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PubMed2005

A new role for p53 in maintaining genetic stability in embryonic stem cells.

Embryonic stem cells (ESCs) are capable of unlimited self-renewal and retain the pluripotency to differentiate into all cell lineages in the body. Since DNA damage occurs during normal cellular proliferation as well as after exposure to DNA damaging agents, it is critical for ESCs to possess stringent mechanisms to maintain genetic stability and prevent the passage of DNA damage to the progeny. Consistent with this notion, the rate of spontaneous mutation in ESCs is several magnitudes lower than that in somatic cells. Our recent findings indicate that tumor suppressor p53 plays an important role in maintaining genetic stability in ESCs by eliminating DNA-damaged ESCs from the replicative ESC pool. In this context, p53 induces the differentiation of DNA-damaged ESCs by directly suppressing the expression of Nanog, which is critical for the self-renewal of ESCs. This newly found role of p53 in cellular differentiation indicates an alternative mechanism for p53 to maintain genetic stability in ESCs and suggests the possibility that p53 might play a similar role in certain tissue stem cells and suppress the development of cancer stem cells.

Animals↗

PubMed2006

Molecular profiles of the mouse postnatal development of the esophageal epithelium showing delayed growth start.

Studies on molecular mechanisms of self-renewal in normal stem cells are required for understanding the cancer stem cell. Self-renewal in many kinds of normal stem cells might be accelerated in the growth of a young organism and in the repair of damaged tissue. This study examined whether the esophagus in growing neonates provides an experimental system for studies on epithelial stem cell renewal. The esophageal epithelium consists of 3 layers, from the luminal side to the bottom: the differentiated, epibasal and basal cell layers. The basal cell layer is known to contain the stem cells for the esophageal epithelium. This basic architecture is observed both in mice and humans. We investigated the basal cells in the mouse neonate by immunostaining with a basal cell marker, nerve growth factor receptor (Ngfr), and compared the basal cell content in the esophageal epithelium between mice and humans. A mouse esophageal epithelial cell primary culture system was developed for studies on the basal cell growth and keratinocyte differentiation, and microarray analysis was conducted for obtaining expression profiles of the basal cells. It was revealed that the growth of the esophageal epithelium begins from postnatal day 3, and that the timing is consistent with membrane localization of Ngfr in the basal cell. An increase in the basal cell number by Ngf treatment is observed in in vitro mouse esophageal epithelium cultures. Furthermore, mRNA overexpression of Pdgfrb encoding platelet derived growth factor receptor beta and Egfr encoding epidermal growth factor receptor is associated with the timing of the growth of the esophageal epithelium in the neonatal mice. This study provides a new experimental model for studies on the growth of the basal cells, which are considered to include the stem cells, and on the enlargement of the body size in young organisms.

Animals↗

PubMed2005

Prostate stem cells and prostate cancer.

Understanding prostate stem cells (PSCs) may provide insight for the design of therapeutics for prostate cancer. We have developed a quantitative in vivo colony-forming assay and have demonstrated that the Sca-1 antigen is present on the surface of a prostate cell subpopulation that possesses multiple stem cell properties. Immunofluorescent analysis demonstrates that Sca-1 is expressed by both basal and luminal cells in the proximal region of the adult prostate, but is not expressed by either lineage in more distal regions. The proximal region has been suggested as the PSC niche based on BrdU label-retention studies and the presence of distinct smooth-muscle cells that produce high levels of TGF-beta. Sca-1 is also expressed by nearly all cells within fetal prostate epithelial chords, suggesting Sca-1 may be conserved on PSCs throughout development. Malignant epithelial cells from TRAMP mice, as well as normal prostate cells with lentiviral-mediated alteration of the PTEN/AKT signaling pathway, give rise to PIN lesions and prostate cancer in vivo. Alteration of PTEN/AKT signaling in Sca-1-enriched PSCs also results in PIN lesions, suggesting that PSCs can serve as one target for prostate carcinogenesis.

Animals↗

PubMed2026

Overcoming cancer resistance in pancreatic cancer: toward dynamic precision oncology.

Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal malignancy, largely because of its profound and evolving therapeutic resistance. Resistance is not determined by a single molecular alteration but arises from interconnected mechanisms, including intrinsic resistance, treatment-induced adaptive resistance, acquired resistance, genomic evolution, clonal selection, cancer stemness, phenotypic plasticity, metabolic adaptation, and tumor microenvironment-mediated effects. Emerging therapeutic approaches targeting KRAS/RAS signaling, stromal and immune components, metabolic dependencies, and DNA damage repair pathways offer opportunities to address these mechanisms, although durable efficacy remains limited by biological heterogeneity and adaptive responses. In this review, we examine therapeutic resistance as an evolutionary and multidimensional process and summarize emerging strategies for overcoming resistance. We further propose a Dynamic Precision Oncology (DPO) framework that extends conventional precision oncology beyond baseline molecular profiling by integrating longitudinal assessment of tumor genomics, circulating tumor DNA, CA19-9, imaging, radiomics, and clinical characteristics. This framework emphasizes iterative detection and characterization of emerging resistance, mechanism-informed treatment adaptation, and subsequent reassessment rather than automatic treatment modification based on a single biomarker. DPO may provide a conceptual framework for integrating evolving tumor biology into treatment decision-making, while prospective studies are needed to validate biomarkers, define actionable thresholds, and determine whether longitudinal resistance-guided strategies improve clinical outcomes in PDAC.

Humans↗

PubMed2003

Cellular and molecular biology of the prostate: stem cell biology.

The normal prostate shows a high degree of cellular organization. The basal layer is populated by prostate epithelial stem cells and a population of transiently proliferating/amplifying (TP/A) cells intermediate to the stem cells and fully differentiated cells. The luminal layer is composed of fully differentiated prostate epithelial cells. Neuroendocrine cells are scattered throughout the gland. This organization is also seen in prostate cancer, where the tumor cell origin (cancer stem cells) can be traced to a normal cell type by characteristic keratin expression patterns. Basal cells showed strong expression of K-[keratin]5, but they were only weakly positive for K18. Luminal cells strongly expressed K18. A subpopulation of basal cells coexpressed K5 and K14. These keratin expression patterns changed with the degree of cell differentiation as well as location. The least differentiated stem cells in the basal layer were positive for K5 and K14, with weak expression for K18. Intermediate stages of differentiation were identified by expression of K5 and K18. Neuroendocrine cells also expressed K5 as well as typical neuroendocrine cell markers (eg, chromogranin A). Evidence supporting the hypothesis that prostate cancer arises from malignant transformation of intermediate stem cells included the presence in prostate cancers of keratin patterns associated with the intermediate stages of differentiation, androgen independence of both prostate cancers and intermediate stem cells, and expression of c-met by both the TP/A intermediate stem cells and tumor cells.

Adenocarcinoma↗

PubMed2004

A distinct "side population" of cells with high drug efflux capacity in human tumor cells.

A subset of stem cells, termed the "side population" (SP), has been identified in several tissues in mammalian species. These cells maintain a high efflux capability for antimitotic drugs. We have investigated whether functionally equivalent stem cells also may be detected in human cancers. We initially examined primary tumor cells from 23 patients with neuroblastoma and cell lines derived from a range of other tumors. A distinct SP was found in neuroblastoma cells from 15 of 23 patients (65%). The SP was capable of sustained expansion ex vivo and showed evidence for asymmetric division, generating both SP and non-SP progeny. These cells also expressed high levels of ABCG2 and ABCA3 transporter genes and had a greater capacity to expel cytotoxic drugs, such as mitoxantrone, resulting in better survival. A SP also was detected in breast cancer, lung cancer, and glioblastoma cell lines, suggesting that this phenotype defines a class of cancer stem cells with inherently high resistance to chemotherapeutic agents that should be targeted during the treatment of malignant disease.

ATP-Binding Cassette Transporters↗

PubMed2005

Molecular insights into the function, fate, and prospects of stem cells.

This article forms a review and an appraisal of the third annual meeting of the International Society for Stem Cell Research (http://www.isscr.org), held in San Francisco on June 23-25, 2005. The focus of the meeting was recent advances in stem cell biology. More than 2,000 scientists from around the world met to discuss stem cell research, clinical applications, and the ethical hurdles facing the field. Major topics highlighted during the meeting included the self-renewal and differentiation of embryonic stem cells as well as adult stem cells. Presentations included diverse topics such as cancer stem cells, tissue-specific stem cells, technology development, and clinical aspects of stem cells. Given the excitement the field has generated, linking basic stem cell research and clinical applications was paramount for discussion at the meeting. With the current resources in molecular biology research, improvements in genetic engineering, postgenomic capabilities, and biotechnological advances, it appears timely that stem cell biology research is headed toward making a major therapeutic contribution to human health.

