratocarcinoma and rat thymus cells produce differentiated cells].
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Animals↗
Isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastoma.
Transformed stem cells have been isolated from some human cancers. We report that, unlike other brain cancers, the lethal glioblastoma multiforme contains neural precursors endowed with all of the critical features expected from neural stem cells. Similar, yet not identical, to their normal neural stem cell counterpart, these precursors emerge as unipotent (astroglial) in vivo and multipotent (neuronal-astroglial-oligodendroglial) in culture. More importantly, these cells can act as tumor-founding cells down to the clonal level and can establish tumors that closely resemble the main histologic, cytologic, and architectural features of the human disease, even when challenged through serial transplantation. Thus, cells possessing all of the characteristics expected from tumor neural stem cells seem to be involved in the growth and recurrence of adult human glioblastomas multiforme.
Adult↗
Negative selection of autologous peripheral blood stem cells.
The use of chemotherapy and/or haematopoietic growth factor-mobilized peripheral blood stem cells (PBSC) has been shown to induce a more rapid haematopoietic recovery than the reinfusion of bone marrow (BM)-derived haematopoietic cells, thus reducing the morbidity and mortality of autologous stem cell transplantation (ASCT). PBSC collections were initially believed to have a lower incidence of tumour cells involvement than BM harvests. However, recent studies have shown that mobilized blood cell products of cancer patients eligible for autografting are frequently contaminated with tumour cells. Whereas positive selection of haematopoietic CD34+ stem cells has been largely used as a means of indirect purging of circulating CD34+ neoplastic cells, few groups have addressed the issue of tumour cell removal by direct targeting of cancer cells using physical or pharmacological strategies. In this chapter we review the available data concerning the contamination of tumour cells in PBSC collections from cancer patients, the functional and kinetic characteristics of primed CD34+ cells which may affect the haematopoietic toxicity of purging procedures developed to eliminate the minimal residual disease (MRD) from BM samples, and the preclinical and clinical results of the selective killing of residual tumour cells from leukaphereses. The limited amount of data published so far do not allow any firm conclusion on the clinical usefulness of purging protocols. Nonetheless, the successful extension of ex vivo purging to PBSC collections may improve the feasibility of randomized studies aimed at determining the importance of tumour-free autografts.
Antigens, CD34↗
Growth factors and cancer.
Recent advances in protein chemistry and genetic engineering have revealed new information about the molecular lesions involved in the induction and maintenance of cancer cells. It is now known that a single base change in the DNA of human cells leads to cancer. The normal pathway of proliferation and differentiation is perturbed by changes to molecules involved in the intracellular biochemical pathways controlled by growth factors. Some cancer cells appear to produce their own growth factor, others have higher concentrations of growth factor receptors on their surface and others have mutated versions of the intracellular proteins linked to the growth factor receptors. This increased understanding of growth control in normal and neoplastic cell populations is gradually providing a foundation for new approaches to cancer therapy.
Animals↗