From: Subject: Cancer Stem Cells--Perspectives on Current Status and Future Directions: AACR Workshop on Cancer Stem Cells -- Clarke et al. 66 (19): 9339 -- Cancer Research Date: Wed, 3 Jan 2007 10:54:26 +0100 MIME-Version: 1.0 Content-Type: multipart/related; type="text/html"; boundary="----=_NextPart_000_0000_01C72F25.891D9060" X-MimeOLE: Produced By Microsoft MimeOLE V6.00.2900.3028 This is a multi-part message in MIME format. ------=_NextPart_000_0000_01C72F25.891D9060 Content-Type: text/html; charset="Windows-1252" Content-Transfer-Encoding: quoted-printable Content-Location: http://cancerres.aacrjournals.org/cgi/content/full/66/19/9339?ijkey=7adc1d7cc69efb88a22b8d29e8ddfee0cfed0437&keytype2=tf_ipsecsha Cancer Stem Cells--Perspectives on Current Status and = Future Directions: AACR Workshop on Cancer Stem Cells -- Clarke et al. = 66 (19): 9339 -- Cancer Research 3D"Cancer
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Special Workshop Report

Cancer Stem Cells=97Perspectives on Current Status and Future = Directions: AACR=20 Workshop on Cancer Stem Cells

Michael F.=20 Clarke1, John E. Dick2, = Peter B.=20 Dirks3, Connie J. Eaves4,=20 Catriona H.M. Jamieson5, D. Leanne=20 Jones6, Jane Visvader7, = Irving=20 L. Weissman8 and Geoffrey M. = Wahl6=20

1 Stanford University School of Medicine, = Stanford,=20 California; 2 University Health Network; 3 = University of=20 Toronto Hospital for Sick Children, Toronto, Ontario, Canada; = 4 Terry=20 Fox Laboratory BC Cancer Research Center, Vancouver, British Columbia, = Canada;=20 5 Moores University of California San Diego Cancer Center;=20 6 The Salk Institute for Biological Studies, La Jolla, = California;=20 7 Walter and Eliza Hall Institute, Parkville, Victoria, = Australia;=20 and 8 Stanford University Medical Center, Palo Alto, = California=20

Requests for reprints: Geoffrey M. Wahl, The = Salk=20 Institute for Biological Studies, 10010 North Torrey Pines Road, La = Jolla, CA=20 92037. Phone: 858-453-4100, ext. 1587; Fax: 858-457-2762; E-mail: wahl{at}salk.edu .

Introduction

A workshop was convened by the AACR to discuss the rapidly = emerging=20 cancer stem cell model for tumor development and progression. = The meeting participants were charged with evaluating data = suggesting=20 that cancers develop from a small subset of cells with = self-renewal=20 properties analogous to organ stem cells. Indeed, one = critical=20 question contemplated at the Workshop was whether tumors = derive=20 from organ stem cells that retain self-renewal properties but = acquire epigenetic and genetic changes required for = tumorigenicity=20 or whether tumor stem cells are proliferative progenitors = that=20 acquire self-renewal capacity. Of course, both mechanisms may = occur and may depend on the organ site. Either mechanism is=20 different from the widely held notion that most cells in a = tumor=20 should be competent for tumor formation. If the cancer stem=20 cell model is correct and if such cells retain the hallmarks = of=20 some tissue stem cells in being rare and entering the cell = cycle=20 infrequently, they could constitute a population that is=20 intrinsically resistant to current therapies designed to kill = cycling=20 cells. The participants critically discussed the need for a = precise=20 definition of cancer stem cells, the requirement for new = markers and=20 more rapid and tractable in vitro and in vivo = assays,=20 and the need to develop drug screening strategies to = selectively=20 target cancer stem cells to generate therapeutics for this=20 subpopulation of cells that could be resistant to classic = treatments=20 while possessing potent tumor-forming capacity.

The Cancer Stem Cell Hypothesis and Its=20 Implications

In the cancer stem cell model of tumors, there is a small subset = of cancer cells, the cancer stem cells, which constitute a = reservoir=20 of self-sustaining cells with the exclusive ability to = self-renew=20 and maintain the tumor. These cancer stem cells have the = capacity=20 to both divide and expand the cancer stem cell pool and to=20 differentiate into the heterogeneous nontumorigenic cancer = cell types=20 that in most cases appear to constitute the bulk of the = cancer=20 cells within the tumor. If cancer stem cells are relatively=20 refractory to therapies that have been developed to eradicate = the=20 rapidly dividing cells within the tumor that constitute the=20 majority of the nonstem cell component of tumors, then they = are=20 unlikely to be curative and relapses would be expected. If = correct,=20 the cancer stem cell hypothesis would require that we rethink = the way we diagnose and treat tumors, as our objective would=20 have to turn from eliminating the bulk of rapidly dividing = but=20 terminally differentiated components of the tumor and be = refocused on=20 the minority stem cell population that fuels tumor growth. = This=20 explains why the cancer stem cell hypothesis is at the center = of a rapidly evolving field that may play a pivotal role in=20 changing how basic cancer researchers, clinical = investigators,=20 physicians, and cancer patients view cancer.

