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OPEN ACCESS ARTICLE
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meeting-report |
aMemorial Sloan-Kettering Cancer Center, New York, New York, USA;
bStanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Palo Alto, California, USA;
cInstitute for Regeneration Medicine, University of California, San Francisco, California, USA;
dMcGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA;
eCity of Hope National Medical Center and Beckman Research Institute, Duarte, California, USA
Key Words. Aberrant differentiation • Adult stem cells • Cancer stem cells • Epigenetic alterations • Glioblastoma Hematopoietic stem cells • Metastasis • Polycomb group proteins • Self-renewal • Stem cell maintenance Stem cell niche • Tumor microenvironment • Tumor stroma
Correspondence: Vinagolu K. Rajasekhar, M.Sc., M.Phil., Ph.D., Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, Rockefeller Research Laboratories, New York, New York 10021, USA. Telephone: 646-247-0060; Fax: 212-717-3627; e-mail: vinagolr{at}mskcc.org
Received August 14, 2007;
accepted for publication October 15, 2007.
First published online in STEM CELLS EXPRESS October 25, 2007.
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ABSTRACT |
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Disclosure of potential conflicts of interest is found at the end of this article.
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INTRODUCTION |
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The keynote address was delivered by the Governor of Victoria, Dr. David de Kretser, who spoke on stem cell potentials, the regulatory enigma, and the application of stem cell knowledge in the understanding of cancer biology. The meeting itself concentrated on the following themes: (a) maintenance of pluripotency: genetic and epigenetic regulatory networks; (b) tumor-inducing stem-like cells; (c) stem cell niche: influence on stem cell maintenance and tumor induction; (d) stem cell differentiation: molecular insights; (e) loss of pluripotency in embryonic stem cells; (f) terminal differentiation of multipotent stem cells; and (g) progress in stem cell therapies, including circumventing rejection by the immune system. In this review, we will discuss the presentations highlighting cancer stem cells and their interaction with the tumor microenvironment. In essence, many of the talks highlighted the importance of the microenvironment in cancer stem cell origin and function, and they converged on two major conclusions: (a) that cancer stem cells display many of the normal adult stem cell characteristics and are present at least in some of the niches that maintain normal stem cells, and (b) that genetic and epigenetic alterations in adult stem cells or in their surrounding cellular context affect their characteristic quiescence, self-renewal capacity, and lineage differentiation potential and thereby facilitate them to become cancer stem cells, depending on the surrounding cellular context.
Normal adult stem cells are believed to reside in unique physiological locations, usually called stem cell niches, that anchor them [1]. The stem cell niches contain various stromal cell types that not only nurture and maintain the stem cells in a quiescent state but also actively regulate their "biochemical life" for self-renewal and required differentiation by modulation of several signaling pathways (stem cell niche homeostasis). Dysregulation in these signaling pathways has been found to disturb the function of stem cell niches. These functional dysregulations may in turn result in the escape of stem cells from the natural niche safeguards that protect against excessive self-renewal, leading first to the development of precancerous conditions and finally to tumorigenesis. Indeed, aberrations are known to occur in functional interactions between cancer cells and cells of their natural environment, a scenario whereby the normal stem cell niche is replaced by the "tumor microenvironment" [2]. Thus, it is important to understand how cancer stem cells are regulated within context of their natural tumor microenvironment. Many of the presentations at this meeting addressed these points, using either genetically manipulated mouse models or conventional stem cell isolation and culture systems involving various available methods [3]. For the convenience of readers, presentations related to cancer stem cells are highlighted in the following sections, whereas an overview of the meeting presentations related to biology of normal stem cells appeared elsewhere during revision of this article [4].
