Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Neoplastic Stem Cells”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 37 records · Page 2Linked to original sources
PubMed1986

Resistance to cancer chemotherapy.

Human cancers are either refractory to chemotherapy, or acquire resistance to it. Although acquired resistance to chemotherapy is generally ascribed to the drug itself, it may be linked with the nature of neoplasia, since normal tissues e.g. gastrointestinal mucosa or bone marrow, do not seem to acquire resistance and their perpetuating sensitivity even undermines effective treatment. According to the theory presented herewith, chemotherapy ultimately fails since it is based on wrong premises. Cancer is regarded here as a metabolic deficiency, originating in stem cell destruction. Besides serving as tissue progenitors, stem cells are postulated to secrete a vital substance 'A' necessary for proper tissue function. Carcinogens interfere with 'A' production mainly by destroying stem cells, which the organism is incapable of fully replenishing, so that less 'A' is produced. This irreversible 'A' deficiency may be replenished solely by a substitute, or substance 'B', produced by a specialized organ, the neoplasm. Since carcinogens continue depleting additional stem cells, the deficiency worsens. In order to keep up with increasing demand the neoplasm has to proliferate more and more until it reaches a stage of decompensation when the harm inflicted by it outweighs its benefit. Stem cell depletion is regarded here as the common final pathway of carcinogens. The theory predicts that following a supply of 'A' producing stem cells or inactivated 'B' producing neoplastic stem cells, the tumor will regress. Tumor regression is achievable also by diminishing the demand for the missing metabolites, which may be accomplished by chemotherapy. 'A' and 'B' are consumed mainly by transitional cells. Upon their elimination the demand for 'A' declines and the tumor may wane. This is regarded here as the main role of chemotherapy in cancer, while its tumoricidal potency is indicated solely for repairing tumor induced function loss. It is proposed here that the good response to chemotherapy by Hodgkin's disease and seminoma is linked with their being partially infective. Both start as genuine smouldering infections turning later into neoplasms. While chemotherapy is adequate only during the infective phase, it is met with mounting resistance when applied during the neoplastic phase.

Antineoplastic Agents↗
PubMed1992

[Expression of immunohistochemical differentiation markers in normal and transformed neoplastic neuroectodermal stem cells].

The cells of primitive neuroectodermal tumours may undergo differentiation and, eventually, may be transformed to neurons, glial cells, and ependymal cells. Early stages of neuroectodermal differentiation may primarily be determined by means of immunohistochemical methods. Immunohistochemical investigations were performed on brains of human foetuses obtained from the 18th to 36th weeks of pregnancy, with a view to elucidating the process of maturation during foetal development and to determining the antigens identifiable in cells in the course of differentiation, following fixation in formalin and embedding in paraffin. Gliafibrillar acid protein (GFAP) and vimentin proved to be of particularly high stability and, consequently, were easily detectable from paraffin material. The same antigens were focally recordable also from eight of 17 primitive neuroectodermal tumours. Clues were rare in these tumours as to neuronal differentiation. This was attributed to instability of neurofilament proteins under conditions of formalin fixation and paraffin embedding.

Adult↗
PubMed1986

Cancer is a metabolic deficiency.

Cancer is regarded here as a metabolic deficiency originating in stem cell destruction. Tissue stem cells are postulated to secrete a vital substance 'A' necessary for proper tissue function. Carcinogens interfere with 'A' production mainly by destroying stem cells which the organism is incapable of fully replenishing so that less 'A' is produced. This irreversible 'A' deficiency may be compensated by a substitute, or substance 'B', produced by a specialized organ, the neoplasm. Since carcinogens continue depleting more and more stem cells, the deficiency worsens. In order to meet the increasing demand, the neoplasm proliferates more and more until reaching a stage of decompensation when the harm inflicted by it outweighs its benefit. Stem cell depletion is regarded here as the final common pathway for carcinogen action. The theory predicts that following a supply of 'A' producing stem cells or inactivated 'B' producing neoplastic stem cells, the tumor will regress.

Animals↗
PubMed1986

Unregulated proliferation of primitive chronic myeloid leukemia progenitors in the presence of normal marrow adherent cells.

