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PubMed2004

From stem cells to cancer: balancing immortality and neoplasia.

In this issue of Oncogene, Serakinci et al show that adult stem cells can be targets for neoplastic transformation. After transducing human adult mesenchymal stem cells (hMSC) with the telomerase hTERT gene, and growing them for many population doublings in culture, Serakinci et al observed that the transduced cells developed characteristics consistent with transformation including loss of contact inhibition, anchorage independence and tumour formation in mice. Underlying these changes were alterations to genes involved in cell cycle regulation and senescence as well as oncogene activation. The importance of these observations is twofold. Firstly, showing that stem cells can become tumours raises a note of caution for stem cell therapeutics. Secondly, the findings lend support to the stem cell hypothesis of cancer development, and provide an experimental system in which the tantalizing hint of new diagnostic, prognostic, and therapeutic opportunities offered by this concept can be explored further.

Adult↗
PubMed2005

Preparation and characterization of monoclonal antibodies against nucleostemin, a protein that controls cell proliferation in stem cells and cancer cells.

Nucleostemin (NS) is a novel protein that promotes the proliferation of stem cells and cancer cells. The aim of this study is to prepare specific monoclonal antibodies against nucleostemin as a tool in nucleostemin research. To generate the antibodies, the cDNA coding nucleostemin was cloned from human gastric cancer cell line NCI-N87 with reverse transcriptase-polymerase chain reaction (RT-PCR). The partial cDNA fragment was inserted into prokaryotic expression vector pGEX-4T1 to make glutathione S-transferase (GST) fusion protein in Escherichia coli, and the whole-length cDNA fragment was cloned into vector pcDNA3 for expression in mammalian cells. The spleen cells, from the BALB/c mouse immunized with the GST-nucleostemin fusion protein, were used to prepare the monoclonal antibody with hybridoma technique. After screening with enzyme-linked immunosorbent assay (ELISA) and subcloning, six specific monoclonal antibodies against nucleostemin were obtained. Moreover, they also worked well in Western blotting, immunoprecipitation, and immunohistochemistry. These antibodies will be helpful in elucidating biological functions and the molecular mechanism of nucleostemin.

Animals↗
PubMed2004

Stem cell origin of cancer and differentiation therapy.

Our forefathers in pathology, on observing cancer tissue under the microscope in the mid-19th century, noticed the similarity between embryonic tissue and cancer, and suggested that tumors arise from embryo-like cells [Recherches dur le Traitement du Cancer, etc. Paris. (1829); Editoral Archiv fuer pathologische Anatomie und Physiologie und fuer klinische Medizin 8 (1855) 23]. The concept that adult tissues contain embryonic remnants that generally lie dormant, but that could be activated to become cancer was later formalized by Cohnheim [Path. Anat. Physiol. Klin. Med. 40 (1867) 1-79; Virchows Arch. 65 (1875) 64] and Durante [Arch. Memori ed Osservazioni di Chirugia Practica 11 (1874) 217-226], as the "embryonal rest" theory of cancer. An updated version of the embryonal rest theory of cancer is that cancers arise from tissue stem cells in adults. Analysis of the cellular origin of carcinomas of different organs indicates that there is, in each instance, a determined stem cell required for normal tissue renewal that is the most likely cell of origin of carcinomas [Lab. Investig. 70 (1994) 6-22]. In the present review, the nature of normal stem cells (embryonal, germinal and somatic) is presented and their relationships to cancer are further expanded. Cell signaling pathways shared by embryonic cells and cancer cells suggest a possible link between embryonic cells and cancer cells. Wilm's tumors (nephroblastomas) and neuroblastomas are presented as possible tumors of embryonic rests in children. Teratocarcinoma is used as the classic example of the totipotent cancer stem cell which can be influenced by its environment to differentiate into a mature adult cell. The observation that "promotion" of an epidermal cancer may be accomplished months or even years after the initial exposure to carcinogen ("initiation"), implies that the original carcinogenic event occurs in a long-lived epithelial stem cell population. The cellular events during hepatocarcinogenesis illustrate that cancers may arise from cells at various stages of differentiation in the hepatocyte lineage. Examples of genetic mutations in epithelial and hematopoietic cancers show how specific alterations in gene expression may be manifested as maturation arrest of a cell lineage at a specific stage of differentiation. Understanding the signals that control normal development may eventually lead us to insights in treating cancer by inducing its differentiation (differentiation therapy). Retinoid acid (RA) induced differentiation therapy has acquired a therapeutic niche in treatment of acute promyelocytic leukemia and the ability of RA to prevent cancer is currently under examination.

