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[Cancer Research 66, 1883-1890, February 15, = 2006]
=A9 2006 American = Association=20 for Cancer Research

Reviews

Cancer Stem Cells: An Old Idea=97A Paradigm Shift=20

Max S. Wicha, Suling Liu = and=20 Gabriela Dontu

University of Michigan Comprehensive Cancer Center, = Ann Arbor,=20 Michigan

Requests for reprints: Max S. Wicha, = University of=20 Michigan Comprehensive Cancer Center, 1500 East Medical Center Drive, = 6303 CCGC,=20 Ann Arbor, MI 48109-0942. Phone: 734-936-1831; Fax: 734-615-3947; = E-mail: mwicha{at}umich.edu .


3D"   =20 Abstract
Top
3D"Abstract
Introduction
The Cancer Stem Cell...
Implications of the Cancer...
References
 
A= lthough=20 the concept that cancers arise from "stem cells" or "germ = cells" was=20 first proposed about 150 years ago, it is only recently that = advances=20 in stem cell biology have given new impetus to the "cancer = stem cell=20 hypothesis." Two important related concepts of this = hypothesis are=20 that (a) tumors originate in either tissue stem cells = or their=20 immediate progeny through dysregulation of the normally = tightly=20 regulated process of self-renewal. As a result of this, = (b)=20 tumors contain a cellular subcomponent that retains key stem = cell=20 properties. These properties include self-renewal, which = drives=20 tumorigenesis, and differentiation albeit aberrant that = contributes=20 to cellular heterogeneity. Recent experimental evidence in a = variety=20 of tumors has lent strong support to the cancer stem cell = hypothesis=20 that represents a paradigm shift in our understanding of=20 carcinogenesis and tumor cell biology. This hypothesis has=20 fundamental implications for cancer risk assessment, early = detection,=20 prognostication, and prevention. Furthermore, the current = development=20 of cancer therapeutics based on tumor regression may have = produced=20 agents that kill differentiated tumor cells while sparing the = rare cancer stem cell population. The development of more=20 effective cancer therapies may thus require targeting this = important=20 cell population. (Cancer Res 2006; 66(4): 1883-90) =


3D"   =20 Introduction
Top
Abstract
3D"Introduction
The Cancer Stem Cell...
Implications of the Cancer...
References
 
I= n a=20 thought-provoking article published in Fortune in 2004, = Leaf,=20 a cancer survivor, poses the question, "Are we losing the war = on=20 cancer?" (1).=20 In this article, he reviews data on the progress made since = the "war=20 on cancer" was declared in 1961. Over this time, there have = clearly=20 been dramatic advances in the treatment of such diseases as = childhood=20 leukemia, Hodgkin's disease, and testicular cancer. = Furthermore, the=20 overall mortality for some of the common epithelial = malignances, such=20 as breast cancer and prostate cancer, have been declining = recently=20 largely due to advances in early detection and prevention.=20 However, as Leaf points out, for the four most common = epithelial=20 malignancies (lung, breast, prostate, and colon cancers), the = survival of patients with metastatic disease has not changed=20 significantly over the past several decades. Despite these=20 statistics, there is considerable optimism in the cancer = research=20 community that new targeted therapies will significantly = improve on=20 the results of empiric-based therapeutics. The ability to=20 specifically target pathways deranged in cancer raises the = hope of=20 developing therapies with enhanced specificity and decreased=20 toxicity. However, as our ability to attack specific targets=20 increases, a fundamental question remains, "Are we targeting = the=20 right cells"? Evidence is accumulating that most, if not all, = malignancies are driven by "a cancer stem cell compartment."=20 Furthermore, these cancer stem cells may be inherently = resistant to=20 our current therapeutic approaches. The cancer stem cell = hypothesis=20 has fundamental implications for understanding the biology of = carcinogenesis as well as for developing new strategies for = cancer=20 prevention as well as new therapies for advanced disease. In = this=20 commentary, we will discuss the cancer stem cell hypothesis,=20 including recent evidence supporting its validity, and the=20 implications of this model for cancer prevention and = therapy.=20


3D"    The=20 Cancer Stem Cell Hypothesis
Top
Abstract
Introduction
3D"The Cancer Stem = Cell...
Implications of the Cancer...
References
 
A= ll=20 tissues in the body are derived from organ-specific stem = cells that=20 are defined by their capacity to undergo self-renewal as well = as to=20 differentiate into the cell types that comprise each organ. = These=20 tissue-specific stem cells are distinguished from embryonic = stem=20 cells in that their differentiation is largely restricted to = cell=20 types within a particular organ. The cancer stem cell = hypothesis has=20 two separate but related components. The first component = concerns the=20 cellular origin of tumors, including the question of whether = tumors=20 arise from tissue stem cells. A second related component of = this=20 hypothesis is that tumors are driven by cellular components = that=20 display "stem cell properties." The concept that cancer might = arise=20 from a rare population of cells with stem cell properties was = proposed about 150 years ago (2=965).=20 Over 40 years ago, it was postulated that tissue-specific = stem cells=20 may be the cell of origin of cancer (6).=20 Over 30 years ago, Pierce (7)=20 proposed that cancers represented a maturation arrest of stem = cells.=20 The concept that tumors contain cell populations with stem = cell=20 properties was also suggested by in vitro "clonogenic = assays"=20 that showed subpopulations of tumor cells with increased=20 proliferative capacity as shown by colony formation in in=20 vitro assays using cells isolated from tumor specimens = (8).=20 A major limitation of these studies, however, was that they = measured=20 in vitro proliferation rather than true self-renewal. = In=20 addition, it has been observed that the production of human = tumor=20 xenografts in animal models required a relatively large = number of=20 cells. However, it was unclear whether this was due to the=20 inefficiency of these cells in promoting tumor growth or to = the=20 existence of rare subpopulations within a tumor that were = uniquely=20 tumorigenic in these systems.

