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Pediatric Research 59:54R-58R (2006)
=A9 2006 International = Pediatric=20 Research Foundation, Inc.
DOI: 10.1203/01.pdr.0000203568.63482.f9 =

Brain Tumor Stem Cells

ICHIRO = NAKANO and=20 HARLEY I. KORNBLUM

Departments of Psychiatry [H.I.K.], Pharmacology = [H.I.K.],=20 Neurosurgery [I.N.], and Pediatrics [I.N., HIK.], David Geffen School of = Medicine at University of California, Los Angeles, Los Angeles, CA, = 90095=20


3D"   =20 ABSTRACT
= TOP
3D"ABSTRACT
= INTRODUCTION
NEURAL STEM CELLS AND...
CRITICAL REGULATOR CANDIDATES OF...
CLINICAL SIGNIFICANCE OF THE...
CONCLUSIONS
REFERENCES
 
C= ancers=20 are composed of heterogeneous cell populations ranging from = highly=20 proliferative immature cells to more differentiated cells of = various=20 cell lineages. Recent advances in stem cell research have = allowed for=20 the demonstration of the existence of cancer stem cells in = acute=20 myeloid leukemia, breast cancer, and, most recently, in brain = tumors.=20 Each of these has some similarities with the normal stem = cells in the=20 corresponding organs. In brain tumors, putative cancer stem = cells=20 have been identified from glioblastoma multiforme, = medulloblastoma=20 and ependymoma. These tumor-derived cells self-renew under=20 clonal conditions, and differentiate into neuron- and = glia-like=20 cells as well as into abnormal cells with mixed phenotypes. = The=20 tumor stem cells, but not the rest of tumor cells form = secondary=20 tumors by transplantation into immunodeficient mouse brain. = In=20 this review, we discuss the cellular and molecular = relationships=20 between brain tumor stem cells and normal neural stem cells,=20 and also the possible clinical implications of brain tumor = stem=20 cells.

Abbreviations:
bFGF, basic fibroblast = growth=20 factor
GBM, glioblastoma multiforme
GFAP, glial = fibrillary=20 acidic protein
LIF, leukemia inhibitory factor
PTEN, = phosphatase and tenascin homolog
TOR, target of rapamycin


3D"   =20 INTRODUCTION
= TOP
= ABSTRACT
3D"INTRODUCTION
NEURAL STEM CELLS AND...
CRITICAL REGULATOR CANDIDATES OF...
CLINICAL SIGNIFICANCE OF THE...
CONCLUSIONS
REFERENCES
 
C= ancers,=20 rather than consisting of single cell types, contain a = variety of=20 different cells with different phenotypic and genetic=20 characteristics. There are numerous tumor types that can be=20 found within the CNS. Metastatic tumors arise from tissue = outside=20 the CNS, and spread hematogenously to the brain. Primary CNS=20 tumors are thought to arise directly from CNS tissue. = Generally,=20 these exclude such intracranial tumors as meningioma and = acoustic=20 neurinoma that, while existing only within the skull, they = are=20 not thought to arise from brain tissue. The most common form = of=20 brain tumors in pediatric patients is medulloblastoma, and in = adults=20 is glioblastoma multiforme (GBM). Both tumor types have = aggressive=20 characteristics, and cause high mortality and morbidity.=20 Medulloblastomas generally occur in the posterior fossa, = although=20 metastases can spread throughout the CNS, including so-called = "drop=20 mets" in the spinal cord. GBM are the most aggressive form of = gliomas, a heterogeneous group of tumors. While medulloblastoma = is=20 often treatable, there is still a high rate of morbidity and=20 mortality. To date, GBM remains one of the most difficult = cancers to=20 treat, with less than 5% of 5-y survival rate, despite of = multiple=20 treatments such as direct surgery, radiation therapy, and=20 chemotherapy. Traditional thinking holds that any (or many) = cells=20 within a tumor will be capable of giving rise to another = tumor (1).=20 The cancer stem cell hypothesis dictates that tumors arise = from a=20 single, self-renewing cell type, which then gives rise to the = rest of=20 the tumor, including a variety of "more differentiated" cell = types.=20 These cancer stem cells would be a minority population within = the=20 tumor. The practical implications of this hypothesis is that = any=20 curative therapy will need to kill or stop the cancer stem = cell from=20 proliferating, whereas therapies targeted at derivatives of = the=20 cancer stem cell will not be curative. Studies have provided = strong=20 evidence for the cancer stem cell hypothesis in leukemia and = in=20 breast cancer (2,3).=20

