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PubMed2006

Cancer stem cells: redefining the paradigm of cancer treatment strategies.

Cancer has been known to arise from long-lived cells in the body and to possess properties in common with undifferentiated, embryonic cells. Recent findings of a population of cells in solid tumors resembling stem cells supports a stem cell model of cancer. A scheme in which all cancers initiate from "activated' stem cells helps bring together data from genetic, cell biology, and epidemiology studies. Cancer can arise from embryonic cells in the case of childhood tumors; hormone-activated stem cells in the case of breast cancer; and following chronic activation of stem cells caused by tissue damage. This scheme helps explain the failure of many cancer therapies, points out deficiencies in certain research approaches, and focuses the problem on a subset of cells that can be explicitly targeted, leading to more efficient therapy.

Animals↗

PubMed2006

Mathematical model for the cancer stem cell hypothesis.

Recent research on the origin of brain cancer has implicated a subpopulation of self-renewing brain cancer stem cells for malignant tumour growth. Various genes that regulate self-renewal in normal stem cells are also found in cancer stem cells. This implies that cancers can occur because of mutations in normal stem cells and early progenitor cells. A predictive mathematical model based on the cell compartment method is presented here to pose and validate non-intuitive scenarios proposed through the neural cancer stem cell hypothesis. The growths of abnormal (stem and early progenitor) cells from their normal counterparts are ascribed with separate mutation probabilities. Stem cell mutations are found to be more significant for the development of cancer than a similar mutation in the early progenitor cells. The model also predicts that, as previously hypothesized, repeated insult to mature cells increases the formation of abnormal progeny, and hence the risk of cancer.

Animals↗

PubMed2006

HEDGEHOG-GLI1 signaling regulates human glioma growth, cancer stem cell self-renewal, and tumorigenicity.

Cancer stem cells are rare tumor cells characterized by their ability to self-renew and to induce tumorigenesis. They are present in gliomas and may be responsible for the lethality of these incurable brain tumors. In the most aggressive and invasive type, glioblastoma multiforme (GBM), an average of about one year spans the period between detection and death [1]. The resistence of gliomas to current therapies may be related to the existence of cancer stem cells [2-6]. We find that human gliomas display a stemness signature and demonstrate that HEDGEHOG (HH)-GLI signaling regulates the expression of stemness genes in and the self-renewal of CD133(+) glioma cancer stem cells. HH-GLI signaling is also required for sustained glioma growth and survival. It displays additive and synergistic effects with temozolomide (TMZ), the current chemotherapeutic agent of choice. TMZ, however, does not block glioma stem cell self-renewal. Finally, interference of HH-GLI signaling with cyclopamine or through lentiviral-mediated silencing demonstrates that the tumorigenicity of human gliomas in mice requires an active pathway. Our results reveal the essential role of HH-GLI signaling in controlling the behavior of human glioma cancer stem cells and offer new therapeutic possibilities.

Animals↗

PubMed2006

Implications of cancer stem cells in the treatment of cancer.

Identification of cancer stem cells (CSCs) in both hematological and solid malignancies suggests that CSCs may be a common phenomenon for most malignancies. Similarly to normal stem cells, CSCs can self-renew and differentiate into progeny cancer cells. Almost all current therapy against cancer targets differentiated cancer cells. CSCs are more resistant to therapy secondary to quiescence, increased expression of antiapoptotic proteins and drug efflux transporters. In this article, we review the current status of CSC research and propose the targeting of CSC cell-surface molecules, signal transduction pathways, the stem cell niche, stem cell differentiation and drug resistance.

Antineoplastic Agents↗

PubMed2004

[Cancer stem cells in pediatric brain tumors].

Cancers are formed by heterogeneous cell types from immature highly proliferative cells to lineage-committed differentiated cells. Transplantation studies have suggested the existence of "cancer stem cells", individual cells capable of producing an entire tumor. 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 pediatric brain tumors. Each of these has some similarities with the normal stem cells in the corresponding organs. For example, leukemia stem cells express some, but not all, markers of hematopoietic stem cells. Regarding pediatric brain tumors, putative cancer stem cells were identified from medulloblastoma and also from glioma. These tumor-derived cells self-renew under clonal conditions, and differentiate into neurons and glia as well as into abnormal cells with mixed phenotypes. Interestingly, the tumor stem/progenitors, enriched in culture, maintained proliferation after 4 weeks from transplantation into neonatal rat brain. In this review, we discuss the difference as well as the similarity between tumor and normal stem cells, and also the possible clinical implication of cancer stem cells.