Evidence supporting the cancer stem cell hypothesis has gained=20 impetus due to recent advances in stem cell biology and the=20 development of new animal models to measure self-renewal and=20 more directly test the validity of this hypothesis. The = concept=20 that cancers arise from the transformation of stem cells is=20 appealing for several reasons. Stem cells by their long-lived = nature are subject to the accumulation of multiple mutations=20 that are required for carcinogenesis. For example, women = exposed=20 to atomic bomb radiation in Hiroshima and Nagasaki developed=20 breast cancer approximately 20 to 30 years after exposure (9).=20 Mutations found in these women's breast cancers are = consistent=20 with those known to be induced by radiation (9).=20 Furthermore, women exposed to radiation during late = adolescents had=20 the highest susceptibility to breast cancer development. This = is=20 thought to be the period when the mammary gland has the = highest=20 number of stem cells (10).=20 Further evidence that stem cells may play a role in = carcinogenesis is=20 the observation that normal stem cells and cancer cells share = several=20 important properties. These include (a) the capacity = for=20 self-renewal, (b) the ability to differentiate, = (c)=20 active telomerase expression, (d) activation of = antiapoptotic=20 pathways, (e) increased membrane transporter activity, = and=20 (f) the ability to migrate and metastasize. Indeed,=20 properties, such as anchorage independence, which have been=20 thought to be a hallmark of transformed cells, have recently=20 been described by us and others as a property of normal = tissue=20 stem cells (11=9613).=20 One of the key early events in transformation may be the=20 dysregulation of the normally highly regulated process of=20 self-renewal. Stem cells are the only cells capable of undergoing=20 self-renewal divisions. In the steady state, these divisions=20 are asymmetric in which a stem cell is able to produce an = exact=20 copy of itself as well as a daughter cell that undergoes=20 differentiation into the lineages found in differentiated = tissues.=20 During stem cell expansion and tumorigenesis, stem cells may = undergo=20 symmetric divisions in which stem cells produce two identical = stem=20 cell progeny, thus allowing for stem cell expansion (ref. 14;=20 Fig.=20 1). During normal development, stem cell self-renewal is=20 regulated by signals from the surrounding stem cell "niche." = As has=20 been elegantly shown in bone marrow transplantation models, a = single hematopoietic stem cell introduced into a lethally=20 irradiated mouse is able to repopulate the stem cell = compartment=20 resulting in reconstitution of the entire hematopoietic = system.=20 Extensive expansion in the stem cell population stops when = this pool=20 is replenished, illustrating the tight control of this = process.=20 We and others have hypothesized that deregulation of this=20 self-renewal process leading to stem cell expansion may be a = key=20 early event in carcinogenesis. Recently, the pathways that = regulate=20 the self-renewal of normal stem cells, including Wnt, Notch, = and=20 Hedgehog, have begun to be elucidated. These signaling = pathways=20 have been implicated in regulating the self-renewal of = hematopoietic,=20 neuronal, and mammary stem cells (14,=20 15).=20 The dysregulation of each of these pathways in rodent models = leads to=20 tumorigenesis. Furthermore, there is substantial evidence = that=20 dysregulation of these pathways also plays an important role = in human=20 carcinogenesis. Defects in the Wnt signaling pathway are seen = early=20 in colon cancer carcinogenesis. Alterations in Hedgehog = signaling=20 were first shown in human basal carcinomas of the skin (16).=20 More recently, evidence for dysregulation of this pathway has = been reported in human pancreatic, gastric, prostate, and = breast=20 carcinomas (17,=20 18).=20 Alterations in Notch signaling have been observed in human = T-cell=20 acute lymphoblastic leukemia, cervical cancer, and breast = cancer (19=9623).=20



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  		Figure 1. Stem cells in = normal=20 development, tissue homeostasis, and carcinogenesis. = A,=20 during normal development, symmetric stem cell self-renewal = results=20 in stem cell expansion. This process is tightly regulated by = components of the stem cell niche. Stem cells differentiate = into a=20 transient amplifying population that undergoes further = proliferation=20 and lineage commitment followed by cell migration, terminal = cell=20 differentiation, and apoptosis of fully differentiated = cells.=20 B, during normal tissue homeostasis, asymmetric = self-renewal=20 of stem cells results in stem cell maintenance. = Proliferation and=20 differentiation of transient amplifying progenitor cells = replaces=20 normal cell loss resulting in tissue homeostasis. C,=20 carcinogenesis may be initiated by stem cell expansion via = symmetric=20 self-renewal. Unlike normal organogenesis, this process is=20 dysregulated resulting in cancer stem cell expansion. = Aberrant=20 differentiation of these cells generates tumor = heterogeneity.=20 Further mutations or epigenetic changes may accompany tumor = invasion=20 and metastasis. Metastases require the dissemination of = cancer stem=20 cells that may remain dormant and be reactivated resulting = in tumor=20 recurrence. In contrast, dissemination of differentiated = tumor cells=20 produces only micrometastasis that do not progress. =

 = ;
Recent=20 studies have suggested that tumors may arise from progenitor = cells=20 and tissue stem cells. Transformation of these cells may = require that=20 they acquire the stem cell property of self-renewal. In = support of=20 this hypothesis, Jamieson et al. showed that chronic = myelogenous=20 leukemia (CML) blast crisis may originate in hematopoietic = progenitor=20 cells as a consequence of dysregulated Wnt signaling, = allowing these=20 cells to self-renew, a property normally restricted to = hematopoietic=20 stem cells (24).=20 Similarly, by transfecting purified populations of = hematopoietic=20 progenitor cells, Kelly and Gilliland showed that AML-ETO may = induce=20 transformation of myeloid progenitor cells enabling them to = acquire=20 the property of self-renewal (25).=20 We have recently proposed that human breast cancers may arise = from=20 the transformation of either mammary stem cells or early = progenitor=20 cells resulting in production of breast cancers with distinct = molecular and clinical phenotypes (26).=20 This concept is also consistent with recent descriptions in=20 transgenic mouse models of mammary tumorigenesis, which suggest = that=20 distinct oncogenes may affect different stem and progenitor = cells=20 resulting in phenotypic differences in mammary tumors (27).=20

The second major component of the cancer stem cell hypothesis = is=20 that tumors contain and are "driven" by cellular components = that=20 display stem cell properties. This concept has gained substantial=20 experimental support recently with the development of animal=20 models that have permitted the direct assessment of stem cell = properties of tumor cell subpopulations. These models have = shown=20 that prospectively identifiable subpopulations of tumor cells = display the defining stem cell properties of self-renewal and = differentiation. Self-renewal drives tumorigenesis, whereas=20 differentiation (albeit aberrant in tumors) contributes to = tumor=20 phenotypic heterogeneity. In 1997, Dick et al. showed that = the=20 ability to transfer human leukemias into nonobese = diabetic/severe=20 combined immunodeficient (NOD/SCID) mice was retained in a = small=20 population of cancer stem cells that like their normal = counterparts=20 displayed the cell surface phenotype = CD34+CD38=96.=20 These cells that comprised <1 in 10,000 leukemia cells = could=20 transfer the human leukemia into NOD/SCID mice, whereas the=20 introduction of thousands of fold higher numbers of cells = that did=20 not bear this phenotype were nontumorigenic. Furthermore, the = leukemias that were produced recapitulated the histologic = phenotype=20 found in the original tumor (28).=20 More recently, this group used cellular marking studies to = show that=20 leukemic stem cells like their normal counterparts are = heterogeneous=20 with varying degrees of self-renewal potential. These = findings=20 suggest that leukemic stem cells, like their normal = counterparts,=20 exist in a hierarchy that is developmentally regulated. This = supports=20 the hypothesis that leukemic stem cells originate from the=20 transformation of normal hematopoietic stem cells (29).=20 Using a similar approach, in collaboration with Michael = Clarke, we=20 showed that human breast cancers contain a cell population=20 characterized by the expression of the cell surface markers=20 CD44+ CD24low lin=96 that have stem = cell=20 characteristics. As few as 200 of these cells, which comprise = between=20 1% and 10% of the total cell population, are able to form = tumors when=20 implanted in NOD/SCID mice (30).=20 In contrast, 20,000 cells isolated from the same tumor that = do=20 not display this cell surface phenotype are unable to form = tumors.=20 Furthermore, consistent with a stem cell model, cancer stem=20 cells are able to generate tumors that recapitulate the = phenotypic=20 heterogeneity found in the initial tumor.