The first cancer which was found to contain stem cells was acute = myeloid leukemia (AML) (2)=20 (Table=20 1). A subfraction of cells in AML resembled normal = hematopoietic=20 stem cells based upon their morphologic and immunohistochimal = characteristics. It was found that this subset of cells, but = not the=20 rest of the tumor cells, could form AML when xenotransplanted = into=20 immnodeficient mice. The corresponding secondary AML in mice=20 possessed similar histopathological characteristics to the = primary=20 tumor. The second cancer type in which caner stem cells were=20 identified was breast cancer (3).=20 In this study, the authors used markers associated with = normal ductal=20 stem cells, to positively (CD44) and negatively (CD24) sorted = cells.=20 When small numbers of these cells were injected into = immunodeficient=20 mice, they formed tumors at very high frequency, while the = stem cell=20 negative fraction did not form tumors. These secondary tumors = were=20 histologically similar to the primary tumors and also = contained a=20 subpopulation of CD44+, CD24=96 cancer stem cells which = could, in=20 turn form tumors in other mice.


View = this=20 table:
[in=20 this window]
[in a new window]
  		Table 1. = Organ-specific cancer=20 stem cells =

 = ;

In addition to providing the first documentations of cancer = stem=20 cells, both of these studies raised the strong possibility = that the=20 origin of the cancer stem cells, themselves, lay in the=20 tissue-specific or adult stem cells resident within the = tissue. Thus,=20 although the cancer stem cell hypothesis does not require = cancer stem=20 cells to be derived from mutations of normal stem cells, = there is=20 evidence to suggest that, at least in these two cancers, such = is the=20 case.


3D"    NEURAL=20 STEM CELLS AND BRAIN TUMOR STEM CELLS =
= TOP
= ABSTRACT
= INTRODUCTION
3D"NEURAL STEM CELLS AND...
CRITICAL REGULATOR CANDIDATES OF...
CLINICAL SIGNIFICANCE OF THE...
CONCLUSIONS
REFERENCES
 
N= eural=20 stem cells are a form of tissue-specific stem cell. They are=20 self-renewing and capable of forming the major cell types = intrinsic=20 to the brain, neurons, astrocytes and oligodendrocytes. = Neural stem=20 cells were originally isolated in culture by exposing = dissociated CNS=20 cells to epidermal growth factor (EGF) in a relatively = minimal medium=20 (4).=20 As a result, large spheres of cells formed from single cells = which=20 could then be re-dissociated and seeded at extremely low = density to=20 produce new spheres, indicating a capacity for self-renewal. = In the=20 proliferative and undifferentiated state, these cells express = the=20 intermediate filament, nestin. However, when EGF is removed, = the=20 cells begin to express markers typical of differentiated = neurons and=20 glia. Thus, these cells meet the criteria of being stem cells = in=20 that they are both self-renewing and multipotent.

Neural stem cells can be isolated from the CNS at virtually = any=20 stage of development after neural tube closure, and possibly = before,=20 through adulthood (4,5).=20 In vivo, neural stem cells are generally reside within = specialized germinal zones situated along the surface of the = neural=20 tube=97the developing and mature ventricular system. However, = there is=20 some heterogeneity of cells that share the critical features = of=20 neural stem cells; self-renewal and multipotency (6).=20 During development, neural stem cells divide rapidly and = extensively=20 self-renew. Some investigators call these cells multipotent=20 progenitors, since, in general, stem cells are thought as = relatively=20 slowly dividing. Radial glia, the bipolar cells extending = from the=20 ventricular to the pial surface of the developing neural tube = have=20 been long perceived as "simple" guides for migrating cortical = neurons. Several recent studies, however, have demonstrated = that=20 radial glia, themselves function as neural stem cells during = prenatal=20 rodent development. Later, in postnatal stages and adulthood, = a type=20 of neural stem cell exists that divides relatively slowly and = produces more rapidly dividing self-renewing progenitors = which, in=20 turn, produces more committed progenitors. Recent evidence = has=20 indicated that these putative, slowly dividing cells express = glial=20 fibrillary acidic protein (GFAP), a classic marker for = astrocytes (7,8).=20 Likewise, in the adult human brain, neural stem cells are = also=20 GFAP-positive cells (9).=20