Adult↗

PubMed2006

Brain tumor stem cells.

Cancers are composed of heterogeneous cell populations ranging from highly proliferative immature cells to more differentiated cells of various cell lineages. Recent advances in stem cell research have allowed for the demonstration of the existence of cancer stem cells in acute myeloid leukemia, breast cancer, and, most recently, in brain tumors. Each of these has some similarities with the normal stem cells in the corresponding organs. In brain tumors, putative cancer stem cells have been identified from glioblastoma multiforme, medulloblastoma and ependymoma. These tumor-derived cells self-renew under clonal conditions, and differentiate into neuron- and glia-like cells as well as into abnormal cells with mixed phenotypes. The tumor stem cells, but not the rest of tumor cells form secondary tumors by transplantation into immunodeficient mouse brain. In this review, we discuss the cellular and molecular relationships between brain tumor stem cells and normal neural stem cells, and also the possible clinical implications of brain tumor stem cells.

Brain Neoplasms↗

PubMed2003

[Hematopoietic stem cell transplant in cancer treatment].

Hematopoietic stem cell transplantation (HSCT) includes bone marrow, peripheral blood, cord blood, autologous, allogeneic, related or unrelated. These transplants have two main roles in cancer treatment, i.e., supportive treatment for marrow toxicity and immunotherapy for cancer cells. HSCT has also severe adverse reaction such as, bacterial fungal or viral infection by neutropenia, or graft versus host disease by the replacement of immune system. In autologous HSCT the main role is to prevent severe marrow toxicity which enables extreme high dose of anticancer drug administration. In allogeneic HSCT the main roles become both, support for marrow toxicity and immunotherapy, which possibly complicated with immunological adverse reactions. In mini-transplant or allogeneic transplant with reduced intensity, the main role is immunotherapy. These three kinds of transplants have each own indication and conducted in 17,472 patients till 2001 in Japan.

Hematopoietic Stem Cell Transplantation↗

PubMed2006

Stem cells signal to the niche through the Notch pathway in the Drosophila ovary.

Stem cells are maintained and retain their capacity to continue dividing because of the influence of a niche. Although niches are important to maintain "stemness" in a wide variety of tissues, control of these niches is poorly understood. The Drosophila germline stem cells (GSCs) reside in a somatic cell niche. We show that Notch activation can induce the expression of niche-cell markers even in an adult fly; overexpression of Delta in the germline, or activated Notch in the somatic cells, results in extra niche cells, up to 10-fold over the normal number. In turn, these ectopic niche cells induce ectopic GSCs. Conversely, when GCSs do not produce functional Notch ligands, Delta and Serrate, the TGF-beta pathway is not activated in the GSCs, and they differentiate and subsequently leave the niche. Importantly, clonal analysis reveals that the receiving end of the Notch pathway is required in the somatic cells. These data show that a feedback loop exists between the stem cells and niche cells. Demonstration that stem cells can contribute to niche function has far-reaching consequences for stem cell therapies and may provide insight into how cancer can spread throughout an organism via populations of cancer stem cells.

Animals↗

PubMed2006

Tetraploidy/aneuploidy and stem cells in cancer promotion: The role of chromosome passenger proteins.

While polyploidy, a state of having fully duplicated sets of chromosomes per cell, has been described in normally developing bone marrow megakaryocytes or as an adaptive response in other cell types, aneuploidy is never detected in normal cells. Tetraploidy or aneuploidy can be induced by several signals and it is highly prevalent in different forms of cancers, suggesting a role for this cell cycle state in promoting cellular transformation. Investigations suggested that loss of heterozygosity of cancer-related genes in stem cells might contribute to genetic instability in progeny cells and to subsequent cancer development. Deregulated expression of chromosome passenger proteins, such as Aurora kinases or Survivin, is a hallmark of various cancers, and experimentally induced changes in these regulators can promote tetraploidy or aneuploidy and loss of heterozygosity. Our studies described an induction of tetraploidy/aneuploidy by a stable form of Aurora-B, leading to acquisition of transformation properties. It is intriguing to speculate that in some cancers, tetraploidy/aneuploidy induced by deregulated expression of a mitotic regulator represents a primary event that leads to unbalanced expression of a cluster of crucial genes and to cellular transformation.