Confirming and extending our findings, Ponti et al. recently=20 reported that, in addition to being tumorigenic,=20 CD44+CD24=96 human breast cancer cells = form tumor=20 mammospheres in vitro, a property that we described = previously=20 for normal mammary stem/progenitor cells (31,=20 32).=20 Furthermore, the stem cell phenotype of these tumor cells was = suggested by their expression of the stem cell markers Oct-4 = as well=20 as by the absence of Cx43 expression. Interestingly, these = cells also=20 produced vascular endothelial growth factor (VEGF) and were = highly=20 angiogenic (31).=20 Lending further support to the cancer stem cell hypothesis = and=20 extending its generality, three groups have independently = shown the=20 existence of a cancer stem cell compartment in human brain = tumors.=20 These cancer stem cells, like their normal counterparts, are=20 able to form neurospheres in vitro and express the = neural stem=20 cell markers CD133 and nestin. Furthermore, as few as 100 of=20 these cells were able to transfer the tumors when injected=20 intracranially into NOD/SCID mice (33,=20 34).=20 In contrast, 105 CD133=96 cells = engrafted but did=20 not produce a tumor. The tumors produced by the = CD133+=20 cells recapitulated the phenotypic heterogeneity found in the = initial=20 tumor (33).=20 Evidence for existence of a clonogenic subpopulation of cells = in=20 human multiple myeloma was recently reported by Matsui et al. = (35).=20 Multiple myeloma cells express syndecan-1 (CD138). However, a = small=20 subpopulation resembling postgerminal center B cells were=20 CD138=96. Only the CD138=96 cells were = clonogenic=20 in vitro and in NOD/SCID mice (35).=20 In the prostate, Xin et al. showed that stem cell antigen-1 = (Sca-1)=20 enriches for a prostate regenerating cell in mouse model and = genetic=20 perturbations of PTEN/AKT produced prostate cancer associated = with a=20 dramatic increase in Sca-1+ cells (36).=20 Further evidence for the existence of a cell population with = stem=20 cell properties in prostate cancer has been reported by = Richardson et=20 al. They found that normal human prostate stem cells = expressed CD133=20 (37).=20 Furthermore, they identified a subpopulation of cells in = human=20 prostate cancer characterized as CD44+/3D{alpha}=202=DF1hi/CD133+=20 with stem cell properties. As few as 500 cells with this = phenotype=20 that constituted 0.1% of total tumor cells formed tumors in=20 NOD/SCID mice, whereas 5 x=20 105 CD44=96 cells failed to form tumors = (38).=20 Evidence for the existence of cancer stem cells in lung = cancer has=20 recently been presented by Kim et al. (39).=20 They identified bronchial alveolar stem cells present at the=20 bronchial alveolar duct junction. These cells exhibited the=20 stem cell properties of self-renewal and multilineage=20 differentiation. These stem cells could be transformed by = K-ras in=20 vitro and could form tumor in mice (39).=20

From these studies, it seems that several stem cell markers = may be=20 shared by cancer stem cells in multiple tumor types. These = include=20 CD44, 3D{alpha}6 integrin, =DF1 integrin, and = CD133=20 (Prominin). These cancer stem cells may not only share = molecular=20 markers but also display dysregulation of similar = self-renewal=20 pathways, such as Wnt, Hedgehog, and Notch. In support of = this=20 concept, we have recently found that Hedgehog signaling may=20 regulate the self-renewal of normal mammary stem cells and = that=20 this pathway is dysregulated in mammary cancer stem cells.1=20 Taken together, these studies suggest that most, if not all,=20 tumors contain a subpopulation of cells that display cancer=20 stem cell characteristics. The relationship between normal = and=20 cancer stem cells is depicted graphically in Fig.=20 1.


3D"   =20 Implications of the Cancer Stem Cell Hypothesis: A Paradigm Shift = in=20 Thinking about Carcinogenesis and Our Approach to Cancer = Prevention and=20 Therapy
Top
Abstract
Introduction
The Cancer Stem Cell...
3D"Implications of the = Cancer...
References
 
<= B>Models=20 of carcinogenesis. "Stochastic models" of carcinogenesis = hold=20 that transformation results from random mutation and subsequent=20 clonal selection. In this model, any cell may be the target = of=20 carcinogenesis. The stem cell model of carcinogenesis, in = contrast,=20 suggests that cancers originate in tissue stem or progenitor = cells=20 probably through dysregulation of self-renewal pathways. This = leads=20 to expansion of this cell population that then may undergo = further=20 genetic or epigenetic changes to become fully transformed. In = addition, epigenetic changes normally involved in cell=20 differentiation contribute to the cellular phenotypic = heterogeneity=20 found in tumors. This model represents a paradigm shift in = our=20 thinking and has fundamental consequences for understanding = the=20 biology of carcinogenesis as well as important clinical = implications=20 for early detection, prevention, and therapy of human = malignancies.=20 These implications are summarized in Fig.=20 2.



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  		Figure 2. Clinical = implications of=20 cancer stem cell model. The cancer stem cell model has = important=20 implications for cancer risk reduction, early detection, = prevention,=20 and treatment. Interventions that reduce normal stem cell = number may=20 decrease cancer risk. Detection of factors secreted by = initiated=20 stem cells may allow for the earlier detection of cancers.=20 Interventions that induce apoptosis or differentiation of = initiated=20 stem cells may be effective in cancer prevention. = Conventional=20 cancer therapies, including cytotoxic agents, selectively = destroy=20 differentiated cancer cells, sparing the cancer stem cell=20 compartment resulting in cancer recurrence at primary or = metastatic=20 sites. Therapies that selectively eliminate cancer stem = cells leave=20 residual nontumorigenic cells resulting in potential cancer = cures. =

 = ;
Biological=20 implications. The cancer stem cell hypothesis has = important=20 biological implications for the development of animal models = of=20 carcinogenesis as well as for understanding key biological = processes,=20 such as stromal-epithelial interactions and metastasis. = Although=20 there has been considerable progress in the development of = mouse=20 models of human cancer, in many cases, these models fail to=20 recapitulate human disease. Many transgenic models use=20 tissue-specific promoters to drive oncogene expression. = However,=20 these tissue-specific genes may be expressed only in = differentiated=20 cells. If stem cells or their immediate progeny are the true=20 targets of transforming events, then the expression of = oncogenes=20 in more differentiated cells may fail to recapitulate actual=20 carcinogenic processes. There is recent evidence that the = expression=20 of oncogenes in primitive cells using direct transfection=20 technologies results in a fundamentally different phenotype = than=20 expression of the same genes driven by tissue-specific = promoters.=20 Welm et al. showed that expression of c-Met and c-Myc driven = by=20 the mammary-specific promoter mouse mammary tumor virus fails = to=20 produce carcinomas, whereas these genes transduced into = primitive=20 cells via a stem cell virus produced mammary carcinomas (40).=20 Kim et al. have developed an animal model that targets normal = lung stem cells to produce adenocarcinomas that resemble = those=20 found in human lung cancers (39).=20

