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PubMed2005

Stem cells and brain cancer.

One of the most devastating CNS pathologies is brain cancer. The undifferentiated character of brain tumor cells and recent reports of cancer stem cells prompt questions regarding the involvement of normal stem/progenitor cells in brain tumor biology, their potential contribution to the tumor itself, and whether they are the cause or the consequence of tumor initiation and progression. The cancer stem cell model proposes a clonally derived brain tumor arising from a cancer stem cell. This tumor cell-of-origin originates from a stem/progenitor or more differentiated cell via acquisition of oncogenic mutations that dysregulate or allow reacquisition of self-renewal mechanisms. The tumor cells differentiate unidirectionally from the cancer stem cell in a way parallel to normal development. However, several properties of brain tumors add complexity to this model. For example, the apparent lineage and differentiation status of tumor cells are significantly affected by signaling abnormalities that are causally related to formation of the tumor. In addition, these tumors recruit normal CNS stem and progenitor cells to the tumor mass leading to the possibility of a heterogeneous and polyclonal cell population. It is likely that a complete description of the role of stem cells in brain tumors will be more complex than our current models.

Animals↗

PubMed2004

Stem cell: balancing aging and cancer.

Stem cells are defined by their self-renewing capacity and the ability to differentiate into one or more cell types. Stem cells can be divided, depending on their origin, into embryonic or adult. Embryonic stem cells derive from early stage embryos and can give rise to cells from all three germ layers. Adult stem cells, first identified in hematopoietic tissue, reside in a variety of adult tissues. Under normal physiologic conditions, adult stem cells are capable of differentiating into the limited cell types that comprise the particular tissue or organ. Adult stem cells are responsible for tissue renewal and exhaustion of their replicative capacity may contribute to tissue aging. Loss of unlimited proliferative capacity in some of the adult stem cells and/or their progenitors may have involved the evolutionary trade-off: senescence prevents cancer but may promote aging. Embryonic stem cells exhibit unlimited self-renewal capacity due to the expression of telomerase. Although they possess some cancer cell characteristics, embryonic stem cells exhibit a remarkable resistance to genomic instability and malignant transformation. Understanding the tumor suppressive mechanisms employed by embryonic stem cells may contribute to the development of novel cancer treatments and safe cell-based therapies for age-related diseases.

Adult↗

PubMed2006

Stem cells and cancer: two faces of eve.

Recent evidence suggests that a subset of cancer cells within some tumors, the so-called cancer stem cells, may drive the growth and metastasis of these tumors. Understanding the pathways that regulate proliferation, self-renewal, survival, and differentiation of malignant and normal stem cells may shed light on mechanisms that lead to cancer and suggest better modes of treatment.

Cell Differentiation↗

PubMed2006

Roots and stems: stem cells in cancer.

Cancer develops from normal tissues through the accumulation of genetic alterations that act in concert to confer malignant phenotypes. Although we have now identified some of the genes that when mutated initiate tumor formation and drive cancer progression, the identity of the cell population(s) susceptible to such transforming events remains undefined for the majority of human cancers. Recent work indicates that a small population of cells endowed with unique self-renewal properties and tumorigenic potential is present in some, and perhaps all, tumors. Although our understanding of the biology of these putative cancer stem cells remains rudimentary, the existence of such cells has implications for current conceptualizations of malignant transformation and therapeutic approaches to cancer.

Cell Transformation, Neoplastic↗

PubMed2004

Persistence of a small subpopulation of cancer stem-like cells in the C6 glioma cell line.

