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Results for “Cancer stemness”

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PubMed2005

Death-from-cancer signatures and stem cell contribution to metastatic cancer.

Genome-wide expression profiling studies reveal a transcriptionally distinct sub-type of human solid tumors with a marked propensity toward metastatic dissemination, highly malignant clinical behavior, and poor therapy outcome in cancer patients diagnosed with the early stage carcinomas of various origins. This sub-set of tumors acquires full metastatic potential, including an emergence and seeding of potent metastasis precursor cells, early in tumor progression. Collectively, these data suggest an early involvement in development of this transcriptionally defined sub-type of human carcinomas of a highly malignant combination of mutant alleles conferring the proclivity to metastasize and/or an engagement in transformation and tumor progression of stem cells and/or early progenitor cells. Enrichment of primary tumors with normal stem cells increases the likelihood of horizontal genomic transfer (large-scale transfer of DNA and chromatin) between stem cells and cancer cells via cell fusion and/or uptake of apoptotic bodies and generation of reprogrammed somatic cell hybrids with self-renewing highly malignant phenotype.

Alleles↗

PubMed2006

A human colon cancer cell capable of initiating tumour growth in immunodeficient mice.

Colon cancer is one of the best-understood neoplasms from a genetic perspective, yet it remains the second most common cause of cancer-related death, indicating that some of its cancer cells are not eradicated by current therapies. What has yet to be established is whether every colon cancer cell possesses the potential to initiate and sustain tumour growth, or whether the tumour is hierarchically organized so that only a subset of cells--cancer stem cells--possess such potential. Here we use renal capsule transplantation in immunodeficient NOD/SCID mice to identify a human colon cancer-initiating cell (CC-IC). Purification experiments established that all CC-ICs were CD133+; the CD133- cells that comprised the majority of the tumour were unable to initiate tumour growth. We calculated by limiting dilution analysis that there was one CC-IC in 5.7 x 10(4) unfractionated tumour cells, whereas there was one CC-IC in 262 CD133+ cells, representing >200-fold enrichment. CC-ICs within the CD133+ population were able to maintain themselves as well as differentiate and re-establish tumour heterogeneity upon serial transplantation. The identification of colon cancer stem cells that are distinct from the bulk tumour cells provides strong support for the hierarchical organization of human colon cancer, and their existence suggests that for therapeutic strategies to be effective, they must target the cancer stem cells.

AC133 Antigen↗

PubMed2006

Epigenetic stem cell signature in cancer.

Embryonic stem cells rely on Polycomb group proteins to reversibly repress genes required for differentiation. We report that stem cell Polycomb group targets are up to 12-fold more likely to have cancer-specific promoter DNA hypermethylation than non-targets, supporting a stem cell origin of cancer in which reversible gene repression is replaced by permanent silencing, locking the cell into a perpetual state of self-renewal and thereby predisposing to subsequent malignant transformation.

Cell Differentiation↗

PubMed2005

The role of adult stem cells in carcinogenesis.

The role of adult stem cells in tissue regeneration has attracted much interest because of its enormous therapeutic potential. Adult stem cells reside in every tissue of the body and have the ability to self-renew and to give rise to a high number of differentiated progeny. These are indeed the essential steps in tissue regeneration, which in some cases occurs constitutively, whereas in other cases happens in response to an injury. The identification of the key factors involved in self-renewal and differentiation pathways is at the top of the agenda of stem cell biologists. Interestingly, a number of factors that govern the fate of adult stem cells also play a role in malignant cell transformation, such as the Wnt cascade, Oct-4, Bmi-1 and Evi1. In addition, rare subpopulations of cancer stem cells were identified for leukemia and other solid tumors. These rare fractions of cancer stem cells are in large part responsible for maintaining the tumor mass, as they have the capacity to self-renew and to generate a high number of progeny via differentiation program. These findings can be considered a major breakthrough in cancer research. Currently, oncologists and stem cell biologists have two main goals: i) the assessment of the consistency of the line that divides adult stem cells and carcinogenesis; ii) to better characterize the biology of cancer stem cells. This new line of investigation may allow for the development of novel therapeutics and cancer diagnostics.