Animals↗

PubMed2006

[Progress of cancer stem cells of solid tumor].

Stem cells have some characteristics similar to tumor cells, and may be the origin of tumor cells. Stem cell-like subpopulation has been isolated and identified from hematopoietic system malignancies and solid tumors, and defined as cancer stem cells. Cancer stem cells play important roles in the initiation and progression of malignancies. Tumor might be a kind of diseases of stem cells, and this finding may help to understand the mechanisms of tumorigenesis and instruct clinical therapeutics.

AC133 Antigen↗

PubMed2005

Prospective identification of tumorigenic prostate cancer stem cells.

Existing therapies for prostate cancer eradicates the bulk of cells within a tumor. However, most patients go on to develop androgen-independent disease that remains incurable by current treatment strategies. There is now increasing evidence in some malignancies that the tumor cells are organized as a hierarchy originating from rare stem cells that are responsible for maintaining the tumor. We report here the identification and characterization of a cancer stem cell population from human prostate tumors, which possess a significant capacity for self-renewal. These cells are also able to regenerate the phenotypically mixed populations of nonclonogenic cells, which express differentiated cell products, such as androgen receptor and prostatic acid phosphatase. The cancer stem cells have a CD44+/alpha2beta1hi/CD133+ phenotype, and we have exploited these markers to isolate cells from a series of prostate tumors with differing Gleason grade and metastatic states. Approximately 0.1% of cells in any tumor expressed this phenotype, and there was no correlation between the number of CD44+/alpha2beta1hi/CD133+ cells and tumor grade. The identification of a prostate cancer stem cell provides a powerful tool to investigate the tumorigenic process and to develop therapies targeted to the stem cell.

AC133 Antigen↗

PubMed2006

Analysis of gene expression and chemoresistance of CD133+ cancer stem cells in glioblastoma.

BACKGROUND: Recently, a small population of cancer stem cells in adult and pediatric brain tumors has been identified. Some evidence has suggested that CD133 is a marker for a subset of leukemia and glioblastoma cancer stem cells. Especially, CD133 positive cells isolated from human glioblastoma may initiate tumors and represent novel targets for therapeutics. The gene expression and the drug resistance property of CD133 positive cancer stem cells, however, are still unknown. RESULTS: In this study, by FACS analysis we determined the percentage of CD133 positive cells in three primary cultured cell lines established from glioblastoma patients 10.2%, 69.7% and 27.5%, respectively. We also determined the average mRNA levels of markers associated with neural precursors. For example, CD90, CD44, CXCR4, Nestin, Msi1 and MELK mRNA on CD133 positive cells increased to 15.6, 5.7, 337.8, 21.4, 84 and 1351 times, respectively, compared to autologous CD133 negative cells derived from cell line No. 66. Additionally, CD133 positive cells express higher levels of BCRP1 and MGMT mRNA, as well as higher mRNA levels of genes that inhibit apoptosis. Furthermore, CD133 positive cells were significantly resistant to chemotherapeutic agents including temozolomide, carboplatin, paclitaxel (Taxol) and etoposide (VP16) compared to autologous CD133 negative cells. Finally, CD133 expression was significantly higher in recurrent GBM tissue obtained from five patients as compared to their respective newly diagnosed tumors. CONCLUSION: Our study for the first time provided evidence that CD133 positive cancer stem cells display strong capability on tumor's resistance to chemotherapy. This resistance is probably contributed by the CD133 positive cell with higher expression of on BCRP1 and MGMT, as well as the anti-apoptosis protein and inhibitors of apoptosis protein families. Future treatment should target this small population of CD133 positive cancer stem cells in tumors to improve the survival of brain tumor patients.

AC133 Antigen↗

PubMed2006

Killing time for cancer stem cells (CSC): discovery and development of selective CSC inhibitors.