Previous studies have shown that Philadelphia (Ph1) chromosome-positive chronic myeloid leukemia (CML) results from the abnormal expansion at the pluripotent stem cell level of a single clone of hemopoietic cells. Although it seems likely that this is related to the heightened proliferative activity characteristic of primitive CML progenitor cell types, the underlying mechanism is unknown. In this report we show that either normal or CML peripheral blood progenitors can be maintained on preestablished normal marrow adherent layers for periods of 1-2 months. Under these conditions numbers of both normal and neoplastic progenitors are usually higher in the adherent layer than in the nonadherent fraction. Moreover, the number of primitive progenitors of high proliferative potential present in the adherent layer is sufficient to allow their cycling status to be determined. Such measurements demonstrate that primitive normal progenitors of blood origin, when cultured in the presence of a preestablished adherent marrow feeder layer, go in and out of cycle after each medium change but in the absence of a feeder layer remain continuously in cycle. In contrast, primitive CML progenitors of either blood or marrow origin cycle continuously regardless of the presence or absence of an adherent feeder layer. We suggest that early expansion of the CML clone is related to an ability of the neoplastic stem cells to ignore or overcome a negative regulatory signal produced by nonneoplastic adherent marrow cells whose normal function is to maintain the stem cell reserve in a quiescent state.

Bone Marrow Cells↗
PubMed1984

Analysis of haemopoiesis: the use of cell markers and in vitro culture techniques in studies of clonal haemopathies in man.

The clonal haemopathies have in common the expansion of a neoplastic stem cell which has retained a variable capacity for differentiation to granulocytes, monocytes, erythrocytes, and platelets. Although normal stem cells are present in such patients, their differentiation is somehow suppressed. However, their presence may be demonstrated either by cell culture studies, employing G6PD as the marker in appropriately selected cases, or by their emergence in patients subjected to marrow ablative chemotherapy. Suppression of normal stem cell growth and development does not require a hyperproliferative marrow, and the current data do not support the notion that normal stem cells are simply reduced in frequency by a vast increase in the numbers of neoplastic progenitors. It is likely, therefore, that such suppression involves cellular signals, operating over short distances (perhaps through cell-to-cell contact), which interfere with normal progenitors. Thus, stem cell culture techniques, in combination with cell markers, have provided a direct and informative way to approach the issues of disease pathogenesis, the kinetics of stem cell differentiation, and the interaction of normal and neoplastic cells in patients with clonal haemopathies.

Cells, Cultured↗
PubMed1980

Feedback in cancer.

The theory presented regards cancer as a systemic disease initiated by carcinogens, and neoplasia as the organism's main defence against it. Carcinogens are assumed to destroy a vital substance "A" which is replenished by a second, "B", produced by neoplastic stem cells. Cancer progression is manifested by a gradual deterioration of the "A" producing machinery accompanied by a compensatory proliferation of neoplastic "B" producing stem cells whose size is therefore closely regulated so as to meet the organism's demands. Any stem cell pool reduction leading to a loss of "A" or "B" is followed by a proliferation of the remaining stem cells to replenish the loss. Such may be observed in chronic lymphoblastic leukemia maintaining a nearly constant elevated peripheral lymphoblast count. Following selective lymphoblast destruction the count is rapidly replenished to its pretreatment level. The same mechanism is assumed to explain the detrimental effect of some surgical interventions on cancer patients. Neoplastic progression is postulated to a obey a "stem cell conservation" principle which when violated is followed either by a stem cell replenishment or aggrevates the patient's conditions. This conservation law introduces a new definition of carcinogenesis: Any process reducing the "A" or "B" producing machinery is regarded as a carcinogen. A definition embracing, surgical extirpation of normal or neoplastic stem cells or cell destruction by irradiation, chemotherapy or chemical carcinogens.

Carcinogens↗
PubMed1997

Expression of estrogen receptors in a normal human breast epithelial cell type with luminal and stem cell characteristics and its neoplastically transformed cell lines.