Neural stem cells have been isolated and enriched from fetal = and=20 adult human brain and grown as neurospheres and adherent = cultures.=20 Human neural stem cells are CD133-positive and CD24-negative = (10).=20 Flow sorting for these markers, greatly enriches cultures for = neurosphere-forming cells, although this set of markers does = not=20 completely purify neural stem cells.

Following the isolation of neural stem cells, there was wide=20 speculation that mutations of neural stem cells were the = origins=20 of many brain tumors. There are several lines of evidence = supporting=20 the hypothesis that brain tumors arise from aberrant neural=20 stem cell proliferation (11)=20 including the fact that many brain tumors contain neuronal = and glial=20 elements and express the intermediate filament nestin (12).=20 Direct evidence for a neural stem cell origin of human brain = tumors=20 is difficult to obtain. However, an elegant series of studies = using=20 transgenic models has demonstrated that nestin-expressing = progenitors=20 overexpressing the oncogene, c-Myc, can give rise to gliomas = and=20 medulloblastomas (13,14).=20 Transformation of GFAP positive cells in vivo can give = rise=20 to gliomas, as well (15).=20 In the past, this finding would have been taken as evidence = of=20 astrocytes being the origin of these experimental tumors, but = now,=20 given that postnatal neural stem cells are known to be GFAP = positive=20 (8),=20 these results are also consistent with a neural stem cell=20 origin.

Despite evidence that neural stem cells can be the source of = brain=20 tumors under some experimental conditions, it is unlikely = that they=20 are the source of all brain tumors. Medulloblastomas are = tumors of=20 the cerebellum. Recent microarray and animal model studies = strongly=20 indicate that the source of many, if not all medulloblastomas = is the=20 external granule cell (16).=20 This cell type, like neural stem cells, is self-renewing, but = it is=20 not multipotent under most conditions. Additionally, many = tumors=20 appear to have origins away from the ventricular surface, the = site of neural stem cells in vivo, making it more likely = that=20 they arise from transformation of other progenitors or more=20 fully differentiated glia. One potential cell of origin could = be the recently identified glial-like cells with a capacity = to=20 self-renew and produce neurons, astrocytes and oligodendrocytes = that=20 are dispersed throughout the cortex and cerebellum, at sites = distant=20 from the ventricular surface (17).=20

Despite the fact that not all brain tumors are likely to be=20 derived from neural stem cells, many brain tumors do contain=20 stem cells within them that bear many similarities to neural=20 stem cells. We found that several brain tumors, including=20 astrocytomas (low and high grade), ependymoma, glioblastoma=20 multiforme, and medulloblastomas contained cells that = proliferated in=20 the presence of EGF, basic fibroblast growth factor (bFGF) = and=20 leukemia inhibitory factor (LIF) under conditions identical = to those=20 reported for embryonic human neural stem cells (18).=20 Others have also obtained similar data with gliomas (19,20)=20 medulloblastomas (20)=20 and ependymomas (21).=20 These cells readily formed neurospheres as shown in Fig.=20 1. Immunocytochemical analysis of these tumor-derived = spheres=20 demonstrated that most expressed nestin (Fig.=20 1). Following growth factor withdrawal, most = tumor-derived=20 spheres gave rise to cells with glial and neuronal morphology = and=20 antigenic characteristics (Fig.=20 1). Tumor-derived spheres could be passaged clonally, and = these=20 clones could again be demonstrated to be multipotent. The = numbers of=20 neuron-like and glial-like cells in each clone within a tumor = were=20 remarkably similar although the relative proportions varied = greatly=20 from tumor to tumor (18).=20