AC133 Antigen↗

PubMed2004

Self-renewal and solid tumor stem cells.

Solid tumors arise in organs that contain stem cell populations. The tumors in these tissues consist of heterogeneous populations of cancer cells that differ markedly in their ability to proliferate and form new tumors. In both breast cancers and central nervous system tumors, cancer cells differ in their ability to form tumors. While the majority of the cancer cells have a limited ability to divide, a population of cancer stem cells that has the exclusive ability to extensively proliferate and form new tumors can be identified based on marker expression. Growing evidence suggests that pathways that regulate the self-renewal of normal stem cells are deregulated in cancer stem cells resulting in the continuous expansion of self-renewing cancer cells and tumor formation. This suggests that agents that target the defective self-renewal pathways in cancer cells might lead to improved outcomes in the treatment of these diseases.

Animals↗

PubMed2004

Integration of glycosphingolipid metabolism and cell-fate decisions in cancer and stem cells: review and hypothesis.

The metabolism of glycosphingolipids is strictly regulated during the mitotic cell cycle. Before the G1-to-S transition, the ceramide and glucosylceramide concentration is elevated. Ceramide induces apoptosis synergistically with the pro-apoptotic protein prostate apoptosis response 4 (PAR-4) that may be asymmetrically inherited during cell division. Only one daughter cell dies shortly after mitosis, a mechanism we suggested to regulate the number of neural stem cells during embryonic development. The progeny cells, however, may protect themselves by converting ceramide to glucosylceramide and other glycosphingolipids. In particular, complex gangliosides have been found to sustain cell survival and differentiation. The cell cycle may thus be a turning point for (glyco)sphingolipid metabolism and explain rapid changes of the sphingolipid composition in cells that undergo mitotic cell-fate decisions. In the proposed model termed "Shiva cycle", progression through the cell cycle, differentiation, or apoptosis may rely on a delicate balance of (glyco)sphingolipid second messengers that modulate the retinoblastoma-dependent G1-to-S transition or caspase-dependent G1-to-apoptosis program. Ceramide-induced cell cycle delay at G0/G1 is either followed by ceramide-induced apoptosis or by conversion of ceramide to glucosylceramide, a proposed key regulatory rheostat that rescues cells from re-entry into a life/death decision at G1-to-S. We propose a mechanistic model for sphingolpid-induced protein scaffolds ("slip") that regulate cell-fate decisions and will discuss the biological consequences and pharmacological potential of manipulating the (glyco)sphingolipid-dependent cell fate program in cancer and stem cells.

Apoptosis↗

PubMed2001

Cancer genesis: stem tumour cells as an MHC-null/HSP70 - very high 'primordial self' escaping both MHC-restricted and MHC-non- restricted immunesurveillance.

I have previously assumed that in tumours there are stem cells, that owing to the morphophysiologic properties shared with embryonal cells I have defined as 'para-embryonal' cells (PECs). Owing to a blocking mutation, PECs might be able to express only the genic program upstream from the block, but not that downstream. As a consequence, PECs might lack in genic differentiated products, such as MHC molecules, and might be very rich in primitive genic products, such as HSP70 molecules. Like embryonal cells, PECs might carry out induction on adjoining hyperplastic cells, thus transforming them, only phenotypically, into 'differentiated para-embryonal cells' (DPECs), endowed with both MHC and HSP70 molecules. In such a way, nuclei of MHC-non-expressing/HSP70-high expressing stem tumour cells might be surrounded by layers of MHC-expressing/HSP70-expressing non-stem tumour cells. Such a structural tumour organization, actually found by C. Cordon Cardo et al. with regard to the MHC molecule expression, might be responsible for interference phenomena versus the MHC-non-restricted immune cells, such as macrophages and NK cells. So, these cells, the only potentially able to recognize and eliminate MHC-non-expressing stem tumour cells (PECs), might spare them, thus rendering cancer a biological process without any natural immunological solution. Now, I would like to theorically demonstrate that cancer might be a process without immunological solution from the very beginning: the first stem tumour cell might be tolerated as a sort of 'primordial self' because of its MHC-null/HSP70-very high phenotype, recognizable by neither the MHC-restricted nor the MHC-non-restricted immunesurveillance systems of the host. Possible biological roles of HSP70 molecules might account for the immunesurveillance escape of stem tumour cells. Existence of these cells appears to be confirmed by the recent experiments of immunotherapy with autologous tumour-specific HSPs carried out by P. K. Srivastava; moreover, their 'self' nature appears to be confirmed by the most recent experiments of compatible bone marrow allograft carried out by A. M. Carella. On this ground, the main steps for a resolutive antitumour immunotherapy are proposed.

