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Results for “Cancer stem cells”

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At least 73 records · Page 4Linked to original sources

PubMed1977

[Increased hematological toxicity of antineoplastic drugs with simultaneous androgenotherapy (author's transl)].

Thirty two patients with malignant lymphoma - mainly Hodgkin's disease - were randomized for simultaneous treatment by high doses of metenolone during MOPP chemotherapy, to reduce its hematological toxicity. The results have shown surprisingly an increased hemato-toxicity in patients receiving androgens, with significantly more marked anemia and thrombocytopenia, reducing the total doses of anti-cancer drugs. This side effect could be explained by a cycling of the hematopoietic stem-cells and call to some caution when androgens are used during cancer chemotherapy.

Androgens↗

PubMed2021

Functional impact of cancer-associated cohesin variants on gene expression and cellular identity.

Cohesin is a ring-shaped protein complex that controls dynamic chromosome structure. Cohesin activity is important for a variety of biological processes, including formation of DNA loops that regulate gene expression. The precise mechanisms by which cohesin shapes local chromosome structure and gene expression are not fully understood. Recurrent mutations in cohesin complex members have been reported in various cancers, though it is not clear whether many cohesin sequence variants have phenotypes and contribute to disease. Here, we utilized CRISPR/Cas9 genome editing to introduce a variety of cohesin sequence variants into murine embryonic stem cells and investigate their molecular and cellular consequences. Some of the cohesin variants tested caused changes to transcription, including altered expression of gene encoding lineage-specifying developmental regulators. Altered gene expression was also observed at insulated neighborhoods, where cohesin-mediated DNA loops constrain potential interactions between genes and enhancers. Furthermore, some cohesin variants altered the proliferation rate and differentiation potential of murine embryonic stem cells. This study provides a functional comparison of cohesin variants found in cancer within an isogenic system, revealing the relative roles of various cohesin perturbations on gene expression and maintenance of cellular identity.

Animals↗

PubMed1979

Thymic hormones.

The thymus produces several polypeptides, which induce lymphocyte differentiation in vitro and in vivo. Several of these polypeptides have been chemically characterized, and three of them have been sequenced and synthesised (alpha 1 thymosin, thymopoietin and the serum thymic factor). Thymic hormones do not act identically on all T-cell subsets: they alter preferentially post-thymic precursor cells, and among mature T cells cytotoxic cells and suppressor cells. Their mode of action at the cellular level involves binding to specific cellular receptors and interaction with adenyl cyclase. Preliminary clinical trials with crude extracts have provided promising results in immunodeficient and cancer patients. The differentiation of T cells from stem cells has been the matter of considerable investigation over the last two decades, since it has been realized that the thymus and its products, the thymus-derived cells (T cells) play a central role in the generation of effector cells in cell-mediated immunity and in the regulation of the various categories of immune responses. That the thymus could act by the intermediate of humoral substances was precociously suggested by MILLER and OSOBA before the observation that thymuses grafted within a cell-impermeable Millipore diffusion chamber restored the immunocompetence of neonatally thymectomized (Tx) mice (1). However, although this experiment was ultimately confirmed by using chambers with well-controlled impermeability (2), MILLER did not pursue the idea of the humoral function of the thymus. Probably, the striking results obtained by DAVIES (3) and other workers, indicating direct migration of functional T cells from the thymus and the poor results initially obtained in trying to reconstitute the immune system of neonatally Tx mice by cell-free thymic extracts contributed to this disappointment. A new impetus was given to the subject in the early 70's when in vitro tests of lymphocyte function became available and when purified extracts of the thymus proved capable of restoring antigen-specific and non-specific immunocompetence of Tx mice. More recently, completely defined synthetic thymic hormones have been obtained. The question is no longer to decide whether thymic hormones exist, but rather to elucidate their biological significance and potential clinical applications. The multiplicity of available factors has created some confusion. It will be the aim of these few pages to review critically the various factors reported in the literature, giving particular emphasis to their pharmacology and their potential use in the modulation of immune responses.

Carrier Proteins↗

PubMed1977

Radiation injury: some aspects of the oncogenic effects.