View = larger=20 version (54K):
[in=20 this window]
[in a new window]
  		Figure 1. Characteristics = of brain=20 tumor stem/progenitor cell. Normal neural stem cells = (left=20 panel) can be enriched as neurospheres in culture, and=20 self-renew. Majority of cells in proliferating neurospheres = are=20 nestin-positive. Once these spheres are induced to = differentiate,=20 they form TuJ1-positive neurons, GFAP-positive astrocytes, = as well=20 as O4-positive oligodendrocytes. Brain tumors (right = panel)=20 contain heterogeneous cell populations. Immunohistochemistry = shows=20 multiple cell types labeled with various markers such as = nestin,=20 TuJ1, and GFAP (A,B). Similar to the normal stem = cells, brain=20 tumor stem cells can be isolated and enriched as spheres = (C),=20 which are highly expressing nestin (D). Besides with = their=20 self-renewal capacity, they also differentiate into multiple = cell=20 types, which exist in the original tumor, such as = TuJ1-positive=20 neuron-like cells (E), GFAP-positive astrocyte-like = cells=20 (E), as well as double positive (arrows in = F)=20 abnormal cells. =

 = ;

The data described above demonstrate the presence of = self-renewing,=20 multipotent progenitors within brain tumors, but do not prove = that they are cancer stem cells. Two studies from different=20 groups, however, do demonstrate this. Galli et al. (22)=20 demonstrated that neurosphere cultures generated from GBM = cells (in a=20 manner very similar to Hemmati et al. (18))=20 could give rise to GBMs in immunodeficient mice. Tumors could = result=20 from cultures that had been expanded from single cells and = bore the=20 same cytogenetic abnormalities as the parent tumors. Singh = et=20 al. (23)=20 used a slightly different strategy. They sorted glioblastomas = and=20 medulloblastomas for CD133 and found that the CD133- positive = cells=20 transplanted at low density readily formed tumors in = immunodeficient=20 mice. These tumors could be re-sorted for CD133 positive = cells,=20 which could then form new tumors in recipient mice. CD133=20 negative cells, even at much higher concentrations, did not = form=20 tumors. More recently, tumorigenic stem cells were isolated = from=20 ependymomas from various brain and spinal cord regions.=20 Interestingly, these cells had the properties of radial glia. = Taken=20 together, the studies of Singh et al. (20,23)=20 Galli et al. (22)=20 and our own study (18)=20 strongly support the hypothesis that at least some brain = tumors=20 contain cancer stem cells with at least some of the = characteristics=20 of neural stem cells.


3D"   =20 CRITICAL REGULATOR CANDIDATES OF SELF-RENEWAL OF BRAIN TUMOR STEM = CELLS=20
= TOP
= ABSTRACT
= INTRODUCTION
NEURAL STEM CELLS AND...
3D"CRITICAL REGULATOR CANDIDATES OF...
CLINICAL SIGNIFICANCE OF THE...
CONCLUSIONS
REFERENCES
 
T= he=20 isolation of cancer stem cells from brain tumors is important = because=20 of the implications that only through attacking these cells, = will we=20 be able to eradicate the tumors that contain them. As stated = above,=20 cancer stem cells and adult stem cells share the properties = of=20 self-renewal and multipotentiality. Several studies have = demonstrated=20 that genes known to play roles in the self-renewal of somatic = stem=20 cells also are likely to play similar roles in cancer stem = cells.=20 Some of these pathways, which are not mutually exclusive, are = described here.


Bmi-1.=20 Bmi-1 is a polycomb transcription factor and is known to regulate=20 chrmomatin remodeling. Bmi-1 has been previously shown to = regulate=20 the proliferation of hematopoetic stem cells as well as = leukemic=20 stem cells (24).=20 Analysis of Bmi-1 mutant mice have shown that it is also = important=20 for self-renewal of normal neural stem cells (25).=20 Bmi-1 binds to p14INKa and p16ARF, and inhibits the = activation of=20 their signaling (26).=20 These two downstream genes are highly expressed in primary = GBM as=20 well as oligodendrocytoma, another type of glioma. The high = level of=20 bmi-1 expression in our tumor-derived progenitors in spheres = (18)=20 suggests that this gene, as well as its signaling pathway, = plays an=20 important role in the proliferation of not only GBM but also = stem=20 cells in GBM. Recently bmi-1 and its associated genes were = found=20 as critical indicators of the prognosis of various cancers=20 including glioma, according to the cDNA microarray data set = (27).=20 This also suggests that bmi-1 and the genes that it regulates = have a strong influence on proliferation of tumor cells. =