Antineoplastic Agents↗
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

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↗
PubMed2004

A molecular view of stem cell and cancer cell self-renewal.

With the recent advances in cell biology and molecular genetics, scientists were able to isolate and culture tissue-specific stem cells from various sources and define their properties. The challenge has now shifted to understanding the genetic programs controlling the stem cell state, i.e. self-renewal and multipotential. Cracking the molecular codes that govern the stem cell state turns out to be a difficult task. This is in part because a single gene may exhibit distinct activities when expressed in different cell types. Comprehending the cell-context dependent readout of any given gene requires an integrated knowledge of the complex cellular machinery, a platform which can be provided by the research on stem cells. This review is an attempt to formulate a model for the self-renewal machinery operating in stem cells and cancer cells. Insight into this issue at the molecular and cellular levels will no doubt facilitate the realization of the stem cell potential in both regenerative medicine and anticancer therapy.

Cell Culture Techniques↗
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

Gene expression profiles of AML derived stem cells; similarity to hematopoietic stem cells.

Tumors contain a fraction of cancer stem cells that maintain the propagation of the disease. The CD34(+)CD38(-) cells, isolated from acute myeloid leukemia (AML), were shown to be enriched leukemic stem cells (LSC). We isolated the CD34(+)CD38(-) cell fraction from AML and compared their gene expression profiles to the CD34(+)CD38(+) cell fraction, using microarrays. We found 409 genes that were at least twofold over- or underexpressed between the two cell populations. These include underexpression of DNA repair, signal transduction and cell cycle genes, consistent with the relative quiescence of stem cells, and chromosomal aberrations and mutations of leukemic cells. Comparison of the LSC expression data to that of normal hematopoietic stem cells (HSC) revealed that 34% of the modulated genes are shared by both LSC and HSC, supporting the suggestion that the LSC originated within the HSC progenitors. We focused on the Notch pathway since Jagged-2, a Notch ligand was found to be overexpressed in the LSC samples. We show that DAPT, an inhibitor of gamma-secretase, a protease that is involved in Jagged and Notch signaling, inhibits LSC growth in colony formation assays. Identification of additional genes that regulate LSC self-renewal may provide new targets for therapy.

Cell Cycle↗
PubMed1996

Detection of cancer cells in peripheral blood stem cells of women with breast cancer by RT-PCR and cell culture.

The benefit of high-dose therapy and blood stem cell reinfusion for women with high-risk breast cancer is currently under investigation. Contaminations of autologous blood stem cells with cancer cells have been described. Cancer micrometastases may be detected by immunocytochemistry, culture techniques and cytokeratin-19 mRNA reverse transcriptase PCR. Women with breast cancer received adjuvant HD-CTM with peripheral blood stem cell (PBSC) support after surgical therapy and 4 cycles conventional chemotherapy. Peripheral blood stem cells were mobilised by G-CsF and harvested after the third or fourth cycle of standard therapy. Aliquots of PBSC-collections (10(7)-2*10(7) cells) were subjected to CK19-mRNA reverse transcriptase PCR. RNA was extracted by standard methods and reverse transcription was performed with MMV-RT. Integrity of RNA was checked by coamplification of housekeeping sequences. Aliquots of the RT-mix were subjected to PCR-amplification with outer and inner primer pairs, subsequently. A second aliquot of 2*10(7) cells was cultured over 42 days in liquid culture. Cytospins were prepared weekly from cultured cells and evaluated by light microscopy with or without prior immunocytochemistry. Ten leukaphereses from 6 women were available for PCR-analysis and cell culture. Six leukaphereses were negative for CK19-mRNA and for detection of cancer cells by culture technique, two samples were positive for CK19-mRNA and culturally enriched cells and two samples were positive for CK19-mRNA and negative for cultured cancer cells. No sample was positive for cultured cells and negative for CK19-mRNA. Overall, the results corresponded in 80%. Two sensitive techniques for the detection of cancer micrometastases were applied to aliquots from 10 leukaphereses of six breast cancer patients with corresponding results in 80%. PCR-mediated detection of cancer cells was confirmed by culture technique and light microscopy, however, further comparison of CK19-PCR with standard techniques like cell culture and immunocytochemistry is still necessary.