The late effects or irradiation stem from cell killing, mutation, and malignant transformation. Cancer is the major somatic late effect of exposure to low dose levels of radiation, and estimates of risk of cancer in man after irradiation are based entirely on human experience. The data for dose-response relationships for the induction of tumors by external irradiation in man have been obtained from a single exposure or a small number of exposures delivered at high dose rates. In contrast, exposure to environmental irradiation is mainly protracted over a long period of time and is delivered at a low dose rate. As yet no allowance has been made for the effect of protraction of the exposure time in estimating the risk of cancer, although an adjustment has been made in the case of estimates of genetic risk. Incidence of tumors has been the only parameter used for risk estimates, but latent period and degree of malignancy, which are probably both dose and dose-rate dependent, influence the nature of the risk from radiation. As the knowledge about the effects of low-level radiation has been accumulated and assimilated over the last 70 years, so has the concern for reasonable standards of safety. There are still problems in the estimation of radiation risks, but at least many of the relevant questions can now be framed. The problems of estimating risks for chemical carcinogens are clearly greater, but the experience gained from radiation studies should help in the design of the necessary experiments.

Age Factors↗

PubMed2024

DGKH-mediated phosphatidic acid oncometabolism as a driver of self-renewal and therapy resistance in HCC.

BACKGROUND AND AIMS: HCC is characterized by metabolic pathway aberrations, which enable cancer cells to meet their energy demands and accelerate malignant progression. Identifying novel metabolic players governing therapy resistance and self-renewal in HCC is crucial, as these properties are likely responsible for tumor recurrence. APPROACH AND RESULTS: Clinical traits and RNA-seq of patients with HCC in The Cancer Genome Atlas were used for weighted gene coexpression network analysis, where 1 module was significantly correlated with advanced pathological stage and stem cell population maintenance. Further analysis of this module by integrating data obtained from HCC patient nonresponders to tyrosine kinase inhibitors identified 361 commonly deregulated genes. Intriguingly, these genes are significantly enriched in the intracellular signal transduction pathway, with diacylglycerol kinase eta (DGKH) ranked as the most enriched gene in poorly differentiated HCC tumors. Clinically, DGKH was elevated in tumor tissues compared to nontumor tissues. Patients with higher DGKH expression exhibited a more undifferentiated state and were less responsive to tyrosine kinase inhibitors. Functional assays using DGKH-manipulated HCC cell lines demonstrated that DGKH augmented aggressive features, including cancer stemness, therapy resistance, and metastasis. Upstream of DGKH , we discovered that the E1A-associated protein p300 (EP300) binds to DGKH's promoter region, thereby increasing its transcriptomic expression. Mechanistically, DGKH promotes mTOR signaling by producing phosphatidic acid. In an immunocompetent mouse model, cotreatment with sorafenib and liver-directed AAV8-mediated Dgkh depletion significantly reduced tumor burden, self-renewal, phosphatidic acid production, and mTOR signaling. CONCLUSIONS: Our research demonstrated that DGKH is a crucial oncometabolic regulator of cancer stemness and therapy resistance, suggesting that inhibiting DGKH may lead to more effective HCC treatment.

Humans↗

PubMed2025

Efficacy of MET-targeting CAR T cells against glioblastoma patient-derived xenograft models.