PTEN and the PI3 Kinase-Akt=20 pathway. Activation of PI3 kinase leads to = phosphoryolation=20 of Akt which, in turn, leads to promotion of proliferation = and cell=20 survival, among other things (28).=20 A part of this cascade includes TOR (target of rapamycin). = Many=20 tumors frequently have enhanced activity of this pathway. = Mutations=20 of the EGF receptor, for example, are frequently found in GBM = and=20 confer a worse prognosis with a more aggressive tumor. = Another=20 mechanism by which this pathway is regulated is via the = phosphatase=20 PTEN (phosphatase and tenascin homolog deleted on chromosome = 10).=20 PTEN suppresses Akt phosphorylation by reversing PI3 = kinase-driven=20 phosphorylation. PTEN is a tumor suppressor gene, and is = frequently=20 deleted in GBM. We have previously demonstrated that PTEN is = a=20 critical regulator of neural stem cell self-renewal, as its = loss=20 induces greater proliferation as well as enhanced recruitment = of=20 neural stem cells from a quiescent to an active cycling state = (29,30).=20

Drugs that interact with this pathway are potential candidates = for=20 treatment of brain tumors. Inhibitors of EGFR activation have = been=20 recently shown to be effective in treating patients with the = EGFR=20 VIII mutation (31),=20 an active form of the receptor. Rapamycin is a drug that = inhibits TOR=20 and is under investigation for a variety of cancers, = including GBM.=20 It is unknown, however, whether these agents selectively = inhibit=20 cancer stem cell proliferation.

Maternal embryonic leucine-zipper kinase=20 (MELK). MELK encodes a serine/threonine kinase with = a=20 leucine-zipper domain, and is a poorly characterized member = of=20 snf1/AMPK family. Several members of this family are known as = tumor=20 survival factors under conditions of nutrient starvation. Our = previous studies demonstrated that normal neural stem cells = highly=20 express MELK. Functional analysis demonstrated that MELK = regulates=20 the self-renewal of murine (32)=20 and human (unpublished) neural stem cells. MELK was recently=20 identified by microarray analysis to be highly correlated = with=20 malignancy of a variety of tumors and to be an important = regulator of=20 cell cycle progression in these cancer cells (33).=20 We have found that MELK is highly expressed in brain tumors = as well=20 as in brain tumor stem cell containing cultures (18).=20 Functional studies in these cultures indicate that MELK = regulates the=20 proliferation of both putative cancer stem cells as well as = non stem=20 cell components (unpublished). The mechanism by which MELK = regulates=20 proliferation in cancer stem cells or other cells is still = unknown.=20 Previous studies have suggested that one mechanism of MELK = action is=20 by regulated the transcription factor B-Myb, a known cell = cycle=20 regulator (32).=20 However, our own preliminary data suggest that this is not = the only=20 function of MELK. MELK has both kinase and RNA processing=20 functions, both of which could contribute to its net = effects.=20

Wnt and Hedgehog signaling in=20 medulloblastomas. As described above, cancer stem = cells have=20 been reported for medulloblastomas, although there is some=20 disagreement in the literature about whether these cells = represent=20 true stem cells. The Wnt and sonic hedgehog signaling = cascades=20 promote the proliferation of numerous cells, including = granule cell=20 progenitors of the cerebellum, the presumed cells of origin = of=20 medulloblastoms. Both have also been directly shown to = regulate the=20 growth of murine and human medulloblastomas (16).=20 Mutations of the sonic hedgehog receptor patched (which = functions to=20 inhibit the pathway) results in the formation of = medulloblastomas in=20 both mice and humans. It remains to be seen whether these = effects are=20 on a cancer stem cell, per se.