HSP70 Heat-Shock Proteins↗

PubMed2004

Acute myeloid leukemia originates from a hierarchy of leukemic stem cell classes that differ in self-renewal capacity.

Emerging evidence suggests cancer stem cells sustain neoplasms; however, little is understood of the normal cell initially targeted and the resultant cancer stem cells. We show here, by tracking individual human leukemia stem cells (LSCs) in nonobese diabetic-severe combined immunodeficiency mice serially transplanted with acute myeloid leukemia cells, that LSCs are not functionally homogeneous but, like the normal hematopoietic stem cell (HSC) compartment, comprise distinct hierarchically arranged LSC classes. Distinct LSC fates derived from heterogeneous self-renewal potential. Some LSCs emerged only in recipients of serial transplantation, indicating they divided rarely and underwent self-renewal rather than commitment after cell division within primary recipients. Heterogeneity in LSC self-renewal potential supports the hypothesis that they derive from normal HSCs. Furthermore, normal developmental processes are not completely abolished during leukemogenesis. The existence of multiple stem cell classes shows the need for LSC-targeted therapies.

Animals↗

PubMed2006

Brain tumor stem cells: new targets for clinical treatments?

The observation of similarities between the self-renewal mechanisms of stem cells and cancer cells has led to the new concept of the cancer stem cell. In cases of leukemia, multiple myeloma, and breast cancer, cells with a high selfrenewal potential have been identified. Furthermore, investigators have shown these cells' ability to drive the formation and growth of the tumor. Brain tumors have also been reported to possess a subpopulation of cancer stemlike cells that have the ability to proliferate, self-renew, and be multipotent. When grafted into mice, these cells are also able to generate a tumor that recapitulates that of the patient from whom the cells were derived. The identification and characterization of this new category of cells call for new therapies capable of selectively targeting and killing these multifaceted cells.

AC133 Antigen↗

PubMed2005

Biology of normal and acute myeloid leukemia stem cells.

The substantial understanding that has been gained over the past 5 decades of the biology of blood formation is largely due to the development of functional quantitative assays for cells at all stages of differentiation, from multipotential stem cells to mature cells. The majority of studies have involved the mouse because the ease with which repopulation studies can be carried out with this animal model allows the assay of complete lineage development from stem cells. In the past decade, advances in repopulation assays for human stem cells using xenotransplantation have greatly enhanced our understanding of human stem cell biology. Importantly, the xenotransplantation methodology has also been used to identify the cancer stem cell that initiates and sustains leukemic proliferation, providing key evidence for the cancer stem cell hypothesis. This hypothesis argues that cancer cells are functionally heterogeneous and hierarchically organized such that only specific cells are capable of sustaining tumor growth and continuously producing the cells that make up the bulk of the tumor. Recent studies have also brought into focus the importance of the intimate relationship between the stem cell (normal or leukemic) and its microenvironment. Coming into view are the molecular players involved in stem cell homing, migration, and adhesion, as well as the cellular components of the microenvironmental niche. Here we review recent studies that have begun, to elucidate the interplay between normal and leukemic human stem cells and their microenvironment.

Animals↗

PubMed2006

Future cancer management with stem cell knowledge and technology.