Although approximately two-thirds of breast cancers are estrogen receptor (ER)-positive, only a small proportion of epithelial cells in the mammary gland express the ER. The origin of the ER-positive breast cancers is unknown. Recently, we have developed a culture method to grow two morphologically and antigenically distinguishable types of normal human breast epithelial cells (HBEC) derived from reduction mammoplasty. In this report, we studied the expression of ER in these two types of cells and their transformed cell lines. The results indicate that Type I HBEC with luminal and stem cell characteristics expressed a variant ER (approximately 48 kd) by Western blot analysis. This variant ER contains a deletion in the DNA binding domain (exon 2) as revealed by RT-PCR analysis. The lack of the DNA-binding domain of the variant ER was also confirmed by the ER-estrogen responsive element binding assay, as well as by the immunofluorescence staining of the ER using anti-ER antibodies which recognize either the C-terminal or N-terminal region. In contrast, Type II HBEC with basal epithelial phenotype are ER-negative. Simian virus 40 (SV40) transformed Type I and Type II HBEC lines also expressed the variant ER. Tumors formed in athymic nude mice by in vitro transformed tumorigenic Type I cell lines, however, expressed a high level of wild type ER which was undetectable in these cells grown in vitro before and after tumor formation. Thus, there appears to be a differential ER mRNA splicing between the in vitro and in vivo mileu.

Adult↗
PubMed2005

Tumorigenic heterogeneity in cancer stem cells evolved from long-term cultures of telomerase-immortalized human mesenchymal stem cells.

Long-term cultures of telomerase-transduced adult human mesenchymal stem cells (hMSC) may evolve spontaneous genetic changes leading to tumorigenicity in immunodeficient mice (e.g., hMSC-TERT20). We wished to clarify whether this unusual phenotype reflected a rare but dominant subpopulation or if the stem cell origin allowed most cells to behave as cancer stem cells. Cultures of the hMSC-TERT20 strain at population doubling 440 were highly clonogenic (94%). From 110 single-cell clones expanded by 20 population doublings, 6 underwent detailed comparison. Like the parental population, each clone had approximately 1.2 days doubling time with loss of contact inhibition. All retained 1,25-(OH)(2) vitamin D(3)-induced expression of osteoblastic markers: collagen type I, alkaline phosphatase, and osteocalcin. All shared INK4a/ARF gene locus deletion and epigenetic silencing of the DBCCR1 tumor suppressor gene. Despite in vitro commonality, only four of six clones shared the growth kinetics and 100% tumorigenicity of the parental population. In contrast, one clone consistently formed latent tumors and the other established tumors with only 30% penetrance. Changing the in vitro microenvironment to mimic in vivo growth aspects revealed concordant clonal heterogeneity. Latent tumor growth correlated with extracellular matrix entrapment of multicellular spheroids and high procollagen type III expression. Poor tumorigenicity correlated with in vitro serum dependence and high p27(Kip1) expression. Aggressive tumorigenicity correlated with good viability plus capillary morphogenesis on serum starvation and high cyclin D1 expression. Thus, hMSC-TERT20 clones represent cancer stem cells with hierarchical tumorigenicity, providing new models to explore the stem cell hypothesis for cancer.

Adult↗
PubMed1992

[Immunohistochemical and ultrastructural study on neoplastic endocrine cells and Paneth's cells in gastric carcinoma].

One hundred and twenty-eight cases of gastric carcinoma were examined with immunohistochemical technic for carcinoembryonic antigen (CEA), human chorionic gonadotropin (HCG), serotonin, gastrin and lysozyme. CEA were observed in 105 cases. Twenty-four cases were positive for HCG, 53 cases for serotonin, 31 cases for gastrin, 89 cases for lysozyme. Sixty-nine cases exhibited more than two hormones or one hormone and lysozyme simultaneously in different cells of the same tumor. Ultrastructurally, sometimes three types of secretory granules were noticed. The electron dense granules in the lysozyme-containing tumor cells were similar to those of Paneth's cells in intestinal metaplasia. The positive rates of the above three hormones, lysozyme and multi-marker expression in diffuse type carcinoma were higher than those in intestinal type, and 42/44 cases of the diffuse type carcinoma were histologically undifferentiated carcinomas or signet-ring cell carcinomas. Lymph node metastasis occurred more frequently in those carcinomas with hormone or lysozyme positivity. These findings suggest that these neoplastic endocrine cells and Paneth's cells have originated from multipotential differentiation of neoplastic stem cells in the stomach, reflecting the state of the gene activity in the tumor cells.

Adenocarcinoma↗
PubMed1989

Characterization of lympho-myeloid-erythroid-megakaryocytic stem cells in peripheral blood of hairy cell leukemia patients.