The concept of the normal stem cell niche has direct relevance = to=20 understanding stromal epithelial interactions that occur = during=20 tumorigenesis in addition to understanding such complex = processes as=20 tumor metastases. For example, homing receptors found on = normal=20 hematopoietic stem cells, such as the cytokine receptor = CXCR4, have=20 been shown to play an important role in promoting metastases = in a=20 variety of tumors, including human breast and prostate = carcinomas (41,=20 42).=20 Recently, carcinoma-associated fibroblasts were shown to = promote=20 angiogenesis, in addition to tumor growth, by secreting SDF-1 = that=20 interacts with CXCR4 expressed by tumor cells and endothelial = cells=20 (43).=20 In addition, properties, such as induction of angiogenesis, = may be=20 inherent in normal stem cells as well as in their transformed = counterparts. Supporting this idea, we have recently found = that=20 Hedgehog signaling regulates the production VEGF by normal = human=20 mammary stem and progenitor cells as well as breast cancer = stem=20 cells.2=20 The clinical course of micrometastases may also reflect stem = cell=20 characteristics of disseminated cells. Up to 30% of women = with newly=20 diagnosed breast cancer and men with prostate cancer exhibit=20 micrometastases in their bone marrow as determined by = immunochemical=20 staining. However, after 10 years, up to 50% of these have = patients=20 have not developed clinically relevant macroscopic disease = (44).=20 A potential explanation for this is that although either stem = cells or their more differentiated progeny may be capable of=20 forming micrometastases, only stem cells have the = self-renewal=20 capacity to create a clinically relevant macroscopic = metastases.=20 In addition, the concept of "tumor dormancy" may directly = relate=20 to stem cell biology. Stem cells usually exist in a quiescent = G0 state and self-renew only when they receive = appropriate=20 signals from their niche environment. By analogy, cancer stem = cells may remain dormant at metastatic sites until they are=20 activated by the appropriate signals from the = microenvironment.=20

Implications for cancer risk assessment, early detection, = molecular=20 profiling, and prevention. The cancer stem cell model has=20 important implications for many aspects of cancer risk = assessment=20 and prevention. If cancer stem cells or their immediate = progeny=20 are the targets for transformation, then cancer risk may be=20 directly related to the number of stem cell targets. Pathways = that influence target number may thus influence cancer risk.=20 For example, it has been suggested that a previously = unrecognized=20 function of the hereditary breast cancer gene BRCA1 may be in = the regulation of normal breast stem cell function (45).=20 An important regulator of stem cell self-renewal of both = normal=20 and transformed stem cells is the polycomb gene Bmi-1 (46=9648).=20 It has recently been shown that Bmi-1 induced down-regulation = of P-16 plays an important role in the regulation of = hematopoietic=20 and neuronal stem cell self-renewal (47,=20 49).=20 Interestingly, recent studies by Holst et al. have suggested = that one=20 of the earliest events in carcinogenesis of the breast may be = the=20 silencing of P-16 expression by gene methylation (50).=20 Together, these studies suggest that Bmi-1 may regulate = normal stem=20 cell self-renewal through down-regulation of P-16. During=20 carcinogenesis, the silencing of this gene through = methylation may=20 result in the constitutive expansion of the stem cell = population. In=20 a similar manner, dysregulation of Wnt signaling may allow = for the=20 expansion of colonic stem cells during early colon cancer=20 carcinogenesis.

The stem cell model also has important implications for the=20 development of markers for the early detection of cancer. = Most=20 currently used tumor markers, such as prostate-specific = antigen=20 for prostate cancer or CA125 for ovarian cancer, are the = products=20 of differentiated cells within tumors. If tumors are to be = detected=20 during earlier stages of carcinogenesis, it may be necessary = to=20 characterize and detect markers made by the cancer stem cell=20 populations. There has been considerable excitement generated = by studies that show that important clinical prognostic and=20 predictive information can be obtained from determining the=20 molecular expression profile of tumors. This is consistent = with=20 the hypothesis that these molecular profiles represent the = cell=20 of origin as well as the differentiation pattern produced by=20 subsequent oncogenic events. We have proposed previously that = the molecular classifications of human breast cancers by gene = expression analysis may reflect different cellular origins of = these subtypes (51).=20 If tumors are driven by a stem cell component, then = elucidation of=20 gene signatures characteristic of these stem cells may = provide=20 important prognostic information. In support of this, Glinsky = et al.=20 developed an 11-gene signature whose expression was regulated = by the=20 stem cell self-renewal gene Bmi-1. Remarkably, expression of = this=20 "stem cell gene" signature was associated with a poor = prognosis for=20 10 different types of human malignancies (52).=20 These studies summarized in an accompanying editorial, "Stem=20 Cell-ness: A Magic Marker for Cancer" (53),=20 provide strong evidence for the clinical relevance of the = cancer stem=20 cell hypothesis. Despite the important prognostic value of = tumor=20 profiling, the cancer stem cell hypothesis predicts that = there will=20 be considerably less value in using molecular profiling to = identify=20 new therapeutic targets. If cancer stem cells comprise only a = minor=20 fraction of total tumor cells and if these cells drive = tumorigenesis,=20 then the profiling of purified populations of cancer stem = cells may=20 identify more important therapeutic targets than profiling = the entire=20 tumor.

The cancer stem cell hypothesis suggests avenues for cancer=20 prevention. If stem cells are the targets of transformation,=20 then strategies that reduce stem cell number might reduce = cancer=20 risk. The use of tamoxifen in primary breast cancer = prevention=20 might occur through such a mechanism. Furthermore, if early=20 events in carcinogenesis involve expansion of the stem cell=20 pool, then interventions that induce either apoptosis or=20 differentiation with a loss of self-renewal capacity in these = cells=20 represent a rational therapeutic approach to cancer = prevention.=20 Although the concept of differentiation therapy for cancer is = not=20 new (54),=20 development of agents that can specifically target initiated = stem=20 cells may provide opportunities to intervene at the earliest = stages=20 of carcinogenesis before significant genetic instability = occurs. This=20 highlights the importance of elucidating the pathways that = control=20 differentiation and survival in these cells.

Implications for cancer therapeutics. The cancer stem cell = model=20 has fundamental implications for the development of new = cancer=20 therapeutic agents. Antineoplastic agents have largely been=20 developed through testing in animal models as well as phase = II=20 human trials. In both of these, the measured outcome has been = shrinkage of tumors. Tumor response is usually defined in the = clinic=20 as the shrinkage of a tumor by at least 50%. However, if = cancer stem=20 cells are inherently resistant to therapeutic agents and if = these=20 cells comprise only a minority of the tumor cell population, = then=20 shrinkage of tumors may reflect the effects of these agents = on the=20 differentiated cells in a tumor rather than the cancer stem = cell=20 component. This may explain why in clinical trials for = advanced=20 cancers, tumor regression often does not translate into = clinically=20 significant increases in patient survival. This has been = shown in=20 many tumor types, including solid tumors and multiple = myeloma, where=20 patient survival does not correlate with changes in the = M-protein=20 levels (55).=20 If the cancer stem cell hypothesis is valid, then we may need = to=20 devise new experimental paradigms other than assessment of = tumor=20 regression for the evaluation of antineoplastic agents. To = develop=20 therapies that target the cancer stem cell population, it = will=20 be important to find and validate intermediate end points = that=20 predict ultimate patient survival. For instance, future = clinical=20 trial design may use such intermediate end points as time to=20 tumor progression following delivery of an agent that can = target=20 cancer stem cells.