Cancer has been proposed as a result of abnormal control of growth and development of stem cells for more than century. This is the "cancer stem cell hypothesis". Both cancer and stem cells share many common especial properties. They are immortal and have good differentiation potential. In addition, organogenesis and carcinogenesis are very similar processes. Recently, more evidence and convincing data from stem cell biology research are supporting this concept. Furthermore, the research provides new promising approaches for cancer diagnosis and treatment based on stem cell knowledge and technology. Upcoming data and evidence may revolutionize cancer management, making it more effective and safer.

Forecasting↗

PubMed2005

A tumour stem cell hypothesis for the origins of prostate cancer.

Cancer stem cells undoubtedly exist in many tumour types, including the prostate. This hypothesis can explain both the heterogeneity of prostate tumours and their variable responses to several conventional therapies. In the longer term, therapies directed against tumour stem cells should offer a real possibility of long-term cure, rather than current palliative therapy. Identifying specific tumour stem-cell markers will enhance this process, but the scarcity of these cells within the mass of more differentiated amplifying progeny that comprise >99.9% of most cancers makes this a severe technical challenge. In addition, many tumour stem-cell markers are probably shared with normal stem cells, both in prostate and in stem cells from other tissues, but tumour-specific patterns of gene expression, probably designed to allow the tumour stem cell to survive outside its protective 'niche' in normal tissues, will be the best initial targets for new therapeutic agents.

Animals↗

PubMed2005

Decatenation checkpoint deficiency in stem and progenitor cells.

The decatenation checkpoint normally delays entry into mitosis until chromosomes have been disentangled through the action of topoisomerase II. We have found that the decatenation checkpoint is highly inefficient in mouse embryonic stem cells, mouse neural progenitor cells, and human CD34+ hematopoietic progenitor cells. Checkpoint efficiency increased when embryonic stem cells were induced to differentiate, which suggests that the deficiency is a feature of the undifferentiated state. Embryonic stem cells completed cell division in the presence of entangled chromosomes, which resulted in severe aneuploidy in the daughter cells. The decatenation checkpoint deficiency is likely to increase the rates of chromosome aberrations in progenitor cells, stem cells, and cancer stem cells.

Animals↗

PubMed2006

Porcine epidermal stem cells as a biomedical model for wound healing and normal/malignant epithelial cell propagation.

This article summarizes research using cells derived from epidermis of the miniature pigs for use as a cell therapy for skin repair and as a model for squamous carcinoma of the head and neck. Stem cells are an important "tool" for biomedical research. Adult stem cells are defined functionally, as cells that have the capacity to self-renew as well as the ability to generate differentiated cells. They are present in defined tissue microenvironments called niches. Asymmetric mitosis allows them to produce one daughter cell with the properties of stem cells (self-renewal) and a second cell with characteristics of progenitor cells, or transit amplifying cells, which proliferate quickly but with a limited number of mitotic divisions. Porcine epidermal stem cells, located in the bulge region of the outer root sheath of hair follicles, migrate in vitro from hair sheaths and because they are resistant to anoikis (detachment induced apoptosis), survive in non-adhesive conditions to form spheroids. These cells express keratins, galectin-1 and their nuclei are rich in DeltaNp63alpha. Interestingly, the multiple phenotype analysis of the human tumor cells in squamous carcinoma of head and neck revealed similarities with epidermal stem cells. These cancer stem cells are usually located on the periphery of the tumor where the invasive front of the tumor responsible for its aggressive behavior is located. In contrast, extensive expression of markers of terminal differentiation such as expression of glycoligands reactive for the endogenous lectin, galectin-3, indicates better tumor prognosis.

Animals↗

PubMed2005

The potential of targeting malignant stem cells as a treatment for leukemia.

Malignant stem cells have recently been described as the source of several types of human cancer. These unique cell types are typically rare and possess properties that are distinct from most other tumor cells. In leukemia, the natural properties of cancer stem cells indicate that current chemotherapy drugs will not be effective. Consequently, new strategies are required that specifically and preferentially target the cancer stem cell population, whilst sparing normal stem cells. This perspective article summarizes recent findings in the leukemia stem cell field and discusses new directions for therapy.