Circulating stem cells with lympho-myeloid-erythroid differentiative capacity have been described in the peripheral blood of hairy cell leukemia (HCL) patients (Michalevicz R. & Revel M. (1987) Interferons regulate the in vitro differentiation of multilineage lympho-myeloid stem cells in Hairy Cell Leukemia. Proc. natn. Acad. Sci. U.S.A. 84, 2307.) The aim of the present work was to enrich the progenitors and characterize their antigenic and growth properties. Peripheral blood (PB) from HCL patients was stained with antibodies (BI3C5 (CD34) and/or My10 as well as RFB7 (CD20) and RFT12 (CD7) and sorted using flow cytometry (FCM) into positive and negative fractions. Peripheral blood cells from several patients showed 4-16% cells positive for the BI3C5/My10. The positive fraction contained all the colony-forming cells and LGEM/LG/LGM colonies were enriched approximately ten-fold as compared to the unsorted population. No colony was found in the negative fraction. All colony forming cells were in the RFB7 and RFT12-negative fractions. Thus, circulating stem cells with lymphoid/myeloid potential can be isolated from PB of HCL patients.

Antibodies, Monoclonal↗
PubMed2006

Expression and functional significance of osteocalcin splicing in disease progression of hematological malignancies.

The aim of this study was to investigate the expression of osteocalcin (OCN) splicing variants in hematological malignancies. We analysed bone marrow obtained from two patients with chronic myeloid leukemia (CML), seven patients with other myeloproliferative diseases (MPD) and four patients with acute myeloid leukemia (AML). RT-PCR analyses were performed in order to assess and quantify spliced (OCNs) and unspliced (OCNu) mRNA, the associated transcription factors (AML1 and AML3) as well as c-KIT which is a marker for activated stem cells. Our data indicate that OCNs mRNA and OCN protein is expressed in c-KIT positive neoplastic stem cells in hematological malignancies.

Alternative Splicing↗
PubMed1985

Establishment and characterization of neoplastic cells from a malignant fibrous histiocytoma. A possible stem cell line.

Using the semisolid agar method, neoplastic three clones were isolated from a malignant fibrous histiocytoma. All clones represented morphologically only one type of cells having fine structure similar to that of histiocyte with multiple filopodia. The clones carrying Fc- and C3-surface receptors showed marked immunophagocytosis. They were positive for acid phosphatase, nonspecific esterase, and alpha-1-antitrypsin. These clones were able to display the potential for production of collagenous matrix. Moreover, inoculations of the each clone into nude mice resulted in productions of malignant fibrous histiocytoma with pleomorphic pattern. These tumors were composed morphologically of various types of cells such as immature, histiocyte-like, fibroblast-like, and multinucleated giant cells. These morphologic alterations of histiocytes occurred in all of the three clones in vitro. These findings suggest that the cloned cells established from the malignant fibrous histiocytoma are neoplastic histiocytes with capability to form various types of cells, a possible stem cell.

Adult↗
PubMed1986

Neoplastic transformation in the planarian: I. Cocarcinogenesis and histopathology.

Although several investigators have reported that exposure to mammalian carcinogens induces abnormal tumorlike growths and teratogenic remodeling in planarians, there is no general agreement that these, or comparable responses in any other invertebrates, model mammalian carcinogenesis. To investigate this question, freshwater planarians of the species Dugesia dorotocephala were exposed to culture water containing an initiator and a promoter, either alone or in combination. Cadmium, a potent carcinogen, was used as an initiator in the protocol. Treatment with sublethal concentrations of cadmium sulfate produced a benign, but persistent, tumor in a small percentage of the planarians. The addition of 12-O-tetradecanoylphorbol-13-acetate (TPA), a phorbol ester and well-known promoter, to the cadmium-containing solutions resulted in the induction of a progressive, potentially lethal, transplantable tumor in a large proportion of the treated flatworms. Light and electron microscopy revealed this particular tumor to be composed both of immature cells and of a single mature cell type: newly differentiated, but transformed, reticular cells. Further examination of the infiltrating tissue formations elucidated the profile of differentiation, from a population of mitotically active transformed stem cells through the transitional stages in the associated reticuloma. These results suggest that 1) the freshwater planarian displays the major phenomenology of mammalian cocarcinogenesis and that 2) the planarian reticuloma models several important features of a neoplastic stem cell disease.

Animals↗
PubMed1986

Neoplastic transformation in the planarian: II. Ultrastructure of malignant reticuloma.