Aneuploidy↗

PubMed2004

Adult human mesenchymal stem cell as a target for neoplastic transformation.

The neoplastic process may involve a cancer stem cell. This concept has emerged largely from the careful analysis of tumour biopsy systems from haematological, breast and brain tumours. However, the experimental systems necessary to provide the cellular and molecular evidence to support this important concept have been lacking. We have used adult mesenchymal stem cells (hMSC) transduced with the telomerase hTERT gene to investigate the neoplastic potential of adult stem cells. The hTERT-transduced line, hMSC-TERT20 at population doubling level (PDL) 256 showed loss of contact inhibition, anchorage independence and formed tumours in 10/10 mice. hMSC-TERT4 showed loss of contact inhibition at PDL 95, but did not exhibit anchorage independence and did not form tumours in mice. Both lines had a normal karyotype but showed deletion of the Ink4a/ARF locus. At later passage, hMSC-TERT4 also acquired an activating mutation in KRAS. In hMSC-TERT20, expression of the cell cycle-associated gene, DBCCR1 was lost due to promoter hypermethylation. This epigenetic event correlated with acquisition of tumorigenicity. These data suggest that the adult hMSCs can be targets for neoplastic transformation and have implications for the development of novel anticancer therapeutics and for the use of hMSC in tissue engineering and transplantation protocols.

Adult↗

PubMed1994

Trends and differentials in mortality from cancers of the oral cavity and pharynx in the United States, 1973-1987.

BACKGROUND: This analysis consisted of an examination of trends and differentials in mortality from cancers of the oral cavity and pharynx in the United States for a recent 15-year period. METHODS: The authors have used national cause-of-death data for the United States and intercensal population estimates to examine mortality from oral and pharyngeal cancers between 1973 and 1987 and to study differentials according to gender, race, and region of residence. RESULTS: The overall mortality rate from these cancers decreased by 19% during the 15-year period, with most of the decline occurring after 1979. Mortality was much higher for men than for women and for blacks than for whites throughout the interval. Despite the overall decline, mortality rates increased among blacks, especially among black men. Mortality was highest in the South Atlantic, New England, and Mid-Atlantic states and lowest in the Mountain states. CONCLUSIONS: The disparity between male and female mortality from oral and pharyngeal cancer stems mainly from differences in the likelihood of developing these cancers, whereas the differences between blacks and whites appears to arise more from differences in survival than in incidence. Different age patterns of mortality for blacks and whites exist, in which mortality among whites, but not among blacks, rises continuously with age. An unexplained finding was that mortality rates were reported to have fallen in recent years, whereas incidence and survival rates have reportedly remained almost unchanged. This apparent inconsistency may have resulted from declines in the incidence of oral and pharyngeal cancers that have been masked by improved detection.

Adolescent↗

PubMed2006

Stem cell homing.

PURPOSE OF REVIEW: Transplantation of hematopoietic stem cells is dependent upon the successful homing, engraftment and repopulation of stem cells in the bone marrow. Stem cell homing through the circulation to the bone marrow is the critical first step in this process. This review discusses the latest progress in defining the molecular processes underlying stem cell homing and the specialized niches where stem cells reside. RECENT FINDINGS: Over the past decade, remarkable advances have been made in characterizing the complex sequence of events involved in stem cell homing to the bone marrow. Specifically, the molecular basis of stem cell adhesion and rolling along bone marrow sinusoidal endothelial cells has been defined, and mechanisms underlying endothelial transmigration and enlodgement in bone marrow niches have now been identified. The processes governing hematopoietic stem cell homing to the bone marrow also regulate hematopoietic stem cell migration to extramedullary tissues and the metastasis of cancer stem cells. Improved understanding of these processes has catalyzed the development of therapies to facilitate stem cell mobilization for clinical purposes. SUMMARY: Several components of the essential process of stem cell homing have now been characterized. Cell adhesion molecules and their ligands, extracellular matrix components, chemokines, and specialized bone marrow niches all participate in the precise regulation of this process.

Animals↗

PubMed2006

First among equals: the cancer cell hierarchy.