Breast Neoplasms↗
PubMed2005

Tumour stem cells and drug resistance.

The contribution of tumorigenic stem cells to haematopoietic cancers has been established for some time, and cells possessing stem-cell properties have been described in several solid tumours. Although chemotherapy kills most cells in a tumour, it is believed to leave tumour stem cells behind, which might be an important mechanism of resistance. For example, the ATP-binding cassette (ABC) drug transporters have been shown to protect cancer stem cells from chemotherapeutic agents. Gaining a better insight into the mechanisms of stem-cell resistance to chemotherapy might therefore lead to new therapeutic targets and better anticancer strategies.

ATP-Binding Cassette Transporters↗
PubMed2004

Fetal human neural progenitors can be the target for tumor transformation.

The hypothesis that stem cells may seed cancer has emerged from the cancer stem cells concept. However, the experimental systems necessary to provide more direct evidence to support the hypothesis have been lacking. We have used fetal neural progenitor cells (hNPC) transduced with the telomerase hTERT gene to investigate the neoplastic potential of hNPCs. The hTERT-transduced line, hNPCs-G3 lost normal diploid karyotype, showed loss of contact inhibition, anchorage independence, and formed neuroblastoma-like tumours in all of 10 mice. These data suggest that hNPCs have the potential for neoplastic transformation. These data have implications for providing a novel tool to test the feasibility of new anticancer treatment strategies and raise the possibility of a risk for the use of hNPCs in cell transplantation.

Animals↗
PubMed2005

Homeobox gene expression in cancer: insights from developmental regulation and deregulation.

Homeobox genes encode transcription factors that play essential roles in controlling cell growth and differentiation during embryonic development. Many homeobox genes are aberrantly expressed in a wide variety of solid tumours, and their deregulation appears to enhance cell survival and proliferation and to inhibit differentiation. In hematologic malignancies, deregulated homeobox genes profoundly perturb self-renewal and proliferation of hematopoietic stem cells and progenitors. It is increasingly recognised that solid tumours, like hematologic malignancies, could arise from cancer stem cells, and that targeting these cells could be the most effective means of inhibiting tumour progression and disease recurrence. Studying the biological effects and mechanisms of homeobox genes in cancers could provide valuable insights into identifying cancer stem cells and targeting the self-renewal pathways in these cell populations.

Cell Transformation, Neoplastic↗
PubMed2004

Comprehensive genomics linking between neural development and cancer: neuroblastoma as a model.

Cancer cells are derived from their precursor cells, which normally develop to the matured cells to form individual organs. Neuroblastoma, one of the most common pediatric solid tumors, originates from possible cancer stem cells derived from the neural crest. During the development, neural crest cells segregate into several lineages such as sensory, enteric and sympathetic neurons. However, the genetic events to cause neuroblastoma occur only in the sympathetic precursor cells or cancer stem cells. Furthermore, spontaneous regression of a subset of neuroblastoma found in patients under one year of age mimics a developmentally programmed neuronal cell death that occurs in normal sympathetic neurons during the perinatal period. Thus, the genetic events to cause neuroblastoma may be programmed to occur in a lineage-specific as well as developmentally regulated manner. In this review, we discuss about the molecular link between neural development and the genesis of neuroblastoma based on our comprehensive genomics approach.