Both stem cells and cancer cells are thought to be capable of unlimited proliferation. Paradoxically, however, some cancers seem to contain stem-like cells (cancer stem cells). To help resolve this paradox, we investigated whether established malignant cell lines, which have been maintained for years in culture, contain a subpopulation of stem cells. In this article, we show that many cancer cell lines contain a small side population (SP), which, in many normal tissues, is thought to contain the stem cells of the tissue. We demonstrate that in the absence of serum the combination of basic fibroblast growth factor and platelet-derived growth factor maintains SP cells in the C6 glioma cell line. Moreover, we show that C6 SP cells, but not non-SP cells, can generate both SP and non-SP cells in culture and are largely responsible for the in vivo malignancy of this cell line. Finally, we provide evidence that C6 SP cells can produce both neurons and glial cells in vitro and in vivo. We propose that many cancer cell lines contain a minor subpopulation of stem cells that is enriched in an SP, can be maintained indefinitely in culture, and is crucial for their malignancy.

Animals↗

PubMed2006

Concise review: cancer/testis antigens, stem cells, and cancer.

In the multistep process of cancer development, the concept that cancer stem cells are derived from normal stem cells that have gradually accumulated various genetic and epigenetic defects is gaining strong evidence. A number of investigations have identified molecular markers that, under normal conditions, are responsible for stem cell homeostasis but are also expressed in tumor "stem cell-like" subpopulations. In this regard, it was recently reported that a group of tumor-specific antigens known as cancer/testis antigens (CTAs) are expressed in human MSCs. It has long been stated that in normal tissue these antigens are exclusively expressed in germ cell precursors; however, based on these results, we suggest that CTAs are expressed at earlier stages during embryogenesis. The tumor-restricted expression of CTAs has led to several immunotherapeutic trials targeting some of these proteins. The clinical implications that these trials may have on the normal stem cell pools, as well as the immunologic properties of these cells, is to date poorly studied and should be considered.

Antigens, Neoplasm↗

PubMed2006

Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells.

Recent advances have highlighted extensive phenotypic and functional similarities between normal stem cells and cancer stem cells. This raises the question of whether disease therapies can be developed that eliminate cancer stem cells without eliminating normal stem cells. Here we address this issue by conditionally deleting the Pten tumour suppressor gene in adult haematopoietic cells. This led to myeloproliferative disease within days and transplantable leukaemias within weeks. Pten deletion also promoted haematopoietic stem cell (HSC) proliferation. However, this led to HSC depletion via a cell-autonomous mechanism, preventing these cells from stably reconstituting irradiated mice. In contrast to leukaemia-initiating cells, HSCs were therefore unable to maintain themselves without Pten. These effects were mostly mediated by mTOR as they were inhibited by rapamycin. Rapamycin not only depleted leukaemia-initiating cells but also restored normal HSC function. Mechanistic differences between normal stem cells and cancer stem cells can thus be targeted to deplete cancer stem cells without damaging normal stem cells.

Animals↗

PubMed2006

Brain cancer stem-like cells.

Both stem cells and cancer cells are thought to be capable of unlimited proliferation. Moreover, many tumours and cancer cell lines express stem cell markers, including adenosine triphosphate (ATP)-binding cassette transporters, by which the cells pump out specific fluorescent dyes as well as anti-cancer drugs, suggesting either that cancer cells resemble stem cells or that cancers contain stem-like cells. Using the common characteristics of brain tumour cells and neural stem cells, several research groups have succeeded in identifying stem-like cells (cancer stem-like cells) in brain tumours and brain cancer cell lines. The purified cancer stem-like cells, but not the other cancer cells, self-renew and form tumours when transplanted in vivo. Thus, cancer stem-like cells in brain tumours might be a crucial target for anti-brain tumour therapy.

Brain Neoplasms↗

PubMed2005

Side population is enriched in tumorigenic, stem-like cancer cells, whereas ABCG2+ and ABCG2- cancer cells are similarly tumorigenic.