BACKGROUND: Genetic alteration of the MET receptor tyrosine kinase frequently occurs in glioblastoma (GBM). Clinically, bevacizumab treatment results in MET signaling activation, leading to GBM recurrence with a more malignant phenotype. While MET has been a promising therapeutic target, MET inhibitors have not been successful in treating GBM patients. MET-directed chimeric antigen receptor (CAR) T cells hold the promise of targeting MET-positive GBM regardless of genetic alterations or kinase activity. METHODS: GBM patient-derived xenografts (PDX) harboring MET amplification (METamp) or PTPRZ-MET fusion (ZM) were propagated in vivo followed by glioma stem cell (GSC) isolation. Cell-based assays were used for comparing GSC survival in response to MET inhibitors and CAR T cells. Multi-panel cytokine release was analyzed to profile MET-CAR T cell activation during co-culture with GBM. Orthotopic tumor growth and real-time imaging were performed to evaluate MET-CAR T cell therapeutic efficacy in vivo. RESULTS: Although GBM are heterogeneous tumors, neuro-sphere cells isolated from METamp or ZM fusion PDX tumors showed universal cognate genetic MET alteration along with GSC markers such as SOX2 and nestin. Both METamp and ZM fusion tumors showed MET overexpression but only the METamp cells presented activated MET signaling which was vulnerable to MET inhibitors. In contrast, MET-CAR T cells specifically inhibited all MET-positive tumor growth regardless of MET activation status. CONCLUSIONS: Whereas MET inhibitors are effective in MET-active tumors, MET-CAR T cells eradicate MET-positive GBM growth in an antigen-dependent manner, demonstrating a promising therapeutic approach for treating MET-positive GBM. MET overexpression, especially METamp and ZM fusion may be used to predefine the GBM patients for treating with MET-CAR T cell therapy.

Glioblastoma↗

PubMed1992

The therapeutic potential of interleukin-1 and tumor necrosis factor on hematopoietic stem cells.

Dose intensity is emerging as a crucial determinant of success in cytotoxic cancer therapy; however, myelosuppression presents as one of the major complications encountered with increased dose intensity. Therefore, investigators are looking at the use of cytokine administration in combination with cytotoxic therapy to overcome this problem. Interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF-alpha) have been shown to be beneficial in protecting the hematopoietic system from radiation and chemotherapy. In this report, we give an overview of studies using IL-1 and TNF-alpha as protective agents and discuss possible mechanisms involved in their protective action. Mice pretreated with IL-1 and/or TNF-alpha were shown to be protected from the lethal effects of radiation and it has been suggested that the mechanism for this protection may be through the production of the antioxidant enzyme manganese superoxide dismutase. Similarly, aldehyde dehydrogenase, an enzyme important in the metabolic pathway of cyclophosphamide compounds, has been implicated as being important in the protection of hematopoietic cells from 4-hydroperoxycyclophosphamide. While IL-1 and TNF-alpha stimulate both of these enzymes, other mechanisms are probably also operative for other forms of chemotherapy, i.e. IL-1 and TNF-alpha were shown to protect hematopoietic progenitors from phenylketophosphamide, a cyclophosphamide derivative that is not metabolized by the enzyme aldehyde dehydrogenase. Furthermore, malignant as well as normal cells may possess receptors for these cytokines; therefore, IL-1 and TNF-alpha will have to be selective in their protection. They must be capable of protecting normal hematopoietic cells while rendering malignant cells susceptible to the toxic actions of the chemotherapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗

PubMed2026

Matrix Metalloprotease 1 (Mmp1) promotes cell fate change for epithelial-to-epithelial transition during regeneration after radiation damage in Drosophila.

Ionizing radiation (IR) is used to treat cancer, but therapeutic failure occurs when surviving cancer cells change fate and regenerate tumors through acquired stem cell-like properties. While transcriptional mechanisms underlying cell fate plasticity have been characterized, the cellular processes enabling cell movement during tissue regeneration remain unclear. We reported previously that hinge cells of the Drosophila larval wing disc convert to pouch fate and translocate to help regenerate the pouch that suffers from more IR-induced apoptosis. We report here that IR increases the expression of extracellular proteins in the hinge, including secreted proteases and cell adhesion modulators. Functional validation using RNA interference revealed that secreted Matrix Metalloprotease 1 (Mmp1) and the related secreted protease homolog Scarface (Scaf) are required in hinge cells for IR-induced cell fate conversion and translocation. IR, we found, induces Mmp1 and scaf transcripts in hinge cells via cell-autonomous JNK signaling. Overexpression of Mmp1 specifically in the hinge was sufficient to elevate Mmp1 protein levels throughout the disc and induced cell fate change of both hinge and non-hinge cells but only in the context of irradiation. Confocal imaging in a time course demonstrated that cells undergoing fate conversion remain within the epithelial layer with little evidence for delamination or epithelial-mesenchymal transition (EMT). We propose that remodeling of the extracellular environment is a critical mechanism that enables cellular reorganization during tissue regeneration. Mmp enzymes are important for cancer biology because of their role in ECM remodeling, extracellular signaling, and EMT. Our findings demonstrate for the first time that Mmp1 is necessary and sufficient for one epithelial cell type to switch to another epithelial cell type after radiation damage. These results provide a mechanistic basis for radiation therapy-induced cell fate plasticity.