Cadmium and phorbol ester induced tumorigenesis in the planarian, Dugesia dorotocephala, develops as a cocarcinogenic process involving initiation and promotion in the progression of neoplastic disease. Treatment of intact planarians with sublethal concentrations of cadmium sulfate and 12-O-tetradecanoylphorbol-13-acetate (TPA) induced a type of infiltrating tumor that proved to be potentially lethal. Surgical transplantation of such tumorous tissues into otherwise healthy planarians resulted in the same histopathological progression to lethality, which confirmed the metastatic nature of the neoplasia. Electron microscopic studies revealed that both the chemically-induced and the transplantation-based tumors involved, exclusively, the proliferation and differentiation of abnormal reticular cells, referred to as reticuloma cells. Reticular cells normally are ameboid, phagocytic, and are thought to provide the planarian with a phylogenetic predecessor of an immune surveillance system. A considerable incidence of mitosis was observed within the tumor areas; and the sequence of differentiation, from transformed stem cells to mature but nonfunctional reticuloma cells, was elucidated. This profile of differentiation supports the concept of cellular derivation via stem cell dynamics as opposed to dedifferentiation. A variety of ultrastructural abnormalities were characterized: several of which tend to substantiate the anaplastic quality of the reticuloma, while others are more specifically diagnostic for malignancy. These findings further extend the potential usefulness of the planarian malignant reticuloma as a model system for the study of neoplastic stem cell diseases.

Animals↗
PubMed2006

Detection of molecular targets on the surface of CD34+/CD38-- stem cells in various myeloid malignancies.

Recent data suggest that myeloid neoplasms are organized hierarchically in terms of self-renewal and maturation of early progenitor cells, similar to normal myelopoiesis. In acute myeloid leukemia (AML), the NOD/SCID mouse-repopulating leukemic stem cells usually co-express CD123 with CD34, but lack CD38. So far, however, little is known about expression of other markers and targets on these progenitors. In the present study, expression of target antigens on CD34+/CD38- cells was analysed by multi-color flow cytometry in patients with AML (n = 18), myelodysplastic syndromes (MDS, n = 6), chronic myeloid leukemia (CML, n = 8) and systemic mastocytosis (SM, n = 9). The IL-3Ralpha chain (CD123) was found to be expressed on CD34+/CD38- cells in a majority of the patients in all disease categories. Independent of the type of disease, the vast majority of these stem cells co-expressed aminopeptidase-N (CD13) and CD44 in all patients. By contrast, the CD34+/CD38- progenitor cells expressed variable amounts of the target receptor CD33, c-kit (CD117) and AC133 (CD133). In conclusion, neoplastic stem cells in various myeloid neoplasms appear to express a similar phenotype including target antigens such as CD13, CD33 and CD44. Since many of these targets are not expressed on all stem cells in all patients, the elimination of the entire clone may require combinations of targeted antibodies or use of additional drugs.

ADP-ribosyl Cyclase 1↗
PubMed1984

Cytomegalovirus replicates in differentiated but not in undifferentiated human embryonal carcinoma cells.

To study the mode of action of human cytomegalovirus, an important teratogenic agent in human populations, the susceptibility of a pluripotent human embryonal carcinoma cell line to the virus was investigated. Viral antigens were not expressed nor was infectious virus produced by human embryonal carcinoma cells after infection, although the virus was able to penetrate these cells. In contrast, retinoic acid-induced differentiated derivatives of embryonal carcinoma cells were permissive for antigen expression and infectious virus production. Replication of human cytomegalovirus in human teratocarcinoma cells may therefore depend on cellular functions associated with differentiation.

Cell Line↗
PubMed2004

MOZ-TIF2, but not BCR-ABL, confers properties of leukemic stem cells to committed murine hematopoietic progenitors.

To better understand the origin of leukemic stem cells, we tested the hypothesis that all leukemia oncogenes could transform committed myeloid progenitor cells lacking the capacity for self-renewal, as has recently been reported for MLL-ENL. Flow-sorted populations of common myeloid progenitors and granulocyte-monocyte progenitors were transduced with the oncogenes MOZ-TIF2 and BCR-ABL, respectively. MOZ-TIF2-transduced progenitors could be serially replated in methylcellulose cultures and continuously propagated in liquid culture, and resulted in an acute myeloid leukemia in vivo that could be serially transplanted. In contrast, BCR-ABL transduction conferred none of these properties to hematopoietic progenitors. These data demonstrate that some, but not all, leukemia oncogenes can confer properties of leukemic stem cells to hematopoietic progenitors destined to undergo apoptotic cell death.

Acute Disease↗