Recently, several human cancers including leukemia and breast and brain tumors were found to contain stem-like cancer cells called cancer stem cells (CSC). Most of these CSCs were identified using markers that identify putative normal stem cells. In some cases, stem-like cancer cells were identified using the flow cytometry-based side population technique. In this study, we first show that approximately 30% of cultured human cancer cells and xenograft tumors examined ( approximately 30 in total) possess a detectable side population. Purified side population cells from two cell lines (U373 glioma and MCF7 breast cancer) and a xenograft prostate tumor (LAPC-9) are more tumorigenic than the corresponding non-side population cells. These side population cells also possess some intrinsic stem cell properties as they generate non-side population cells in vivo, can be further transplanted, and preferentially express some "stemness" genes, including Notch-1 and beta-catenin. Because the side population phenotype is mainly mediated by ABCG2, an ATP-binding cassette half-transporter associated with multidrug resistance, we subsequently studied ABCG2+ and ABCG2- cancer cells with respect to their tumorigenicity in vivo. Although side population cells show increased ABCG2 mRNA expression relative to the non-side population cells and all cancer cells and xenograft tumors examined express ABCG2 in a small fraction (0.5-3%) of the cells, highly purified ABCG2+ cancer cells, surprisingly, have very similar tumorigenicity to the ABCG2- cancer cells. Mechanistic studies indicate that ABCG2 expression is associated with proliferation and ABCG2+ cancer cells can generate ABCG2- cells. However, ABCG2- cancer cells can also generate ABCG2+ cells. Furthermore, the ABCG2- cancer cells form more and larger clones in the long-term clonal analyses and the ABCG2- population preferentially expresses several "stemness" genes. Taken together, our results suggest that (a) the side population is enriched with tumorigenic stem-like cancer cells, (b) ABCG2 expression identifies mainly fast-cycling tumor progenitors, and (c) the ABCG2- population contains primitive stem-like cancer cells.

ATP Binding Cassette Transporter, Subfamily G, Mem↗

PubMed2026

Emodin Induces AIF-Associated Apoptosis and Suppresses Wnt/β-Catenin Signaling in Colorectal Cancer Stem-Like Cells.

Colorectal cancer (CRC) remains a major cause of cancer-related mortality due to therapeutic resistance. Because colorectal cancer stem-like cells (CRCSCs) play a central role in tumor initiation and progression, therapeutic strategies addressing CSC-enriched populations are urgently needed. In this study, we investigated the anticancer effects of emodin, a natural anthraquinone, in CSC-enriched tumorsphere models. Emodin significantly suppressed the viability and self-renewal capacity of HCT116- and SW480-derived CSCs. It induced G0/G1 cell cycle arrest and markedly downregulated stemness-associated markers (CD44, CD133, ALDH1A1, SOX2, NANOG, and OCT4). Importantly, emodin-induced cell death was characterized by mitochondrial dysfunction, increased mitochondrial reactive oxygen species, loss of membrane potential, and nuclear translocation of apoptosis-inducing factor (AIF). This cytotoxicity was not rescued by the pan-caspase inhibitor Z-VAD-FMK, confirming caspase-independent apoptosis. Furthermore, network pharmacology and experimental validation identified GSK3β as a key target. Emodin reduced Wnt/β-catenin signaling by decreasing β-catenin stabilization and nuclear accumulation. Crucially, a rescue experiment utilizing LiCl confirmed that emodin's suppressive effects are mechanistically dependent on the GSK3β/Wnt/β-catenin axis. Collectively, emodin suppresses CRCSC characteristics in vitro by downregulating Wnt/β-catenin signaling and inducing AIF-associated caspase-independent apoptosis, highlighting its therapeutic potential against CRC.

Apoptosis-inducing factor (AIF)↗

PubMed2006

Invasive growth: a MET-driven genetic programme for cancer and stem cells.

Metastasis follows the inappropriate activation of a genetic programme termed invasive growth, which is a physiological process that occurs during embryonic development and post-natal organ regeneration. Burgeoning evidence indicates that invasive growth is also executed by stem and progenitor cells, and is usurped by cancer stem cells. The MET proto-oncogene, which is expressed in both stem and cancer cells, is a key regulator of invasive growth. Recent findings indicate that the MET tyrosine-kinase receptor is a sensor of adverse microenvironmental conditions (such as hypoxia) and drives cell invasion and metastasis through the transcriptional activation of a set of genes that control blood coagulation.