Cancer Stem Cells: An Old Idea Reemerging at = an=20 Important Time

It has long been known from light microscopic studies that both=20 normal tissues and the tumors that develop within them = comprise=20 a heterogeneous collection of cell types, frequently = including=20 immune cells, a stroma consisting of various mesenchymal and=20 endothelial cells, and a variety of normal or malignant cells = specific to the tissue. Cells within the tumor often seem to=20 correspond to different stages of development. Epithelial = cancers,=20 for example, typically contain cells exhibiting divergent = nuclear=20 morphologies and differentiation features. Prevailing = explanations=20 for the observed tumor cell heterogeneity include influences = of=20 the microenvironment and genomic instability that generate = the=20 genetic and epigenetic changes, which prevent faithful and = accurate=20 replication and transmission of stable genotypes and = phenotypes. Such=20 instability could also explain why tumors typically contain a = subset=20 of cells that are refractory to most treatments. However, an=20 alternative (or complementary) emerging concept is that = malignant=20 cell populations may reflect the continuing operation of = perturbed=20 differentiation processes. Inherent to such a model is the = formation=20 of malignant populations consisting of a developmentally = defined=20 hierarchy of heterogeneous phenotypes derived from a small = subset of=20 "cancer stem cells."

Hematopoietic Stem Cells Have Led the=20 Way

Human cells fulfilling the properties expected of drug-resistant = cancer stem cells were initially isolated from blood cancers. = Tritium-labeling studies conducted on a variety of blood = cancers=20 in the 1960s showed the existence of a subset of = primitive-appearing=20 cells with cycling properties different from the majority of=20 tumor cells. These early tritium-labeling studies, coupled = with=20 genetic studies suggesting that many leukemias contained an=20 immature cell population capable of generating postmitotic = progeny,=20 predicted the existence of a leukemic stem cell.

Studies of acute myelogenous leukemia (AML) in the 1990s provide = compelling evidence for the existence of a cancer stem cell=20 subpopulation. Efforts to define the cell of origin of = hematopoietic=20 cancers were greatly enhanced by specific and quantitative = assays,=20 extensive lineage maps, and the availability of cell surface=20 markers for distinct cell types comprising this system. For=20 human AML, cancer stem cells were defined as those cells = capable=20 of regenerating human AML cell populations in irradiated = transplanted=20 nonobese diabetic (NOD)/severe combined immunodeficient = (SCID)=20 mice. The AML stem cells possessing this property were found = to=20 display a CD34+CD38=96 cell surface phenotype, = similar=20 to that typical of normal human primitive hematopoietic = progenitors.=20 This suggested that the AML stem cells may have originated = from=20 normal stem cells rather than arising from more committed=20 progenitors, although as will be discussed, this may not = necessarily=20 be the case for all cancer stem cells.

Definition: What Is a Cancer Stem = Cell?

An accurate definition is critical to enable researchers working = in the same or different systems to compare cells exhibiting = a=20 common set of properties. The consensus definition of a cancer = stem=20 cell that was arrived at in this Workshop is a cell within a = tumor=20 that possess the capacity to self-renew and to cause the=20 heterogeneous lineages of cancer cells that comprise the = tumor.=20 Cancer stem cells can thus only be defined experimentally by = their=20 ability to recapitulate the generation of a continuously = growing=20 tumor. The implementation of this approach explains the use = of=20 alternative terms in the literature, such as "tumor-initiating = cell"=20 and "tumorigenic cell" to describe putative cancer stem = cells.=20

It must be emphasized that proliferation is not synonymous with=20 self-renewal. A self-renewing cell division results in one or = both daughter cells that have essentially the same ability to = replicate and generate differentiated cell lineages as the = parental=20 cell. Stem cells have the ability to undergo a symmetrical=20 self-renewing cell division, causing identical daughter stem = cells=20 that retain self-renewal capacity, or an asymmetrical = self-renewing=20 cell division, resulting in one stem cell and one more=20 differentiated progenitor cell. In addition, it is thought = that stem=20 cells may divide symmetrically to form two progenitor cells,=20 which could lead to stem cell depletion. Promoting this form = of=20 division would be a way to deplete the cancer stem cell = population=20 and may constitute an alternative strategy to inducing cell=20 death to treat cancer.