Animals↗
PubMed2004

Stem cells and cancer; the polycomb connection.

Proteins from the Polycomb group (PcG) are epigenetic chromatin modifiers involved in cancer development and also in the maintenance of embryonic and adult stem cells. The therapeutic potential of stem cells and the growing conviction that tumors contain stem cells highlights the importance of understanding the extrinsic and intrinsic circuitry controlling stem cell fate and their connections to cancer.

Animals↗
PubMed2006

Targeting stem cells in brain tumors.

Stem cells are commonly defined as undifferentiated cells capable of self-renewing and giving rise to a large number of differentiated progeny. It is becoming increasingly apparent that there exist cancer stem cells (CSCs) from which the cells of any given malignancy arise, whereby only a few cells out of a population of cancer cells are able to initiate tumor formation. These CSCs, like their normal counterparts, are characterized by self-renewal and the ability to "differentiate" into all of the cell types in the original tumor. Current chemotherapeutic strategies involve using non-specific cytotoxic agents that target rapidly cycling cells. Although this may reduce disease burden in many cases, these therapies may miss the rare, self-renewing population that truly gives rise to the malignancy (the CSC). This review will focus on the recent discovery of stem cell-like cells in human brain tumors, putative "brain cancer stem cells," which exhibit the properties of self-renewal and the ability to recapitulate the original tumor heterogeneity. Dissecting the molecular mechanisms that underlie the ability of these cells to self-renew and maintain quiescence may allow the development of novel therapeutic strategies that will allow for more efficacious and less toxic therapies for these devastating malignancies.

Animals↗
PubMed2005

Accumulated chromosomal instability in murine bone marrow mesenchymal stem cells leads to malignant transformation.

Despite recent emerging evidence suggesting that cancer stem cells subsist in a variety of tumors, it is not yet fully elucidated whether postnatal stem cells are directly involved in tumorigenesis. We used murine bone marrow-derived mesenchymal stem cells (BMMSCs) as a model to test a hypothesis that tumorigenesis may originate from spontaneous mutation of stem cells. In this study, we demonstrated that murine BMMSCs, after numerous passages, obtained unlimited population doublings and proceeded to a malignant transformation state, resulting in fibrosarcoma formation in vivo. Transformed BMMSCs colonized to multiple organs when delivered systemically through the tail vein. Fibrosarcoma cells formed by transformed BMMSCs contained cancer progenitors, which were capable of generating colony clusters in vitro and fibrosarcoma in vivo by the second administration. The mechanism by which BMMSCs transformed to malignant cells was associated with accumulated chromosomal abnormalities, gradual elevation in telomerase activity, and increased c-myc expression. Moreover, BMMSCs and their transformed counterpart, fibrosarcoma-forming cells, demonstrated different sensitivity to anti-cancer drugs. BMMSCs/fibrosarcoma transformation system may provide an ideal system to elucidate the mechanism of how stem cells become cancer cells and to screen anti-sarcoma drugs.

Animals↗
PubMed2005

Treating cancer with embryonic stem cells: rationale comes from aging studies.

In an earlier poster paper (1) we proposed that cancer can be viewed not only as a fatal disease but also as a local aberrant, rejuvenation, in an organism, and this fact can be useful for developing new anti-aging and anti-cancer treatments. In this paper we provide additional evidence from human and experimental animal studies in support of this view. First, we discuss cancer genes as candidate targets for anti-aging interventions. We review examples in which the life of experimental animals has been prolonged in situations of increased activity of proto-oncogenes - or decreased activity of tumor suppressors - in normal (non-cancerous) cells in vivo. Studies of genetic polymorphisms revealed similar effects on longevity in humans. Second, we discuss the possibility of treating cancer with embryonic stem cells. The fact that cancer cells do not, age, means that these cells overcome aging host cells. However, cancer cells can be suppressed by young and quickly proliferating non-cancer cells, such as embryonic stem cells. The grafting of these cells in the tumor environment could be a prospective non-toxic anti-cancer treatment. We discuss recent evidence in support of this view.

Animals↗