3D"   =20 CLINICAL SIGNIFICANCE OF THE CANCER STEM CELL THEORY=20
= TOP
= ABSTRACT
= INTRODUCTION
NEURAL STEM CELLS AND...
CRITICAL REGULATOR CANDIDATES OF...
3D"CLINICAL SIGNIFICANCE OF = THE...
CONCLUSIONS
REFERENCES
 
T= he=20 isolation of cancer stem cells is an important step in the=20 understanding of tumor biology. However, there are also = practical=20 implications in the diagnosis and treatment of brain for the=20 clinician.


Significance for = brain tumor=20 stratification. Traditional anatomic/pathologic=20 categorization of tumors have very limited ability to = completely=20 stratify patients into meaningful subgroups for prognosis and = intervention. Protein expression by immunohistochemistry has = greatly=20 enhanced the potential link between pathologic diagnosis and=20 prognosis. However, relative lack of useful antibodies shows = the=20 limitation of this strategy. Recently, large scale gene = expression=20 study by microarray and analyses of specific pathways have = been more=20 successful at regrouping patients within broad histologic = categories=20 (16).=20 The existence of caner stem cells raises the possibility that = expression profiling and molecular pathway analysis of these = cells=20 will provide further useful stratification of tumors. For = example,=20 one might isolate cancer stem cells from individual patients = and then=20 analyze gene or protein expression profiles as well as the=20 activity of the specific pathways described above (Fig.=20 2).



View = larger=20 version (20K):
[in=20 this window]
[in a new window]
  		Figure 2. Clinical = implication for=20 cancer stem cell theory. =

 = ;

Significance for brain=20 treatment. The isolation and demonstration of brain = tumor=20 stem cells, suggests that, for those tumors that contain such = cells,=20 treatment can only be gauged as successful if the stem cell = component=20 is successfully eradicated (Fig.=20 2). Since, by their nature, stem cells are heartier and = more=20 resistant to insult, this may prove to be a daunting task. = There are=20 several potential avenues to address this issue, however. = First,=20 since cancer stem cells may use specific molecular pathways = to drive=20 their self-renewal, one might use known and = as-yet-to-be-discovered=20 selective inhibitors of these pathways to attack them. In = fact, as=20 intimated above, two groups of agents, EGF receptor = inhibitors and=20 rapamycin-related compounds, that are already in clinical = trial and=20 showing some promise are predicted to inhibit cancer stem = cell=20 self-renewal (31).=20 Another way to attack cancer stem cells would be to use them = as=20 targets for small molecule screens, an approach that we are = taking.=20 Finally, if specific antigens are expressed by cancer stem = cells,=20 then these antigens could be used in immunotherapies, which = have=20 already shown some promise in the treatment of glioma.

Are there implications for neural=20 repair. Neural stem and progenitor cells are = potential=20 sources of therapy for a wide variety of disorders, ranging = from=20 enzymatic deficiency to neurodegenerative disease. It is well = known=20 that transplantation of pluripotent embryonic stem cells into = the=20 brain or other tissue can result in teratoma formation. The=20 possibility that neural stem and progenitor cells can give = rise to=20 tumors theoretically raises the possibility that = transplantation of=20 the cells could result in tumor formation. It is important to = state,=20 however, that this simply has not been shown to be the case, = at=20 least in the short to moderate timespans used in animal = studies.=20 To our knowledge, despite more than one thousand reports of=20 neural stem and progenitor cell transplantation, none have=20 reported malignant transformation.


3D"   =20 CONCLUSIONS
= TOP
= ABSTRACT
= INTRODUCTION
NEURAL STEM CELLS AND...
CRITICAL REGULATOR CANDIDATES OF...
CLINICAL SIGNIFICANCE OF THE...
3D"CONCLUSIONS
REFERENCES
 
T= he=20 isolation and initial characterization of brain tumor stem = cells=20 provides hope that new avenues of therapy will be opened up. = However,=20 many questions remain before our fully utilizing these = discoveries.=20 Among these are the following: Do all brain tumors contain = cancer=20 stem cells? What are the differences and similarities between = cancer=20 stem cells from different tumors? Does malignant progression = of low=20 grade to high grade gliomas directly involve brain tumor stem = cells?=20 Is CD-133 the best marker for the prospective isolation of = cancer=20 stem cells? Can we attack brain tumor stem cells without = attacking=20 normal neural stem cells? Would this matter? These questions = and many=20 others highlight the early state of this field and the great=20 amount of work needed before putting the discovery of cancer = stem=20 cells to productive use.