Primary cancer cells exhibit heterogeneity in their proliferative ability. The cancer stem cell (CSC) model accounts for this heterogeneity by proposing that each cancer consists of a small population of CSCs that are capable of unlimited growth and self-renewal and a much larger population of cells, descendants of the CSCs, that have lost self-renewal capacity. The CSC model has important implications for cancer therapy. Eradication of CSCs, the cells responsible for maintenance of the neoplasm, would be necessary and sufficient to achieve cure. By extension, both the frequency of stem cells in a tumor and their propensity to undergo self-renewal (Psr) would have a direct impact on the curability of that tumor. The Psr is a critical biological characteristic of CSCs-small differences in Psr have enormous impact on the probability of success in cancer therapy. Differentiation therapy, defined as treatment that reduces the Psr of CSCs, is one approach to targeting CSCs.

Animals↗

PubMed2006

PU.1 and Junb: suppressing the formation of acute myeloid leukemia stem cells.

Improved understanding of the molecular pathways that suppress the genesis and maintenance of cancer stem cells will facilitate development of rationally targeted therapies. PU.1 is a transcription factor that is required for normal myelomonocytic differentiation in hematopoiesis, and reduced PU.1 activity has been associated with myeloid leukemogenesis in man and in mouse models. A recent study by Steidl et al. demonstrates that Junb and Jun, two AP-1 transcription factors, are critical downstream effectors of the tumor suppressor activity of PU.1, and that reduced expression of Junb, in particular, may be a common feature of acute myeloid leukemogenesis.

Animals↗

PubMed1993

Cellular origin of cancer: dedifferentiation or stem cell maturation arrest?

Given the fundamental principle that cancer must arise from a cell that has the potential to divide, two major nonexclusive hypotheses of the cellular origin of cancer are that malignancy arises a) from stem cells due to maturation arrest or b) from dedifferentiation of mature cells that retain the ability to proliferate. The role of stem cells in carcinogenesis is clearly demonstrated in teratocarcinomas. The malignant stem cells of teratocarcinomas are derived from normal multipotent stem cells and have the potential to differentiate into normal benign mature tissue. A widely studied model supporting dedifferentiation has been the putative origin of hepatocarcinomas from "premalignant" foci and nodules induced in the rat liver by chemicals. However, the dedifferentiation concept for hepatocarcinogenesis is challenged by more recent interpretations indicating that hepatocellular carcinoma arises from maturation arrest caused by aberrant differentiation of determined stem cells. Either hypothesis is supported by the cellular changes that occur in the rodent liver after different hepatocarcinogenic regimens. The formation of foci and nodules from altered hepatocytes supports dedifferentiation; the proliferation of small oval cells with the potential to differentiate into either biliary ducts or hepatocytes supports arrested maturation of determined stem cells. It is now postulated that foci and nodular change reflect adaptive changes to the toxic effects of carcinogens and not "preneoplastic" stages to cancer. The stem cell model predicts that genotoxic chemicals induce mutations in the determined stem cell which may be expressed in its progeny. Proliferation of initiated cells is induced by promoting events which also allow additional mutations to occur.

Animals↗

PubMed2006

Stem cell markers: ABCG2 and MCM2 expression in retinoblastoma.

BACKGROUND/AIM: The authors studied the expression of cancer stem cell surface marker, ABCG2, and neural stem cell marker, MCM2, in retinoblastoma and correlated clinicopathologically. METHODS: Among 39 retinoblastomas, 18 tumours were not subjected to preoperative/postoperative chemotherapy, 15 tumours underwent postoperative chemotherapy, and six tumours had preoperative chemotherapy. There were 20 tumours with no invasion and 19 tumours with invasion of choroid/optic nerve. ABCG2 and MCM2 expression was studied by immunohistochemistry. RESULTS: ABCG2 was positive in six of six and MCM2 was positive in five of six tumours that had recurred in the orbit or metastasised. ABCG2 was positive in 15/19 tumours with invasion. MCM2 was positive in 16/19 tumours with invasion. Invasive tumours showed higher expression of ABCG2 (p < 0.01) and MCM2 (p < 0.01) proteins. There was no correlation with differentiation and laterality of the tumours. Non-neoplastic retina was positive for ABCG2 and MCM2. CONCLUSION: ABCG2 and MCM2 were expressed more in invasive tumours. Further studies are needed to understand the significance of ABCG2 and MCM2 expression in retinoblastoma.

ATP Binding Cassette Transporter, Subfamily G, Mem↗