Can cancer be cured or will it have to be controlled as a chronic disease? Despite a better understanding of the biology of tumour cells, the treatment of most cancers has not significantly changed for the past three decades. Are current cancer drugs targeted at the wrong kind of cells? Accumulating evidence has implicated that cancer is a disease of stem cells. In this context, a small fraction of cancer cells adopt the properties of stem cells. In some cases, the cancer stem cells (CSC) could be the close derivative of normal tissue stem cells. In either situation, the net result will be the same, in that CSC are the cells to be used as targets in the development of molecular and pharmaceutical therapies to treat and prevent human cancer. This could be a paradigm shift in the treatment of cancer, away from targeting the blast cells and towards the targeting of the CSC. A challenge to this approach will be to find a way to specifically target CSC without toxicity to normal cells. In this article, we propose how CSC can be used in therapy programs (target identification, drug discovery, etc.). Therefore, in the future, it might be possible to rid a patient of all his/her cancer cells, including the cancer stem cells.

Animals↗

PubMed2006

Breast cancer stem cells: an overview.

The theory that cancer may be originated and sustained by a small proportion of stem-like, self-renewing cells (termed 'cancer stem cells') has gained support in recent years. Breast cancer stem cells have been identified as CD44+CD24- breast tumour cells and have recently been isolated and propagated in vitro. It has been demonstrated that these cells exclusively retain the ability to form new tumours in mouse models and that they display stem/progenitor cell properties. The ability to identify breast cancer stem cells in vivo and to propagate them in vitro provides the means to compare them with normal cells, in order to investigate from which cell they originate, which molecular alterations critically affect them, and how they interact with the microenvironment. Elucidation of these critical points is essential to develop new therapeutic strategies and to improve diagnosis and prognosis for breast cancer patients.

Breast Neoplasms↗

PubMed2005

Multiple drug resistance in cancer revisited: the cancer stem cell hypothesis.

The failure to eradicate cancer may be as fundamental as a misidentification of the target. Current therapies succeed at eliminating bulky disease but often miss a tumor reservoir that is the source of disease recurrence and metastasis. Recent advances in the understanding of tissue development and repair cause us to revisit the process of drug resistance as it applies to oncogenesis and tumor heterogeneity. The cancer stem cell hypothesis states that the cancer-initiating cell is a transformed tissue stem cell, which retains the essential property of self-protection through the activity of multiple drug resistance (MDR) transporters. This resting constitutively drug-resistant cell remains at low frequency among a heterogeneous tumor mass. In the context of this hypothesis, the authors review the discovery of MDR transporters in cancer and normal stem cells and the failure of MDR reversal agents to increase the therapeutic index of substrate antineoplastic agents.

ATP Binding Cassette Transporter, Subfamily B↗

PubMed2007

Beyond tumorigenesis: cancer stem cells in metastasis.

The importance of cancer stem cells (CSCs) in tumor-initiation has been firmly established in leukemia and recently reported for a variety of solid tumors. However, the role of CSCs in multistage cancer progression, particularly with respect to metastasis, has not been well-defined. Cancer metastasis requires the seeding and successful colonization of specialized CSCs at distant organs. The biology of normal stem cells and CSCs share remarkable similarities and may have important implications when applied to the study of cancer metastasis. Furthermore, overlapping sets of molecules and pathways have recently been identified to regulate both stem cell migration and cancer metastasis. These molecules constitute a complex network of cellular interactions that facilitate both the initiation of the pre-metastasis niche by the primary tumor and the formation of a nurturing organ microenvironment for migrating CSCs. In this review, we surveyed the recent advances in this dynamic field and propose a unified model of cancer progression in which CSCs assume a central role in both tumorigenesis and metastasis. Better understanding of CSCs as a fundamental component of the metastatic cascade will lead to novel therapeutic strategies against metastatic cancer.

Animals↗

PubMed2005

Cancer stem cell characteristics in retinoblastoma.