Therapeutic resistance of cancer stem cells. By virtue of = their=20 fundamental importance in organogenesis, normal stem cells = have=20 evolved mechanisms that promote their survival and resistance = to apoptosis. For example, during normal mammary involution=20 following lactation, there is massive apoptosis of = differentiated=20 cells, whereas stem cells are spared and regenerate the gland = during subsequent pregnancies. Inherent resistance of normal=20 stem cells to apoptosis is also observed in patients = undergoing=20 cytotoxic chemotherapy. When patients are given = nonmyeloablative=20 doses of cytotoxic chemotherapy, they experience a transient=20 decrease in their WBC counts. This is caused by apoptosis of=20 differentiated neutrophils and myeloid precursors. Stem cells = in the bone marrow are not ablated by these doses of = chemotherapy=20 and are able to regenerate a normal hematopoietic system = after=20 several weeks. Similarly, many of the gastrointestinal side=20 effects of chemotherapy are caused by induction of apoptosis = in=20 differentiating colonic epithelial cells. These dying cells = are=20 regenerated by gut stem cells that survive these chemotherapeutic=20 insults. Just as normal stem cells may be resistant to the = induction=20 of apoptosis by cytotoxic agents and radiation therapy, = cancer=20 stem cells may display increased resistance to these agents=20 compared with more differentiated cells that comprise the = bulk=20 of tumors. Supporting this concept, Guzman et al. have shown=20 that leukemic stem cells are more resistant to chemotherapy=20 than are the more differentiated myeloblastic cells that = constitute=20 the vast majority of cells in leukemia (56).=20 Similarly, Matsui et al. have shown that myeloma stem cells = are=20 resistant to many therapies being used to treat myeloma = including=20 chemotherapy and the proteosome inhibitor Velcade (35,=20 57).=20 There are several molecular mechanisms that may account for = the=20 resistance to apoptosis of cancer stem cells. These include=20 (a) cell cycle kinetics. Many cancer stem cells are = not=20 cycling and are in G0 and thus resistant to cell=20 cycle=96specific chemotherapy agents (58).=20 (b) DNA replication and repair mechanisms. Stem cells = may be=20 resistant to DNA-damaging agents by virtue of being able to = undergo=20 asynchronous DNA synthesis in addition to displaying enhanced = DNA=20 repair (59=9663).=20 (c) During asynchronous DNA synthesis, the parental = "immortal"=20 DNA strand always segregates with the stem cell and not the=20 differentiating progeny. This process may be regulated by P53 = (64).=20 This prevents the stem cell compartment from accumulating = mutations=20 associated with replication or from being affected by = DNA-damaging=20 agents. (d) Antiapoptotic proteins. Stem cells express = higher=20 levels of antiapoptotic proteins, such as members of the = Bcl-2=20 family and inhibitors of apoptosis, than do differentiated = cells (65).=20 (e) Transporter proteins. Stem cells express high levels = of=20 transporter proteins, such as ABCG2 (BCRP), as well as=20 P-glycoprotein. The development of effective immunologic = approaches=20 to cancer therapy may also be affected by the existence of = cancer=20 stem cells. Many of these therapies have involved targeting=20 cells that express tumor-specific antigens. These antigens = may=20 be selectively expressed on differentiated tumor cells. = Cancer=20 stem cells that do not express these antigens may thus be = spared=20 by these immunologic interventions.

The concept of cancer stem cells also has implications for the=20 development of targeted therapies. Arguably, the most = successful=20 targeted therapy has been the development of imatinib that = targets=20 BCR-Abl in patients with CML. The vast majority of patients=20 with early stages of CML are put into a remission by = administration=20 of imatinib. However, recent studies have suggested that = although=20 imatinib may target differentiated and progenitor CML cells, = it=20 does not eliminate CML stem cells that harbor this mutation.=20 Following withdrawal of imatinib in animal models or the = development=20 of a resistant clone in patients, the disease reappears with=20 kinetics predicted by a stem cell model (66).=20 These studies suggest that the cure of CML will require the=20 elimination of BCR-Abl containing CML stem cells.

If the ultimate cure of various cancers depends on the = elimination=20 of cancer stem cells, one can question why several = malignancies,=20 such as testicular carcinoma in men and choriocarcinoma in = women,=20 are curable with chemotherapy even in advanced disease, = whereas=20 the majority of common epithelial malignancies are not. One=20 might speculate that the stem cell component of testicular = carcinoma=20 and choriocarcinoma are inherently different from those in = other=20 tissues, because these tumors arise in germ cells. Indeed,=20 chemotherapy treatment of these tumors often produces = residual masses=20 that are benign teratomas composed of differentiated cells. = An=20 understanding of the inherent differences between stem cells = of=20 testicular cancer and choriocarcinoma compared with those = from other=20 tumors may provide new clues for the development of therapies = for=20 more common tumor types.

Opportunities for new therapeutics. The cancer stem cell = model=20 suggests that it may be necessary to alter the current = paradigm=20 in drug development. Eradication of cancers may require the=20 targeting and elimination of cancer stem cells. Thus, one = must=20 devise strategies that can selectively kill these cancer stem = cells while sparing normal stem cells, such as those in the = gut=20 and bone marrow. This represents a challenge because many = pathways,=20 such as those involved in self-renewal, are shared by cancer = stem=20 cells and their normal counterparts. However, a variety of = recent=20 studies using animal models that have targeted these pathways = indicate the feasibility of this approach. For example, Notch = signaling requires processing by the enzyme 3D{gamma}=20-secretase.=20 An inhibitor of this enzyme has been recently shown to have=20 activity against breast cancers that over express Notch1 (67,=20 68).=20 Agents targeting Hedgehog signaling have recently been shown = to have=20 antineoplastic activity. The Hedgehog inhibitor cyclopamine = that=20 specifically inhibits Hedgehog signaling was used to treat = animals=20 bearing a variety of tumor xenografts. Cyclopamine caused = dramatic=20 regression of tumors that did not recur following cessation = of=20 treatment. Furthermore, at least over brief periods, the=20 administration of these agents seemed to be nontoxic (17).=20 A Hedgehog pathway inhibitor, HhAntag, with greater activity = than=20 cyclopamine has recently been shown to block medulloblastoma=20 formation in a transgenic mouse model (69).=20 These studies support the feasibility of selectively targeting = the=20 cancer stem cell population. The elimination of this key cell = population may result in improved therapeutic outcomes for = patients=20 with even advanced cancers.


3D"   =20 Acknowledgments =
 
Grant support:=20 NIH grants R01-CA101860 and P30CA46592, Department of Defense = grant=20 BC030214, and The Susan G. Koman Foundation grant = PDF0503599.=20


3D"   =20 Footnotes
 
Note: Max Wicha has financial holdings = and is a=20 scientific advisor for OncoMed Pharmaceuticals.

1 Submitted for = publication.=20

2 In preparation. =

Received 9/ 1/05; revised 10/27/05; accepted 11/23/05.