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CANCER STEM CELLS |
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Rapidly accumulating evidence from various laboratories has shown that in several forms of human cancer, only a minority subpopulation of cancer cells is endowed with the capacity to form new tumors when transplanted into immunodeficient mice. The population of cells selectively endowed with tumorigenic capacity can be prospectively purified from whole tumor tissues by virtue of a surface marker expression profile (phenotypic isolation) and is currently defined as the cancer stem cell population. Conventional chemotherapy and/or radiation therapies are not usually designed to target a specific cell subpopulation, and their clinical efficacy is measured by their capacity to induce regression of bulk tumor lesions. It is therefore difficult to know whether traditional antitumor treatments are able to target cancer stem cells, which are thought to be resistant to such treatments [6, 7]. Thus, the concept of cancer stem cells provides a fascinating conceptual framework with which to interpret the phenomenon of tumor relapse, as well as the heterogeneity found inside tumors in terms of aberrant cell proliferation and differentiation [8].
Basic progress in cancer stem cell research relies on precise identification of cancer stem cell markers that distinguish them both from their nontumorigenic progeny and from normal adult stem cells in corresponding healthy tissues. Currently, an intense debate is ongoing as to whether cancer stem cells originate from adult stem cells or from mature, committed progenitors and/or even terminally differentiated cells that have abnormally acquired self-renewal capacity (Fig. 1) [9]. It has also been suggested that niche cells could also be a primary target for the carcinogenic insult to adult stem cell(s), thereby inducing the formation of cancer stem cell(s) and inciting a tumorigenic response [10]. Thus, the molecular mechanisms underlying the genesis of cancer stem cells are still obscure. Therefore, identification of unique cell surface markers for cancer stem cell isolation could provide new tools to address these questions and allow for further molecular and functional characterizations. In this regard, Piero Dalerba (Michael F. Clarke's group, Stanford Institute for Stem Cell Biology and Regenerative Medicine, Palo Alto, CA) presented a series of experiments that identified CD166 as an additional new surface marker that could be used in combination with EpCAM and CD44 for the isolation of human colorectal cancer stem cells. Interestingly, in the same study, normal human colorectal mucosa also contained cell populations expressing a surface marker profile identical to that of the cancer stem cells (EpCAMhigh/CD44+/CD166+), although in fewer numbers compared with the tumors, which the authors suggested as possible evidence for common functional hierarchy in stem cell-mediated development of normal and cancerous mucosa [11].
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MULTIPLE TYPES OF MULTIPOTENT ADULT STEM CELLS IN CANCER DEVELOPMENT |
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Elaine Fuchs (Rockefeller University, New York, NY), who gave a plenary talk at the first scientific session of the meeting, described her studies on adult tissue homeostasis as maintained by skin stem cells and the associated niche. Fuchs's group has identified and characterized resident populations of stem cells, each associated with a basement membrane and adjacent to stroma. They have shown that the quiescent follicle stem cells, located in a niche called the bulge, are multipotent and can generate epidermis, sebaceous glands, and hair follicles when grafted and that they replenish the sebaceous gland or epidermal stem cells that are defective or absent as a consequence of genetic alteration or injury. In collaboration with colleagues at Rockefeller University, Fuchs's group has found that the nuclei of these cells can be reprogrammed to generate all the tissues of a mouse when transferred into enucleated oocytes. By exploring the mechanisms underlying stem cell activation in the skin, the group has uncovered links to cancer-like disorders. In one study, loss of transcriptional repressor Blimp1 is associated with elevated expression of c-Myc, resulting in sebaceous gland hyperplasia. In another, stabilization of β-catenin, either through expression of an N-terminally truncated β-catenin or through loss of bone morphogenetic protein (BMP) receptor signaling, is associated with precocious activation of the bulge cells and formation of hair follicle tumors [20]. Finally, compromising other signaling pathways leads to epidermal proliferation and progression to squamous cell carcinomas. Therefore, it is suggested that when defective, the mechanism of stem cell activation in different niches leads to the development of different types of skin tumors. Interestingly, in some cases (e.g., loss of BMP receptor signaling), stem cell quiescence was relinquished in promoting tumorigenesis; in others (e.g., expression of an N-terminally truncated β-catenin), stem cell quiescence was not lost. Fuchs discussed the possible significance of such findings with regard to the concept of cancer stem cells, suggesting that the number of cancer-producing cells is likely to be predicated on the extent to which a series of mutations affects the quiescent state of a stem cell niche.