Animals↗

PubMed2005

[Study on the mechanisms of imatinib-resistance of cancer stem-like cells in K562/Vp16 cell line].

OBJECTIVE: To elucidate the mechanisms of imatinib resistance involved in some chronic myeloid leukemia (CML) cells overexpressing P-glycoprotein (P-gp). METHODS: Generation of resistant K562 cell line K562/Vp16 overexpressing P-gp was achieved by exposure of K562 cells to stepwise increase of concentrations of Vp16. A small set of side population (SP) with the characteristics of stem cells being capable of efflux fluorescent dye Hoechst 33342 in the cell line was isolated by flow cytometry. The mechanisms involved in K562/Vp16 SP cells resistant to imatinib were studied. RESULTS: The levels of BCR/ABL and ABL proteins in K562 cells were similar to those in K562/Vp16 non-SP and K562/Vp16 SP cells. The 170 KDa P-gp was detected in K562/Vp16 and K562/Vp16 SP cells at similar levels but not in K562 cells. Compared with K562/Vp16 non-SP cells, K562/Vp16 SP cells were more resistant to imatinib, which could hardly be reversed by many multidrug resistance inhibitors. In addition, in vivo study showed that the malignancy of K562/Vp16 cells was largely attributed to the SP cells. CONCLUSIONS: Bcr/Abl gene amplification and multidrug-resistant gene 1 (mdr1) overexpression might not be an important clinical mechanism in the diversity of resistance to imatinib treatment, and the development of drug resistance by leukemia cells may be at least partly due to a rare SP of tumor stem-like cells which drives leukemia occurrence and maintenance. These SP cells might be targeted for effective cancer therapy.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2006

Apoptosis: the suicide solution in cancer treatment and chemoprevention.

Cancer cells evade death by dysregulating the relevant apoptotic pathways, but they can be induced to die by both conventional chemotherapy and molecularly targeted agents; therefore, the development of drugs that selectively induce apoptosis in cancer cells is one of the most highly prioritised agendas in cancer treatment research. To completely eradicate cancer, it might be necessary to kill the cancer stem cells, which can self renew, proliferate and regenerate both primary and metastatic tumours. In this regard, there is encouraging evidence that apoptosis can be selectively induced in cancer stem cells and not in normal adult somatic stem cells. Finally, killing premalignant cells is a valid strategy for cancer chemoprevention and, indeed, it has been discovered that several cancer chemopreventive agents exert proapoptotic effects. Taken together, the concept of selectively inducing apoptosis in premalignant and malignant cells can have broad implications for cancer chemoprevention, treatment and perhaps even cure.

Animals↗

PubMed2005

Normal and neoplastic stem cells.

Stem cells are cells that at the single cell level both self-renew and give rise to differentiated progeny. Self renewal is the property that distinguishes stem cells and progenitors, and in the blood-forming system explains why haematopoietic stem cells (HSCs), not progenitors, are the only cells capable of providing rapid and sustained regeneration of the blood-forming system after ablation by cancer chemo- and radiotherapies. Cancer-free prospectively purified HSCs regenerate the haematopoietic system of patients as rapidly as a marrow or mobilized blood transplant, but without the risk of re-seeding the body with cancer cells. Further, purified allogeneic HSCs can establish donor-specific tolerance to subsequent tissue grafts. However, in contrast to widely-publicized reports of HSC plasticity, we have not been able to show transdifferentiation of HSC to muscle, heart, brain or gut, and conclude that rare cell fusions and incomplete purifications are likely explanations for the other published results. The ability to self-renew is also potentially dangerous, as poorly regulated self renewal is, we believe, a central lesion in all cancers. We have recently shown that myeloid leukaemias in mouse and human are often driven by rare leukaemia (cancer) stem cells which are at the progenitor stage of differentiation, but have activated the self-renewing cell division pathway normally used only by HSCs. Similar cancer stem cells have been isolated in other tumours.

Animals↗