3D"   =20 References
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Abstract
Introduction
The Cancer Stem Cell...
Implications of the Cancer...
3D"References
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In the accompanying article, Hill presents his views that = the=20 current evidence is not conclusive regarding the existence of = cancer stem cells in solid tumors. Although we agree that = much=20 remains to be learned about tumor stem cells, we feel that = the=20 substantial biological and clinical implications of this = model=20 justify intensive research in this area. Hill points to = several=20 theoretical and methodologic questions regarding the = experimental=20 evidence for the existence of cells with stem cell properties = in solid tumors. He points out that the relative inefficiency = of transferring human tumors to xenografts may be due to = inherent=20 inefficiencies in the systems rather than tumor = subpopulations=20 that differ in their tumorigenicity. We believe that the = recent=20 prospective identification of solid tumor stem cells in a = variety=20 of malignancies, including breast cancer, brain cancer, and=20 prostate cancer, provide strong evidence that "not all cancer = cells are equal." Only a relatively small percentage of cells = with characteristic cell surface markers are able to be = serially=20 passaged in immunocompromised mice, a demonstration of their=20 self-renewal capacity. We do, however, agree with Hill that=20 tumor stem cells may themselves be heterogeneous with varying = self-renewal capacity. Indeed, as stated in our article, this = has recently been shown for human leukemias. We also agree = with=20 his statement that the microenvironment is important in = determining=20 the behavior of transplanted cells. In our review, we stress=20 the importance of the stem cell niche in normal stem cell = function=20 and the tumor microenvironment in tumor growth and = progression.=20 For this reason, solid tumor xenograft models of breast and=20 brain cancer have used orthotopic installation of tumors to = the=20 mammary fat pad or brain, respectively. Hill contends that = genetic=20 instability drives tumor development, so that the relationship=20 between stem cell behavior and differentiation might change=20 during tumor progression. Although genetic instability = undoubtedly=20 plays an important role in tumor progression, molecular = profiling=20 studies suggest that the biological behavior of tumors is = inherent=20 in the initial tumor. This is more consistent with a tumor = stem=20 cell model in which tumor behavior is largely determined by = the=20 cell of origin and its genetic profile. Hill also speculates = that=20 differentiated tumor cells that have "lost the ability to = manifest as=20 cancer stem cells might regain the ability next week or next = month."=20 However, we are unaware of any direct evidence of = de-differentiation=20 of tumor cells. In xenograft models, differentiated tumor = cells from=20 tumors fail to form tumors when transplanted even after long = periods=20 of observation. Finally, it is important to distinguish = between=20 markers that may serve to identify tumor stem cells from = molecules=20 that play important roles in stem cell behavior. In many = cases, the=20 markers present on tumor stem cells mimic that of their = normal stem=20 cell counterparts. Thus, the argument that proteolytic = digestion of=20 solid tumors changes cell surface markers has no direct = bearing on=20 the behavior of these cells when they are introduced into=20 immunocompromised mice.

In summary, cancer stem cells were first described in human=20 leukemias. Accumulating evidence in a variety of solid tumors = suggest that these tumors may also be driven by a subset of=20 cells that display stem cell properties. Further studies = should=20 lead to a greater understanding of the biology of these cells = with significant implications for cancer treatment and = prevention.=20