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BETWEEN CANCER STEM CELLS AND CELLS OF TUMOR MICROENVIRONMENT |
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Regulation of multiple stem cell pools in an organ or tissue depends on the degree of their niche occupancy and/or their niche-dependent signals [14]. Direct genetic alteration(s) and/or a dysregulated crosstalk(s) between signaling pathways of the cancer stem cells and the cells of their microenvironment have also been implicated as important determinants of functional tumor microenvironment preceding cancer development [24–27]. Studies involving the pre-exposure of cleared fat pads to chemical carcinogens before reconstituting the mammary glands with epithelial cells have revealed the tumor microenvironment as an epigenetic modifier that can, either positively or negatively, modulate the malignant behavior of genetically aberrant cancer cells [28]. Coevolution of cancer and stromal cellular responses has thus been largely recognized in tumorigenesis [29], and the niche cells are viewed as direct activators of tumor-inducing cells [10] that could potentially represent cancer stem cells. A broad spectrum of biochemical (e.g., hypoxia), and physiological (e.g., cell cycle control) cellular dysregulations in the tumor microenvironment is suggested to participate in the onset of heritable (genetic and epigenetic) alterations that in turn promote/accelerate tumor progression by producing heterogeneous tumor tissue containing aberrantly differentiated cancer stem cells (Fig. 1). Recent in-depth molecular genetic approaches were presented at the meeting as attempts to decipher the molecular function of tumor microenvironment in oncogenesis associated with blood cancers (such as myeloproliferative diseases), as well as solid tumors.
Myeloid Tumors
Emmanuelle Passegué (Institute for Regeneration Medicine, University of California, San Francisco, CA) reported that cancer stem cells originating from HSCs lacking the AP-1 transcription factor JunB display a highly aberrant interaction with their microenvironment. JunB is a well-known tumor suppressor, and its loss in HSCs is associated with a myeloproliferative disorder and leukemia development [30]. JunB-deficient HSCs show dysregulation of a large array of genes associated with cell-cell and cell-matrix interactions that have also been implicated in the maintenance of HSCs in their bone marrow niche. As a consequence, JunB-deficient HSCs display a rapid loss of self-renewal capacity in serial transplantation assays associated with impaired long-term multilineage reconstitution ability, migratory response, and loss of quiescence. In parallel, JunB-deficient HSCs expand in number and contribute to leukemia initiation and propagation in transplanted mice. Passegué speculated on the importance of this intrinsic loss of microenvironmental regulation for the emergence of cancer stem cell activity during cancer initiation.
Carl Walkley (Stuart Orkin's group, Dana-Farber Cancer Institute and Children's Hospital, Boston, MA) presented elegant molecular investigations using a conditional deletion strategy, which revealed an Rb-dependent interaction between myeloid-derived cells and their bone marrow microenvironment, a novel role for the classic tumor suppressor Rb. The bone marrow microenvironment regulates proliferation of adult HSCs, and perturbation of this interaction results in myeloproliferation. Interestingly, the Rb is interestingly dispensable for self-renewal and lineage specification of the HSCs. Only a combined loss of Rb in both myeloid cells and their microenvironment results in the manifestation of myeloproliferative diseases. HSCs are associated with two functionally distinct microenvironments, namely the osteoblastic (for HSC quiescence) and vascular (for HSC proliferation) niches. The loss of Rb appears to first affect the niche for HSC quiescence, which in turn leads to HSC mobilization and potentially initiates myeloproliferative diseases, such as those representing a preleukemic condition [31].