Cell Hypoxia↗

PubMed2005

Spontaneous human adult stem cell transformation.

Human adult stem cells are being evaluated widely for various therapeutic approaches. Several recent clinical trials have reported their safety, showing them to be highly resistant to transformation. The clear similarities between stem cell and cancer stem cell genetic programs are nonetheless the basis of a recent proposal that some cancer stem cells could derive from human adult stem cells. Here we show that although they can be managed safely during the standard ex vivo expansion period (6-8 weeks), human mesenchymal stem cells can undergo spontaneous transformation following long-term in vitro culture (4-5 months). This is the first report of spontaneous transformation of human adult stem cells, supporting the hypothesis of cancer stem cell origin. Our findings indicate the importance of biosafety studies of mesenchymal stem cell biology to efficiently exploit their full clinical therapeutic potential.

Adipose Tissue↗

PubMed2007

A perivascular niche for brain tumor stem cells.

Cancers are believed to arise from cancer stem cells (CSCs), but it is not known if these cells remain dependent upon the niche microenvironments that regulate normal stem cells. We show that endothelial cells interact closely with self-renewing brain tumor cells and secrete factors that maintain these cells in a stem cell-like state. Increasing the number of endothelial cells or blood vessels in orthotopic brain tumor xenografts expanded the fraction of self-renewing cells and accelerated the initiation and growth of tumors. Conversely, depletion of blood vessels from xenografts ablated self-renewing cells from tumors and arrested tumor growth. We propose that brain CSCs are maintained within vascular niches that are important targets for therapeutic approaches.

AC133 Antigen↗

PubMed2006

Characterization of stem cell-like cancer cells in immune-competent mice.

Recently, the cancer stem cell hypothesis has gained significant recognition as the descriptor of tumorigenesis. Although previous studies relied on transplanting human or rat tumor cells into immunecompromised mice, our study used the Hoechst 33342 dye-based side population (SP) technique to isolate and transplant stem cell-like cancer cells (SCLCCs) from the 4T1 and NXS2 murine carcinoma cell lines into the immune-competent microenvironment of syngeneic mice. 4T1 cells displayed an SP of 2% with a Sca-1(high)c-Kit(-)CD45(-) phenotype, whereas NXS2 cells contained an SP of 0.2% with a Sca-1(high)CD24(high)c-Kit(-)CD45(-)GD (high)(2) phenotype. Reverse transcription-polymerase chain reaction (RT-PCR) further revealed up-regulation in SP cells of ABCG2, Sca-1, Wnt-1, and TGF-beta2. Additionally, 4T1 and NXS2 SP cells exhibited increased resistance to chemotherapy, and 4T1 SP cells also showed an increased ability to efflux doxorubicin, which correlated with a selective increase in the percentage of SP cells found in the tumors of doxorubicin-treated mice. Most importantly, SP cells showed a markedly higher repopulation and tumorigenic potential in vivo, which correlated with an increased number of cells in the SP compartment of SP-derived tumors. Taken together, these results show that we successfully characterized SCLCCs from 2 murine carcinoma cell lines in the immune-competent microenvironment of syngeneic mice.

Animals↗

PubMed2006

[Cancer initiating cell theory: popularity and controversies].

The cancer stem cell model proposes that most tumors are derived from a single cell that is transformed into a cancer-initiating cell (cancer stem cell). Cancer stem cells have the capacity to proliferate, differentiate, and form tumors in vivo. However, the origin of cancer stem cells remains controversial. Normal stem cells are regarded as an ideal candidate for the origin of cancer stem cells when take similar characters and signaling pathways between them into consideration. In addition,cell fusion is an important physiologic process during development and tissue repair,and is closely related to several fundamental features of tumors,and thus could be involved in the development of cancer stem cells.