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HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF=20 CONTENTS
Cancer = Research Clinical Cancer=20 Research
Cancer=20 Epidemiology Biomarkers & Prevention Molecular=20 Cancer Therapeutics
Molecular=20 Cancer Research Cell Growth=20 & Differentiation
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To = view a=0A= copy of this license, visit = http://creativecommons.org/licenses/by-sa/2.5/ or=0A= send a letter to Creative Commons, 559 Nathan Abbott Way, Stanford, = California=0A= 94305, USA.=0A= =0A= Attribution: Leave my name and web address in this script intact.=0A= =0A= Not Supported in Opera=0A= ----------------------=0A= * user/password authentication=0A= * responseXML data member=0A= =0A= Not Fully Supported in Opera=0A= ----------------------------=0A= * async requests=0A= * abort()=0A= * getAllResponseHeaders(), getAllResponseHeader(header)=0A= =0A= */=0A= // IE support=0A= if (window.ActiveXObject && !window.XMLHttpRequest) {=0A= window.XMLHttpRequest =3D function() {=0A= var msxmls =3D new Array(=0A= 'Msxml2.XMLHTTP.5.0',=0A= 'Msxml2.XMLHTTP.4.0',=0A= 'Msxml2.XMLHTTP.3.0',=0A= 'Msxml2.XMLHTTP',=0A= 'Microsoft.XMLHTTP');=0A= for (var i =3D 0; i < msxmls.length; i++) {=0A= try {=0A= return new ActiveXObject(msxmls[i]);=0A= } catch (e) {=0A= }=0A= }=0A= return null;=0A= };=0A= }=0A= // Gecko support=0A= /* ;-) */=0A= // Opera support=0A= if (window.opera && !window.XMLHttpRequest) {=0A= window.XMLHttpRequest =3D function() {=0A= this.readyState =3D 0; 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i < this._headers.length; i++) {=0A= if (header =3D=3D '*' || this._headers[i].h =3D=3D header) {=0A= ret +=3D this._headers[i].h + ': ' + this._headers[i].v + '\n';=0A= }=0A= }=0A= return ret;=0A= };=0A= this.getResponseHeader =3D function(header) {=0A= var ret =3D getAllResponseHeader(header);=0A= var i =3D ret.indexOf('\n');=0A= if (i !=3D -1) {=0A= ret =3D ret.substring(0, i);=0A= }=0A= return ret;=0A= };=0A= this.setRequestHeader =3D function(header, value) {=0A= this._headers[this._headers.length] =3D {h:header, v:value};=0A= };=0A= this.open =3D function(method, url, async, user, password) {=0A= this.method =3D method;=0A= this.url =3D url;=0A= this._async =3D true;=0A= this._aborted =3D false;=0A= this._headers =3D [];=0A= if (arguments.length >=3D 3) {=0A= this._async =3D async;=0A= }=0A= if (arguments.length > 3) {=0A= opera.postError('XMLHttpRequest.open() - user/password not = supported');=0A= }=0A= this.readyState =3D 1;=0A= if (this.onreadystatechange) {=0A= this.onreadystatechange();=0A= }=0A= };=0A= this.send =3D function(data) {=0A= if (!navigator.javaEnabled()) {=0A= alert("XMLHttpRequest.send() - Java must be installed and = enabled.");=0A= return;=0A= }=0A= if (this._async) {=0A= setTimeout(this._sendasync, 0, this, data);=0A= // this is not really asynchronous and won't execute until the = current=0A= // execution context ends=0A= } else {=0A= this._sendsync(data);=0A= }=0A= }=0A= this._sendasync =3D function(req, data) {=0A= if (!req._aborted) {=0A= req._sendsync(data);=0A= }=0A= };=0A= this._sendsync =3D function(data) {=0A= this.readyState =3D 2;=0A= if (this.onreadystatechange) {=0A= this.onreadystatechange();=0A= }=0A= // open connection=0A= var url =3D new java.net.URL(new = java.net.URL(window.location.href), this.url);=0A= var conn =3D url.openConnection();=0A= for (var i =3D 0; i < this._headers.length; i++) {=0A= conn.setRequestProperty(this._headers[i].h, this._headers[i].v);=0A= }=0A= this._headers =3D [];=0A= if (this.method =3D=3D 'POST') {=0A= // POST data=0A= conn.setDoOutput(true);=0A= var wr =3D new = java.io.OutputStreamWriter(conn.getOutputStream(), this._getCharset());=0A= wr.write(data);=0A= wr.flush();=0A= wr.close();=0A= }=0A= // read response headers=0A= // NOTE: the getHeaderField() methods always return nulls for me :(=0A= var gotContentEncoding =3D false;=0A= var gotContentLength =3D false;=0A= var gotContentType =3D false;=0A= var gotDate =3D false;=0A= var gotExpiration =3D false;=0A= var gotLastModified =3D false;=0A= for (var i =3D 0; ; i++) {=0A= var hdrName =3D conn.getHeaderFieldKey(i);=0A= var hdrValue =3D conn.getHeaderField(i);=0A= if (hdrName =3D=3D null && hdrValue =3D=3D null) {=0A= break;=0A= }=0A= if (hdrName !=3D null) {=0A= this._headers[this._headers.length] =3D {h:hdrName, = v:hdrValue};=0A= switch (hdrName.toLowerCase()) {=0A= case 'content-encoding': gotContentEncoding =3D true; break;=0A= case 'content-length' : gotContentLength =3D true; break;=0A= case 'content-type' : gotContentType =3D true; break;=0A= case 'date' : gotDate =3D true; break;=0A= case 'expires' : gotExpiration =3D true; break;=0A= case 'last-modified' : gotLastModified =3D true; break;=0A= }=0A= }=0A= }=0A= // try to fill in any missing header information=0A= var val;=0A= val =3D conn.getContentEncoding();=0A= if (val !=3D null && !gotContentEncoding) = this._headers[this._headers.length] =3D {h:'Content-encoding', v:val};=0A= val =3D conn.getContentLength();=0A= if (val !=3D -1 && !gotContentLength) = this._headers[this._headers.length] =3D {h:'Content-length', v:val};=0A= val =3D conn.getContentType();=0A= if (val !=3D null && !gotContentType) = this._headers[this._headers.length] =3D {h:'Content-type', v:val};=0A= val =3D conn.getDate();=0A= if (val !=3D 0 && !gotDate) this._headers[this._headers.length] = =3D {h:'Date', v:(new Date(val)).toUTCString()};=0A= val =3D conn.getExpiration();=0A= if (val !=3D 0 && !gotExpiration) = this._headers[this._headers.length] =3D {h:'Expires', v:(new = Date(val)).toUTCString()};=0A= val =3D conn.getLastModified();=0A= if (val !=3D 0 && !gotLastModified) = this._headers[this._headers.length] =3D {h:'Last-modified', v:(new = Date(val)).toUTCString()};=0A= // read response data=0A= var reqdata =3D '';=0A= var stream =3D conn.getInputStream();=0A= if (stream) {=0A= var reader =3D new java.io.BufferedReader(new = java.io.InputStreamReader(stream, this._getCharset()));=0A= var line;=0A= while ((line =3D reader.readLine()) !=3D null) {=0A= if (this.readyState =3D=3D 2) {=0A= this.readyState =3D 3;=0A= if (this.onreadystatechange) {=0A= this.onreadystatechange();=0A= }=0A= }=0A= reqdata +=3D line + '\n';=0A= }=0A= reader.close();=0A= this.status =3D 200;=0A= this.statusText =3D 'OK';=0A= this.responseText =3D reqdata;=0A= this.readyState =3D 4;=0A= if (this.onreadystatechange) {=0A= this.onreadystatechange();=0A= }=0A= if (this.onload) {=0A= this.onload();=0A= }=0A= } else {=0A= // error=0A= this.status =3D 404;=0A= this.statusText =3D 'Not Found';=0A= this.responseText =3D '';=0A= this.readyState =3D 4;=0A= if (this.onreadystatechange) {=0A= this.onreadystatechange();=0A= }=0A= if (this.onerror) {=0A= this.onerror();=0A= }=0A= }=0A= };=0A= };=0A= }=0A= // ActiveXObject emulation=0A= if (!window.ActiveXObject && window.XMLHttpRequest) {=0A= window.ActiveXObject =3D function(type) {=0A= switch (type.toLowerCase()) {=0A= case 'microsoft.xmlhttp':=0A= case 'msxml2.xmlhttp':=0A= case 'msxml2.xmlhttp.3.0':=0A= case 'msxml2.xmlhttp.4.0':=0A= case 'msxml2.xmlhttp.5.0':=0A= return new XMLHttpRequest();=0A= }=0A= return null;=0A= };=0A= }=0A= ------=_NextPart_000_00B2_01C70A5F.B7A8C390 Content-Type: application/octet-stream Content-Transfer-Encoding: quoted-printable Content-Location: http://cancerres.aacrjournals.org/javascript/ajax/utility.js /************************************************************************= *****=0A= * javascript/ajax/utility.js=0A= *=0A= * Utility functions for working with XMLHttpRequest data.=0A= *=0A= * Copyright 2006 Board of Trustees of the Leland Stanford Junior = University.