Animals↗

PubMed1992

[Gene transfer and gene therapy].

The application of gene transfer technology to human gene therapy has been intensively investigated during the last decade. The first human clinical trials in adenosine deaminase deficiency and metastatic melanoma recently demonstrated the feasibility and safety of using retroviral gene transduction for human gene therapy. Many problems remain to be solved for a better understanding of the functioning of genes to be transferred, a better efficiency of gene transfer and genetic correction by site-specific targeting in vivo, a better knowledge of the biological properties of target cells such as totipotent hematopoïetic stem cells. Clinical developments are expected in genetic diseases (immunodeficiency, thalassemia, hemophilia) and non genetic disorders (lymphokine gene therapy for cancer).

Child↗

PubMed1992

Non-haematological toxicity limiting the application of sequential high dose chemotherapy in patients with advanced breast cancer.

A programme of repeated high dose chemotherapy for advanced breast cancer was developed using (1) cyclophosphamide 4 g/m2 followed by autologous peripheral blood stem cell (PBSC) collection; (2) three cycles of conventional dose chemotherapy; (3) high dose cyclophosphamide, cisplatin, and carmustine with PBSC rescue; and (4) high dose etoposide and melphalan with PBSC rescue. Fifteen eligible patients had advanced poor prognosis breast cancer either at initial diagnosis (one patient) or at relapse (14 patients). During the course of the protocol, there were three treatment related deaths, two patient withdrawals due to debilitating toxicity, five patient withdrawals due to disease progression, and one patient withdrawal due to inadequate collection of PBSC. The remaining four patients did not complete the planned protocol as the programme was terminated because of the unacceptable morbidity and mortality. They were treated with an alternative high dose chemotherapy protocol which was well tolerated. This study highlights the significant problems associated with a complex sequential high dose chemotherapy regimen. Cyclophosphamide mobilized PBSC infused following high dose chemotherapy enables rapid haematological recovery. However the non-haematological toxicity following high dose chemotherapy regimens is often severe and may limit the application of certain sequential high dose chemotherapy combinations in patients with breast cancer.

Adult↗

PubMed2024

DKK1-SE recruits AP1 to activate the target gene DKK1 thereby promoting pancreatic cancer progression.

Super-enhancers are a class of DNA cis-regulatory elements that can regulate cell identity, cell fate, stem cell pluripotency, and even tumorigenesis. Increasing evidence shows that epigenetic modifications play an important role in the pathogenesis of various types of cancer. However, the current research is far from enough to reveal the complex mechanism behind it. This study found a super-enhancer enriched with abnormally active histone modifications in pancreatic ductal adenocarcinoma (PDAC), called DKK1-super-enhancer (DKK1-SE). The major active component of DKK1-SE is component enhancer e1. Mechanistically, AP1 induces chromatin remodeling in component enhancer e1 and activates the transcriptional activity of DKK1. Moreover, DKK1 was closely related to the malignant clinical features of PDAC. Deletion or knockdown of DKK1-SE significantly inhibited the proliferation, colony formation, motility, migration, and invasion of PDAC cells in vitro, and these phenomena were partly mitigated upon rescuing DKK1 expression. In vivo, DKK1-SE deficiency not only inhibited tumor proliferation but also reduced the complexity of the tumor microenvironment. This study identifies that DKK1-SE drives DKK1 expression by recruiting AP1 transcription factors, exerting oncogenic effects in PDAC, and enhancing the complexity of the tumor microenvironment.

Humans↗

PubMed1976

Increase in circulating stem cells following chemotherapy in man.