Received December 7, 2005; accepted = December 21,=20 2005.

Correspondence: Harley I. Kornblum, M.D., Ph.D., Address for=20 mailing corresponding author and proofs: Departments of = Psychiatry,=20 Pharmacology, and Pediatrics, David Geffen School of Medicine = at UCLA, Los Angeles, CA 90095; e-mail: hkornblum{at}mednet.ucla.edu

Some of the work described here was supported by a Jonsson = Comprehensive=20 Cancer Center Interdisciplinary Grant.


3D"   =20 REFERENCES
= TOP
= ABSTRACT
= INTRODUCTION
NEURAL STEM CELLS AND...
CRITICAL REGULATOR CANDIDATES OF...
CLINICAL SIGNIFICANCE OF THE...
CONCLUSIONS
3D"REFERENCES
&nb= sp;

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P. O.=20 Sakariassen, L. Prestegarden, J. Wang, K.-O. Skaftnesmo, R. = Mahesparan, C.=20 Molthoff, P. Sminia, E. Sundlisaeter, A. Misra, B. B. Tysnes, M. = Chekenya,=20 H. Peters, G. Lende, K. H. Kalland, A. M. Oyan, K. Petersen, I. = Jonassen,=20 A. van der Kogel, B. G. Feuerstein, A. J. A. Terzis, R. Bjerkvig, = and P.=20 O. Enger
Angiogenesis-independent tumor growth mediated = by=20 stem-like cancer cells
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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_01BF_01C70A6D.453C6F10 Content-Type: application/octet-stream Content-Transfer-Encoding: quoted-printable Content-Location: http://www.pedresearch.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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quoted-printable Content-Location: http://www.pedresearch.org/javascript/entrez/callback.js /************************************************************************= *****=0A= * javascript/entrez/callback.js=0A= *=0A= * Entrez Linking callback to populate content box.=0A= *=0A= * Copyright 2006 Board of Trustees of the Leland Stanford Junior = University.=0A= = *************************************************************************= ***/=0A= =0A= /*=0A= * Execute callback to fill content box with Entrez Linking information.=0A= */=0A= function entrez_callback(pmid, callback_url) {=0A= /*=0A= * MSIE 5.5 and below have issues with the JavaScript=0A= * used for Entrez Linking. For now we have to disable=0A= * the callback until we can track down a proper fix=0A= * (or everybody sanely upgrades to version 6 or 7!).=0A= */=0A= if (navigator) {=0A= var appname =3D navigator.appName;=0A= if (appname =3D=3D "Microsoft Internet Explorer") {=0A= var userAgent =3D navigator["userAgent"];=0A= var s =3D "MSIE ";=0A= var n =3D -1; =0A= if ((n =3D userAgent.indexOf(s)) !=3D -1) {=0A= var v =3D parseFloat(userAgent.substring(n+s.length));=0A= if (v < 6) {=0A= return;=0A= }=0A= }=0A= }=0A= }=0A= =0A= /*=0A= * Acquire table row element to update, initiate callback=0A= * to update table with Entrez Links.=0A= */=0A= var tr =3D document.getElementById('entrez_callback_'+pmid);=0A= if (!tr) {=0A= return;=0A= }=0A= var req =3D new XMLHttpRequest();=0A= if (!req) {=0A= return;=0A= }=0A= req.onreadystatechange =3D function() {=0A= if (req.readyState =3D=3D 4 && (req.status =3D=3D 200 || req.status = =3D=3D 304)) {=0A= var src =3D req.responseXML.documentElement;=0A= var dst =3D document.createDocumentFragment();=0A= for (var i =3D 0; i < src.childNodes.length; i++) {=0A= copy_xml_to_html(src.childNodes[i], dst);=0A= }=0A= var tbl =3D tr.parentNode;=0A= tbl.replaceChild(dst, tr);=0A= }=0A= }=0A= req.open('GET', callback_url, true);=0A= req.send(null);=0A= }=0A= ------=_NextPart_000_01BF_01C70A6D.453C6F10--