=0A= = *************************************************************************= ***/=0A= =0A= /*=0A= * Copy XML nodes into an HTMLElement. This effectively=0A= * clones XML markup which uses XHTML naming conventions=0A= * into an HTML DOM.=0A= */=0A= function copy_xml_to_html(src, dst) {=0A= if (src.nodeType =3D=3D 1) { /* Node.ELEMENT_NODE */=0A= var e =3D document.createElement(src.nodeName);=0A= for (var i =3D 0; i < src.childNodes.length; i++) {=0A= copy_xml_to_html(src.childNodes[i], e);=0A= }=0A= for (var i =3D 0; i < src.attributes.length; i++) {=0A= var n =3D src.attributes[i].name;=0A= var v =3D unescape_xml_string(src.attributes[i].value); =0A= e.setAttribute(n, v);=0A= if (n =3D=3D "class") {=0A= e.className =3D v;=0A= }=0A= else if (n =3D=3D "style") {=0A= set_css_style(v, e, "");=0A= }=0A= }=0A= dst.appendChild(e);=0A= }=0A= else if (src.nodeType =3D=3D 3) { /* Node.TEXT_NODE */=0A= dst.appendChild(document.createTextNode(src.nodeValue));=0A= }=0A= }=0A= =0A= /* =0A= * It is unclear that this is the right thing to be calling=0A= * from copy_xml_to_html, but it appears that Safari decides=0A= * to convert & to the NCR #, and then encodes that=0A= * NCR to &%26%2338;. So, I'm going to treat the DOM Attr=0A= * value as a plain string, and run our XML string input=0A= * through the decoding routine below.=0A= */=0A= function unescape_xml_string(s) {=0A= return s.replace(/'/g, "'")=0A= .replace(/'/g, "'")=0A= .replace(/"/g, "\"")=0A= .replace(/"/g, "\"")=0A= .replace(/>/g, ">")=0A= .replace(/>/g, ">")=0A= .replace(/</g, "<")=0A= .replace(/</g, "<")=0A= .replace(/&/g, "&")=0A= .replace(/&/g, "&");=0A= }=0A= =0A= /*=0A= * Parse set of CSS rules and apply them to an element.=0A= * This is quite horrifying, but I'm unable to determine=0A= * how else to handle this with IE 6. FireFox and other=0A= * sane browsers let you simply set the style attribute=0A= * or use e.style.setProperty(rule, value, priority),=0A= * IE 6 appears to have neither of these capabilities..=0A= */=0A= function set_css_style(css, e, priority) {=0A= var rules =3D css.split(";");=0A= for (var i =3D 0; i < rules.length; i++) {=0A= var nvpair =3D rules[i].split(":");=0A= if (nvpair.length =3D=3D 2) {=0A= try {=0A= var name =3D nvpair[0]; /* style attribute */=0A= var value =3D nvpair[1]; /* attribute value */=0A= =0A= /*=0A= * For each possible style attribute, set the=0A= * appropriate style property in the element.=0A= */=0A= if (name =3D=3D "background") {=0A= e.style.background =3D value;=0A= }=0A= else if (name =3D=3D "background-attachment") {=0A= e.style.backgroundAttachment =3D value;=0A= }=0A= else if (name =3D=3D "background-color") {=0A= e.style.backgroundColor =3D value;=0A= }=0A= else if (name =3D=3D "background-image") {=0A= e.style.backgroundImage =3D value;=0A= }=0A= else if (name =3D=3D "background-position") {=0A= e.style.backgroundPosition =3D value;=0A= }=0A= else if (name =3D=3D "background-position-x") {=0A= e.style.backgroundPositionX =3D value;=0A= }=0A= else if (name =3D=3D "background-position-y") {=0A= e.style.backgroundPositionY =3D value;=0A= }=0A= else if (name =3D=3D "background-repeat") {=0A= e.style.backgroundRepeat =3D value;=0A= }=0A= else if (name =3D=3D "behavior") {=0A= e.style.behavior =3D value;=0A= }=0A= else if (name =3D=3D "border") {=0A= e.style.border =3D value;=0A= }=0A= else if (name =3D=3D "border-bottom") {=0A= e.style.borderBottom =3D value;=0A= }=0A= else if (name =3D=3D "border-bottom-color") {=0A= e.style.borderBottomColor =3D value;=0A= }=0A= else if (name =3D=3D "border-bottom-style") {=0A= e.style.borderBottomStyle =3D value;=0A= }=0A= else if (name =3D=3D "border-bottom-width") {=0A= e.style.borderBottomWidth =3D value;=0A= }=0A= else if (name =3D=3D "border-collapse") {=0A= e.style.borderCollapse =3D value;=0A= }=0A= else if (name =3D=3D "border-color") {=0A= e.style.borderColor =3D value;=0A= }=0A= else if (name =3D=3D "border-left") {=0A= e.style.borderLeft =3D value;=0A= }=0A= else if (name =3D=3D "border-left-color") {=0A= e.style.borderLeftColor =3D value;=0A= }=0A= else if (name =3D=3D "border-left-style") {=0A= e.style.borderLeftStyle =3D value;=0A= }=0A= else if (name =3D=3D "border-left-width") {=0A= e.style.borderLeftWidth =3D value;=0A= }=0A= else if (name =3D=3D "border-right") {=0A= e.style.borderRight =3D value;=0A= }=0A= else if (name =3D=3D "border-right-color") {=0A= e.style.borderRightColor =3D value;=0A= }=0A= else if (name =3D=3D "border-right-style") {=0A= e.style.borderRightStyle =3D value;=0A= }=0A= else if (name =3D=3D "border-right-width") {=0A= e.style.borderRightWidth =3D value;=0A= }=0A= else if (name =3D=3D "border-style") {=0A= e.style.borderStyle =3D value;=0A= }=0A= else if (name =3D=3D "border-top") {=0A= e.style.borderTop =3D value;=0A= }=0A= else if (name =3D=3D "border-top-color") {=0A= e.style.borderTopColor =3D value;=0A= }=0A= else if (name =3D=3D "border-top-style") {=0A= e.style.borderTopStyle =3D value;=0A= }=0A= else if (name =3D=3D "border-top-width") {=0A= e.style.borderTopWidth =3D value;=0A= }=0A= else if (name =3D=3D "border-width") {=0A= e.style.borderWidth =3D value;=0A= }=0A= else if (name =3D=3D "bottom") {=0A= e.style.bottom =3D value;=0A= }=0A= else if (name =3D=3D "clear") {=0A= e.style.clear =3D value;=0A= }=0A= else if (name =3D=3D "clip") {=0A= e.style.clip =3D value;=0A= }=0A= else if (name =3D=3D "color") {=0A= e.style.color =3D value;=0A= }=0A= else if (name =3D=3D "cssText") {=0A= e.style.Sets =3D value;=0A= }=0A= else if (name =3D=3D "cursor") {=0A= e.style.cursor =3D value;=0A= }=0A= else if (name =3D=3D "direction") {=0A= e.style.direction =3D value;=0A= }=0A= else if (name =3D=3D "display") {=0A= e.style.display =3D value;=0A= }=0A= else if (name =3D=3D "font") {=0A= e.style.font =3D value;=0A= }=0A= else if (name =3D=3D "font-family") {=0A= e.style.fontFamily =3D value;=0A= }=0A= else if (name =3D=3D "font-size") {=0A= e.style.fontSize =3D value;=0A= }=0A= else if (name =3D=3D "font-style") {=0A= e.style.fontStyle =3D value;=0A= }=0A= else if (name =3D=3D "font-variant") {=0A= e.style.fontVariant =3D value;=0A= }=0A= else if (name =3D=3D "font-weight") {=0A= e.style.fontWeight =3D value;=0A= }=0A= else if (name =3D=3D "height") {=0A= e.style.height =3D value;=0A= }=0A= else if (name =3D=3D "ime-mode") {=0A= e.style.imeMode =3D value;=0A= }=0A= else if (name =3D=3D "layout-flow") {=0A= e.style.layoutFlow =3D value;=0A= }=0A= else if (name =3D=3D "layout-grid") {=0A= e.style.layoutGrid =3D value;=0A= }=0A= else if (name =3D=3D "layout-grid-char") {=0A= e.style.layoutGridChar =3D value;=0A= }=0A= else if (name =3D=3D "layout-grid-line") {=0A= e.style.layoutGridLine =3D value;=0A= }=0A= else if (name =3D=3D "layout-grid-mode") {=0A= e.style.layoutGridMode =3D value;=0A= }=0A= else if (name =3D=3D "layout-grid-type") {=0A= e.style.layoutGridType =3D value;=0A= }=0A= else if (name =3D=3D "left") {=0A= e.style.left =3D value;=0A= }=0A= else if (name =3D=3D "letter-spacing") {=0A= e.style.letterSpacing =3D value;=0A= }=0A= else if (name =3D=3D "line-break") {=0A= e.style.lineBreak =3D value;=0A= }=0A= else if (name =3D=3D "line-height") {=0A= e.style.lineHeight =3D value;=0A= }=0A= else if (name =3D=3D "list-style") {=0A= e.style.listStyle =3D value;=0A= }=0A= else if (name =3D=3D "list-style-image") {=0A= e.style.listStyleImage =3D value;=0A= }=0A= else if (name =3D=3D "list-style-position") {=0A= e.style.listStylePosition =3D value;=0A= }=0A= else if (name =3D=3D "list-style-type") {=0A= e.style.listStyleType =3D value;=0A= }=0A= else if (name =3D=3D "margin") {=0A= e.style.margin =3D value;=0A= }=0A= else if (name =3D=3D "margin-bottom") {=0A= e.style.marginBottom =3D value;=0A= }=0A= else if (name =3D=3D "margin-left") {=0A= e.style.marginLeft =3D value;=0A= }=0A= else 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