Kateri Moore (Princeton University, Princeton, NJ) also presented studies on the role of Wnt signaling in stem cell maintenance and showed that expression of a Wnt-inhibitor, specifically in a bone marrow niche cell, can alter HSC potential. HSCs in this "Wnt-less" environment are compromised in their ability to self-renew, whereas multipotent progenitor cells proliferate and expand. These studies open up opportunities for further molecular investigations aimed at understanding the clinical development of cancer-like diseases in the context of altered tumor microenvironment.
Solid Tumors
Luis Parada (University of Texas Southwestern Medical Center, Dallas, TX) extended studies to identification of the cell of cancer origin and the function of its microenvironment for tumor formation in neurofibromatosis patients, using conditional knockout mouse model systems [32]. The presentation focused on three major points: (a) glioma origin is niche-specific, as demonstrated by conditional knockout mouse models; (b) stem cells with activated Ras signaling induce glioma formation; and (c) stem-like characteristics, such as neurosphere formation, clonality, and self-renewal properties, are verified in these oncogenically activated neural precursor cells. The neurofibromatosis is caused by mutations in the NF1 tumor suppressor gene encoding a GTPase-activating protein. Normally, the NF1 negates oncogenic Ras signaling by increasing the GTP hydrolysis. The onset of malignant cancers in neurofibromatosis patients requires an additional inactivation of tumor suppressors or activation of oncogenes. Similarly, conditional loss of NF1 and p53 in nestin-expressing mouse brain neural precursors only at the subventricular zone (a niche where neural stem cells are known to reside beside the hippocampus in mouse brain) manifested as malignant astrocytoma with full penetrance. As the nestin promoter is active in neural stem cells, the tumor induction here is broadly attributed as a consequence of stem cell disease. Since not all glioblastomas are associated with NF1 loss or mutation, a prolonged activation of Ras (albeit at low levels) in mice that are compound heterozygotes for p53 and NF1 in CNS cells is argued as a plausible mechanism underlying glioma formation. Using tissue-specific conditional knockout models, the role of heterozygosity, even in the microenvironment, has previously been realized as a requisite for neurofibroma tumorigenesis. In that context, the cells of cancer origin (NF–/– Schwann cells) promoted the infiltration of NF1-heterozygous mast cells into the niche via stem cell factors. Mast cells subsequently facilitated the microenvironment for tumor formation by secreting various factors, including mitogens, angiogenic factors, etc. Similar studies during NF1-independent gliomagenesis would be of considerable interest as well.
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EPIGENETIC INFLUENCE ON CANCER STEM CELLS |
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Aberrations in the expression of the polycomb group proteins are often associated with the development of cancer [35]. Epigenetic silencing of tumor suppressor genes is the primary contribution to oncogenic transformation of cells involving overexpression of polycomb group proteins and/or modification of DNA methylation patterns [36, 37]. Since the original identification of Bmi-1 as a c-Myc cooperating oncogene [38, 39], the role of polycomb group proteins have increasingly been identified as key regulators in adult stem cell self-renewal during normal conditions [40, 41], as well as in oncogenic transformation during aberrant cellular conditions [35, 41, 42]. Induced expression of Bmi1 has been shown to increase symmetrical cell divisions in adult stem cells and expanded multipotent progenitors in vitro and to enhance HSC-repopulating ability in vivo [43]. Although Bmi1 is essential for cerebellar development, its overexpression leads to pathogenesis of medulloblastomas involving the proliferation of stem cells or committed cerebellar precursor cells [44]. Aberrant expression of Bmi1 was also found in malignant human mammary stem cells and in cultured cancer stem cells from brain tumors [35].
There was a considerable discussion at this meeting on potential epigenetic strategies for understanding the molecular regulation of cancer stem cell identity and regulation. Owen Witte (University of California, Los Angeles, CA) presented evidence for the functional role of Bmi1 in the self-renewal of prostate spheres, which contain putative stem cells similar to those found in mammary spheres and neurospheres. It was also shown that Bmi1 is prominently increased in the earliest stages of prostate development. On a different note, metastatic prostate cancers also contain increased levels of polycomb proteins, although the physiological meaning remains to be understood.