Animals↗

PubMed2005

Stem cells in the etiology and treatment of cancer.

Using approaches first applied in human leukemias, recent progress has been made in the identification of putative cancer stem cells in several different carcinomas and other solid cancers. Additional studies have suggested that cancer stem cells may be derived not only from transformation of quiescent, long-term stem cells but also from short-lived progenitors that then obtain the ability to undergo self-renewal. Therefore, the heterogeneity observed in many types of human cancers may reflect the activation of specific oncogenes and/or loss of specific tumor suppressor genes and the different stem and/or progenitor cell populations in which these genetic or epigenetic events occur. Similarities have been observed in the pathways regulating stem cell homing and metastasis, and increasing evidence also suggests that treatment failure and the recurrence of human cancer may reflect the intrinsic quiescence and drug resistance of cancer stem cells.

Drug Resistance, Neoplasm↗

PubMed2006

Multipotent, dedifferentiated cancer stem-like cells from brain gliomas.

In modern cancer biology, external factors and niches can act on differentiated tissue cells to cause cancer by inducing dedifferentiation of mature adult cells. Recently, we discovered that dedifferentiation of glioma cancer cells alters the expression of mature and neural stem cell (NSC)-related genes, in that cancer cells adjust to the serum-deprived environment and cell-to-cell interaction by down-regulating genes associated with neural mature markers and up-regulating genes that are primitive NSC markers. Neurogenesis of dedifferentiated glioma cancer cells also showed a highly increased neuronal marker associated with highly decreased glial and oligodendrocyte cell markers. After treatment with chemotherapeutic drugs, dedifferentiated cancer cells showed strong drug resistance and continued active cell growth. After grafting to severe combined immunodeficient (SCID) mouse brains, dedifferentiated cancer stem cells migrated and continued active proliferation for more than 4 weeks. We also performed microarray analysis and characterized the gene expression patterns in control cancer cells with dedifferentiated cancer stem-like cells. We delineated specific numbers of important proliferation signaling proteins, primitive neural lineage-related proteins, cancer genes, and transporter genes. In this report, we propose that the dedifferentiation process of brain tumor and normal tissue may contribute to the malignancy and aggressiveness of the brain cancer.

Animals↗

PubMed2006

Transformation from committed progenitor to leukaemia stem cell initiated by MLL-AF9.

Leukaemias and other cancers possess a rare population of cells capable of the limitless self-renewal necessary for cancer initiation and maintenance. Eradication of these cancer stem cells is probably a critical part of any successful anti-cancer therapy, and may explain why conventional cancer therapies are often effective in reducing tumour burden, but are only rarely curative. Given that both normal and cancer stem cells are capable of self-renewal, the extent to which cancer stem cells resemble normal tissue stem cells is a critical issue if targeted therapies are to be developed. However, it remains unclear whether cancer stem cells must be phenotypically similar to normal tissue stem cells or whether they can retain the identity of committed progenitors. Here we show that leukaemia stem cells (LSC) can maintain the global identity of the progenitor from which they arose while activating a limited stem-cell- or self-renewal-associated programme. We isolated LSC from leukaemias initiated in committed granulocyte macrophage progenitors through introduction of the MLL-AF9 fusion protein encoded by the t(9;11)(p22;q23). The LSC were capable of transferring leukaemia to secondary recipient mice when only four cells were transferred, and possessed an immunophenotype and global gene expression profile very similar to that of normal granulocyte macrophage progenitors. However, a subset of genes highly expressed in normal haematopoietic stem cells was re-activated in LSC. LSC can thus be generated from committed progenitors without widespread reprogramming of gene expression, and a leukaemia self-renewal-associated signature is activated in the process. Our findings define progression from normal progenitor to cancer stem cell, and suggest that targeting a self-renewal programme expressed in an abnormal context may be possible.

Animals↗