The number of circulating granulocytic stem cells (CFU-C) was determined by the in vitro methylcellulose technique in cancer patients receiving intermittent chemotherapy. In 17 patients studied prior to therapy, the median CFU-C concentration per 2 X 10(5) mononuclear cells plated was six, compared to a posttreatment median of 23 in 21 patients (p less than 0.001). Large numbers of stem cells were obtained by leukopheresis and cryopreserved with a 99.5% median CFU-C recovery. Cyclical changes in the concentration of stem cells with maximum values of 20 times baseline were demonstrated in a patient studied at weekly intervals during multiple courses of treatment. It was estimated that, at peak CFU-C concentrations, a quantity of stem cells equivalent to that present in a bulk bone marrow harvest could be obtained from the peripheral blood by a 17-liter pheresis. These results suggest that it may be practical to obtain an adequate number of stem cells from the peripheral blood to study autologous stem cell infusion as a means of averting myelosuppression in patients receiving intensive chemotherapy.

Blood Cell Count↗

PubMed1992

[Biomolecules suppressing myelopoiesis].

Hematopoietic stem cells are capable of self-replication and differentiation to lineage-committed progenitor cells. The progenitors proliferate and differentiate to lineage-specific, morphologically recognizable precursors and, finally, to terminal circulating blood cells. These homeostatic mechanisms are regulated by a complex set of interacting growth stimulatory and inhibitory factors that are produced by, or in collaboration with, the tissue's regulatory microenvironment. A number of well-characterized cytokines have been implicated in the negative regulation of hematopoiesis: ferritin H-subunit (HF), lactoferrin (Lf), prostaglandin E (PGE), tumor necrosis factor (TNF), interferon (IFN), transforming growth factor-beta (TGF beta), acetyl-N-Ser-Asp-Lys-Pro (AcSDKP) or thymosin-beta 4, pyroGlu-Glu-Asp-Cys-Lys (pEEDCK), macrophage inflammatory protein-1 alpha (MIP-1 alpha), inhibin, superoxide dismutase (SOD), glutathione (GSH) and others not well-known yet. The role of inhibitors in restraining stem cells from entering the cell cycle and protecting them from the toxic side effects of chemotherapeutic drugs is opening an alternate strategy for the treatment of cancer patients.

Amino Acid Sequence↗

PubMed1976

Cancer, retrodifferentiation, and the myth of Faust.

The close relationship at the molecular level between cellular differentiation and neoplasia has been evidenced by the discovery in adult individuals of fetospecific antigens and fetal type isozymes associated with many spontaneous and experimentally induced malignant tumors. One question in relation with this finding is whether cancerous tumors develop from the differentiation of a tissue reserve of stem cells or by a process of retrodifferentiation, i.e., the nucleocytoplasmic stepwise reversion of cells toward stationary states with simplified structure and less information content. The question is not merely academic; elucidation of the nature of the target cells from which neoplastic growth emerges has obviously physiopathological and therapeutic implications. This contribution is an analysis of the nature and the mechanism of cellular retrodifferentiation and a discussion of its possible role in regeneration and metaplasia, as well as in neoplastic development. Throughout living systems, retrodifferentiation appears as a common adaptive process for the maintenance of cell integrity against deleterious agents of varied etiology (physical, chemical,and viral). While preserving the entire information encoded on its genome, cells undergoing retrodifferentiation lose morphological and functional complexity by virtue of a process of self-deletion of cytoplasmic structures and the transition to a more juvenile pattern of gene expression. This results in a progressive uniformization of originally distinct cell phenotypes and to a decrease of responsiveness to regulatory signals operational in adult cells. Retrodifferentiation is normally counterbalanced by a process of reontogeny that tends to restore the terminal phenotypes from where the reversion started. This explains why retrodifferentiation remains invariably associated to cell regeneration and tissue repair. There is an ever growing evidence that neoplastic transformation in vivo and in vitro is frequently preceded and/or accompanied by biochemical, morphological, and behavioral transitions characteristic of a cell undergoing retrodifferentiation. Contrary to what occurs in regenerating tissues, the "unbalanced" character of tumor-associated retrodifferentiation seems to be a property linked to cancer. The question arises why a unique mechanism of cell rejuvenation is in physiological conditions (regeneration), followed by a process of reontogeny, while in neoplasia the process remains incomplete or does not occur and leads to the emergence of a population of persistently dividing cells. It is to be hoped that a careful study of retrodifferentiation in physiological and tumoral models will help to distinguish that which in neoplastic development can be relevant to an adaptive cell behavior from that which might eventually be the result of specific or constitutive alterations.