PURPOSE: There is increasing evidence that cancer stem cells contribute to tumor progression and chemoresistance in a variety of malignancies, including brain tumors, leukemias, and breast carcinomas. In this study, we tested the hypothesis that retinoblastomas contain subpopulations of cells that exhibit cancer stem cell properties. METHODS: The following sources of retinoblastoma cells and tissues were examined for the presence of stem cell markers by immunocytochemistry: retinoblastoma tumors from mice transgenic for the SV40 T-antigen (driven by the beta-luteinizing hormone promoter), cell pellets of human Y79 and WERI-Rb27 retinoblastoma cell lines, and archival human retinoblastoma pathological specimens. Hoechst dye exclusion, mediated by the stem cell surface marker ABCG2 (ATP-binding cassette transporter, G2 subfamily), was assessed by flow cytometry in mouse tumors and WERI-Rb27 cells. RESULTS: Small numbers of retinoblastoma cells (less than 1%) exhibited immunoreactivity to stem cell markers ABCG2, aldehyde dehydrogenase 1 (ALDH1), MCM2 (minichromosome maintenance marker 2), SCA-1 (Stem cell antigen-1), and p63. Hoechst dye uptake in mouse tumors and WERI-Rb27 cells was enhanced by addition of 50 microM Verapamil, consistent with activity of the calcium-sensitive ABCG2 protein. Flow cytometric analysis confirmed the presence of small subpopulations of cells excluding Hoechst dye in mouse retinoblastoma tumors (0.3%) and WERI-Rb27 cells (0.1%) in a verapamil-sensitive manner. ABCG2 and ALDH1 positive cells were Hoechst-dim, as seen by dual labeling in vitro. CONCLUSIONS: Mouse and human retinoblastoma tumor cells contain a small subpopulation of cells that exhibit a cancer stem cell-like phenotype. Especially significant is the expression of ABCG2 in mouse and human tumor cells, a calcium-sensitive cell surface protein that not only acts to exclude Hoechst dye, but also confers resistance to over 20 different chemotherapeutic agents. These findings point to a heterogeneity in retinoblastoma tumors that may have significant impact on future treatment strategies.

Aldehyde Dehydrogenase↗

PubMed2006

Delivering cancer stem cell therapies - a role for nanomedicines?

Cancer stem cells (CSCs), i.e. cancer cells that can self-renew, constitute only a minority of the cells of a tumour, but, because of their ability to initiate and repopulate tumours, failure to control CSCs can potentially lead to tumour re-growth, even though the bulk tumour may have been treated successfully. Nanomedicines improve spatio-temporal control over drug kinetics and distribution, thus opening the prospect of safer and more specific therapies to address the challenges posed by CSCs. In particular, these systems have the potential to facilitate CSC-aware therapy by overcoming resistance to conventional cytotoxic drugs and by targeting novel therapies to the tumour and CSC-marker positive cells. This review examines the implications of the CSC paradigm specifically for the development of nanomedicines, i.e. therapies based on macromolecules or supramolecular aggregates.

Antineoplastic Agents↗

PubMed2017

Surface PD-L1, E-cadherin, CD24, and VEGFR2 as markers of epithelial cancer stem cells associated with rapid tumorigenesis.

Cancer cells require both migratory and tumorigenic property to establish metastatic tumors outside the primary microenvironment. Identifying the characteristic features of migratory cancer stem cells with tumorigenic property is important to predict patient prognosis and combat metastasis. Here we established one epithelial and two mesenchymal cell lines from ascites of a bladder cancer patient (i.e. cells already migrated outside primary tumor). Analyses of these cell lines demonstrated that the epithelial cells with surface expression of PD-L1, E-cadherin, CD24, and VEGFR2 rapidly formed tumors outside the primary tumor microenvironment in nude mice, exhibited signatures of immune evasion, increased stemness, increased calcium signaling, transformation, and novel E-cadherin-RalBP1 interaction. The mesenchymal cells on the other hand, exhibited constitutive TGF-β signaling and were less tumorigenic. Hence, targeting epithelial cancer stem cells with rapid tumorigenesis signatures in future might help to combat metastasis.

B7-H1 Antigen↗

PubMed2006

Potential gene therapy strategies for cancer stem cells.

To be maximally effective, therapy of cancer must be directed against both the resting stem cells and the proliferating cells of the cancer. The cell populations of both normal and cancer tissues consist of resting stem cells, proliferating transit-amplifying cells, terminally differentiating cells and dying (apoptotic) cells. The difference between normal tissue renewal and growth of cancers is that some of the transit-amplifying cells in the cancer population do not mature into terminally differentiating cells, but instead continue to proliferate and do not die (maturation arrest). Because of this the number of cancer cells increase, whereas the cell population of normal tissues remains a relatively constant. Conventional radiation treatment and chemotherapy kill the actively proliferating transit- amplifying cells of the cancer. Differentiation therapy, using specific targeted inhibitors of activation, effectively induces differentiation of the proliferating transit-amplifying cancer cells. However, even if the proliferating cancer cells are completely inhibited or eliminated, the cancer stem cells may restore the transit-amplifying population, so that clinical remission is usually temporary. The hypothesis presented in this paper is that successful cancer therapy must be directed against both the resting stem cells and the proliferating cells of the cancer. This may be possible if specific stem cell signals are inhibited using gene therapy, while at the same time attacking proliferating cells by conventional radiation treatment or chemotherapy. With advances in approaches using specific inhibitory RNA, such combination therapy may now be possible, but critical problems in delivering the inhibitory effect specifically to the cancer stem cells have yet to be worked out.