Maarten van Lohuizen (The Netherlands Cancer Institute, Amsterdam, The Netherlands), continuing his pioneering studies, presented data that identified tumor suppressor Ink4a/ARF-independent Bmi1 targets in brain cancer, in addition to the established finding that Ink4a/ARF is a critical Bmi1 target gene in stem cells and cancer [45]. Additional data presented included the following: (a) loss of Bmi1 affects cellular differentiation, and (b) Bmi1 is a critical target for sonic hedgehog signaling, which is also associated with stem cell biology. On the other hand, it is also known that distinct epigenetic (DNA methylation) changes occur even in the stromal fibroblasts and myoepithelial cells of breast tumor tissues, in addition to breast epithelial cancer cells [46]. Thus, it is suggested that aberrant tumor microenvironment is maintained by epigenetic alterations in stromal cells as well. The role of polycomb group proteins has not yet been investigated in the tumor microenvironment in the context of cancer development.
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CANCER STEM CELLS IN THE CONTEXT OF METASTASIS |
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Eric Lagasse (University of Pittsburgh Medical School, Pittsburgh, PA) presented new data demonstrating that cancer stem cells isolated from human metastatic colon cancers appear to have succumbed to different chromosomal instabilities, as observed from clonally derived tumor-inducing populations. Therefore, it was suggested that a metastatic progression of colon cancer may involve an orchestration of both the hierarchy and stochastic models of cancer, and consequently a pool of genetically heterogeneous cancer stem cells is generated. Interestingly, these tumor cells still maintain the self-renewal and lineage differentiation properties of stem cells, implying that cancer stem cells are derived from adult stem cells that succumbed to specific chromosomal instability.
In addition, Loen Hansford (David Kaplan's group, Hospital for Sick Children, Toronto, ON, Canada) presented studies indicating that the bone marrow of relapsed neuroblastoma patients serves as a metastatic niche for tumor-inducing cells. Neuroblastoma is a common pediatric sympathetic nervous system tumor that can manifest both as well-differentiated low-stage tumors and as homogenously undifferentiated high-stage tumors. Dissociated cells from both primary tumors of different clinical stages and bone marrow metastases formed self-renewing spheres under neurosphere culture conditions. Moreover, the primary tumor-derived spheres differentiated into neurons and neuroblasts under neurogenic conditions. Orthotopic transplantation of prospectively isolated cells from neuroblastoma metastatic bone marrow tumors resulted in neuroblastoma development and subsequent metastases in SCID mice. Bone marrow metastases of neuroblastoma are therefore thought to be a potential natural resource for isolating tumor-inducing cells, as well as for predicting cancer relapses. It is expected that this system may also be suitable for understanding tumor-inducing stem cells in the functional context of their tumor microenvironment.
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FUTURE OUTLOOK |
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-secretase inhibitors depleted the cancer stem cell population in glioblastomas (Xing Fan, Charles Eberhart's group, Johns Hopkins University, Baltimore, MD). Although the sensitivity of normal stem cells to this chemotherapeutic inhibition has yet to be examined in detail, these studies form the earliest attempts to selectively target cancer stem cells. Exploiting the previous findings that intravenously injected bone marrow-derived mesenchymal stem cells (MSCs) engraft into a solid tumor microenvironment [51], Michael Andreeff (M.D. Anderson Cancer Center, Houston, TX) also demonstrated that interferon-β-expressing human MSCs abrogated the tumor growth of mouse orthotopic breast cancers, as well as lung metastases. Recent progress in stem cell drug discovery efforts to understand the regulation of normal stem cells (such as that described by Sheng Ding, Scripps Research Institute, La Jolla, CA [52]) appears to unveil the future development of cancer stem cell-based antitumor therapeutics. |
DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST |
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ACKNOWLEDGMENTS |
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REFERENCES |
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Abstract
Introduction