Adaptation, Physiological↗

PubMed2026

hPSC models in cancer mechanisms and therapeutic discovery.

Despite major advances in cancer genomics and immunotherapy, the field remains limited by experimental models that fail to faithfully recapitulate human tumor initiation, genetic context, and immune-tumor interactions. Traditional animal and immortalized cell models often lack predictive power for therapeutic response and toxicity. Recent advances in human pluripotent stem cell (hPSC) technology have transformed this landscape, enabling the generation of patient-specific cancer models, multicellular organoids and assembloids, and scalable immune effector cells. These platforms now permit mechanistic dissection of tumorigenesis, reconstruction of human tumor microenvironments, and development of off-the-shelf immunotherapies. This review will synthesize these emerging findings, define key technological and biological gaps, and outline future directions for integrating hPSC-based modeling into precision oncology and translational cancer research.

cancer immunotherapy↗

PubMed1975

Effects of bleomycin on mouse bone-marrow stem cells.

The mouse hematopoietic stem-cell population was tested by the spleen colony technique for effects of the antineoplastic agent bleomycin (BLM). The time response of normal bone marrow was investigated by a single dose of BLM (400 mg/kg) between 0 and 72 hours. The dose response was studied over a wide range of doses (from 40 to 1,600 mg/kg) at a 4-hour exposure. Additional experiments concerned 1) the fraction of colony-forming units in the S phase after BLM administration (by means of pulse hydroxyurea treatment), 2) the response of bone marrow stimulated by endotoxin, and 3) the effects of split-dose treatments. The relatively low toxicity of BLM on both the differentiated and stem-cell populations of unstimulated bone marrow was confirmed and detailed. This drug exhibited peculiar, proliferation-dependent cell inactivation kinetics. Furthermore, BLM induced parasynchronous behavior in the unstimulated stem-cell population. The various aspects of BLM action are discussed with regard to its use in cancer chemotherapy.

Animals↗

PubMed1992

Mammary gland mass and breast cancer risk.

Evidence indicates that early life events and conditions, possibly extending to the intrauterine stages of life, and including energy restriction in early life, affect the risk of breast cancer. The mechanism of this effect is likely to be through a reduction in mammary gland mass and, inferentially, the total number of ductal stem cells. The evidence derives from epidemiologic and animal studies. It can explain certain epidemiologic findings that cannot be accounted for by more established breast cancer risk factors, including the more frequent occurrence of breast cancer in the left breast and the higher incidence of this disease among caucasian women than among Asian women in Asia.

Breast↗

PubMed1992

[Autoantibodies in paraneoplastic polioencephalomyelitis: 8 cases].

Antibodies directed against the central nervous system were looked for by indirect immunohistochemistry in the sera of 8 patients with paraneoplastic neurological syndrome (group 1), 21 cancer patients without neurological signs, 23 patients with miscellaneous neurological diseases and 63 normal subjects (groups 2 to 4). Four patients in group 1 had very high titres of antibodies. In 2 patients with small-cell lung carcinoma associated with sensory neuropathy the antibody recognized the cytoplasm and nucleus of all neurons. A 37 Kd protein was recognized by Western blot. A woman with cancer of the ovary and cerebellar syndrome exhibited an antibody against Purkinje's cell cytoplasm with a band of about 50-55 Kd at Western blot. In a woman with chronic uveitis and cerebellar atrophy with disappearance of Purkinje's cells the antibody (in blood and CSF) recognized certain layers of the retina as well as glial cells and cells present in the subependymal areas of the brain. Two bands of 46 and 59 Kd were revealed by Western blot. Immunoglobulins were detected in the cytoplasm of white matter cells in the cerebellum and brain stem. Among the other groups, one patient with lung cancer had a moderate titre of neuronal antinuclear antibody. The Western blot test was negative. The relevance of these antibodies for the diagnosis and treatment is discussed.

Aged↗