Animals↗

PubMed2026

Rewiring Cellular Context as A Central Mechanism Governing Cancer Stem Cell Survival: Insights from ESC Comparisons.

Cancer stem cells (CSCs) drive tumor initiation, metastasis, and therapy resistance, yet their remarkable persistence remains poorly understood. While CSCs share stemness attributes with embryonic stem cells (ESCs), including self-renewal, transcriptional plasticity, and permissive chromatin, they exhibit a fundamentally divergent regulatory logic that prioritizes survival over developmental fidelity. ESCs maintain globally open chromatin that supports transcriptional hyperactivity but predisposes them to apoptosis under genotoxic stress, whereas CSCs maintain dynamically inducible, permissive chromatin at survival loci while repressing differentiation programs, enabling adaptive stress responses. We advance the hypothesis that CSC persistence emerges not from any single factor, but from the integrative rewiring of signaling cascades (Wnt/β-catenin, Notch, Hedgehog, PI3K/AKT/mTOR), stress-responsive transcription factors (HIFs, NF-κB, STAT3), and core pluripotency networks (OCT4, SOX2, NANOG) within a survival-centric context, reinforced by dynamic chromatin remodeling, inducible super-enhancer landscapes, and microenvironmental cues (hypoxia, inflammation, matrix stiffness). Within this framework, the E2F family serves as a key contextual integrator: in ESCs, constitutive E2F activity triggers p53-mediated apoptosis upon DNA damage, preserving genomic integrity; in CSCs, deregulated E2F activity redirects transcription toward DNA repair, antioxidant defenses, and anti-apoptotic programs. This functional divergence underscores that phenotypic outcome is determined by the broader cellular and epigenetic landscape rather than any single factor. We conclude that CSC persistence is an emergent property of this integrated, survival-centric program, fundamentally distinct from the developmental imperative of ESCs. Effective therapeutic strategies must therefore move beyond targeting individual pathways to dismantle the interconnected regulatory networks that define the CSC survival context, offering a more robust approach to overcome therapy resistance and prevent tumor relapse.

Cancer Stem Cells (CSCs)↗

PubMed2006

Most early disseminated cancer cells detected in bone marrow of breast cancer patients have a putative breast cancer stem cell phenotype.

PURPOSE: The presence of disseminated tumor cells (DTC) in the bone marrow of breast cancer patients is an acknowledged independent prognostic factor. The biological metastatic potential of these cells has not yet been shown. The presence of putative breast cancer stem cells is shown both in primary tumors and distant metastases. These cells with a CD44(+)CD24(-/low) phenotype represent a minor population in primary breast cancer and are associated with self-renewal and tumorigenic potential. Recognizing the potential effect of prevalence of putative stem cells among DTC, we evaluated the bone marrow DTC. EXPERIMENTAL DESIGN: We employed the double/triple-staining immunohistochemistry protocol and modified the established bone marrow cytokeratin (CK) staining protocol by adding steps for additional antigens, CD44 and/or CD24. We evaluated 50 bone marrow specimens, previously categorized as CK(+) from early breast cancer patients. CK(+) cells were examined for CD44 and CD24 expression by light microscopy, fluorescence microscopy, and spectral imaging. RESULTS: We detected the putative stem cell-like phenotype in all CK(+) specimens. The mean prevalence of putative stem/progenitor cells was 72% and median prevalence was 65% (range, 33-100%) among the overall DTC per patient, compared with primary tumors where this phenotype is reported in <10% of cells. CONCLUSIONS: This is the first evidence of the existence of the putative stem-like phenotype within the DTC in bone marrow in early breast cancer patients. All patients had a putative stem cell phenotype among the DTC and most individual DTC showed such phenotype. Future molecular characterization of these cells is warranted.

Bone Marrow↗