Cancer Stem Cells in Solid = Tumors

Evidence for the existence of cancer stem cells in solid tumors=20 has been more difficult to obtain for several reasons. Cells=20 within solid tumors are less accessible, and functional = assays=20 suitable for detecting and quantifying normal stem cells from = many organs have not yet been developed. Therefore, the cell=20 surface markers required to isolate such cells have not been=20 identified. There has been some impressive work in this area=20 recently, including the demonstration that single mouse = mammary=20 cells can be transplanted and reconstitute a complete mammary = gland. Cells have also been isolated from human breast tumors = that can cause breast cancer in NOD/SCID mice through serial=20 transplantations, suggesting a capacity for self-renewal. = These=20 cells were CD44+CD24=96/low in eight of nine = patients=20 and established tumors in recipient animals when as few as = one=20 hundred cells were transplanted, whereas tens of thousands of = breast cancer cells with a different marker set failed to = induce=20 tumors. Brain tumor stem cells that can produce serially=20 transplantable brain tumors in NOD/SCID mice have also been = isolated=20 from human medulloblastomas and glioblastomas. These cells = can be=20 enriched by sorting for CD133+, a marker found on = normal=20 neural stem cells, and the transplantation of one hundred=20 CD133+ tumor cells was sufficient to initiate the=20 formation of a tumor in recipient animals. In contrast, no = mice=20 injected with the negative population developed brain tumors. = More=20 recently, cells have been isolated from human prostate cancer = patients that can produce serially transplantable prostate = tumors in=20 NOD/SCID mice. Sorting for Hoechst dye=96excluding side = population (SP)=20 cells and cells expressing CD44 allowed the isolation of a = population=20 enriched for cells with this ability. Together, these studies = reveal that only a small subset of cells in several different = tumor types is capable of tumor formation in such transplant=20 assays. These data are consistent with the cancer stem cell=20 hypothesis. Nonetheless, caution needs to be exerted when=20 interpreting transplantation assays as described in the = section on=20 functional and phenotypic assays.

Clarifying the Concepts and = Definitions

The term cancer stem cell has led to some confusion. Many = interpret=20 the term cancer stem cell to mean that such cells derive from = the stem cells of the corresponding tissue. Cancer stem cells = may indeed arise from normal stem cells by mutation of genes=20 that make the stem cells cancerous, but this may not be the=20 case in all tumors. For example, in blast crisis chronic = myelogenous=20 leukemia (CML), a committed granulocyte-macrophage progenitor = may acquire self-renewal capacity and thus "reacquire" = stem-like=20 properties due to the effects of later mutations. It is = conceivable=20 that more differentiated cells can, through multiple = mutagenic=20 events, acquire the self-renewal capacity and immortality = that=20 typify cancer stem cells. In both of these examples, a = differentiated=20 cell, not the tissue stem cell, eventually evolves to become = a=20 full-blown cancer stem cell.

The term tumor-initiating cell can also cause confusion. In = some=20 of the seminal studies in this field, the term "cancer = initiating"=20 has been used to refer to the ability of these cells to = initiate=20 tumors when transplanted. The tumor-initiating cell is often = used to=20 mean the cell that causes a tumor (or leukemia) in xenograft = models=20 of human cancer. Some have extrapolated that the cell that = initiates=20 a tumor xenograft is the same as the cell that received the = first=20 oncogenic "hits" in the patient. It is clear that the cancer = stem=20 cell capable of forming a tumor at one point in time might = change=20 during the progression of the disease. Thus, a tumor may be = initiated=20 by a set of mutations leading to transformation of one cell = type, but=20 progressive mutations occurring during the evolution of the = tumor may=20 result in the acquisition of stem cell properties by a second = cell type at a later time (Fig.=20 1 ). The stem cells within an individual tumor may = constitute a=20 moving target, that is, the cells that drive growth at one = point in=20 time may not be identical to those doing so at another stage = in tumor=20 evolution or during metastasis. Furthermore, the genetic and=20 epigenetic instability that are fundamental properties of = tumor=20 biology can induce cellular heterogeneity within the stem and = nonstem=20 cell populations of the tumor. Evidence was given that = specific=20 oncogenes or mutations could play a significant role in = determining=20 the target cell that eventually becomes malignant. Animal = models will=20 be useful for understanding the origins of cells with the = properties=20 expected of cancer stem cells and when and where they arise = during=20 cancer initiation and progression.



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  		Figure 1. Some potential = mechanisms=20 by which tissue stem cells generate cancer. Several = potential routes=20 by which mutations can accumulate in stem cells to generate = cancer,=20 based on data presented at the AACR Cancer Stem Cell = Workshop.=20 A, normal cells divide within a niche (green) = and can=20 accumulate mutations over time. B, stem cells may = have=20 acquired mutations that enable them to survive and = self-renew within=20 an alternative niche. This may enable a population of mutant = stem=20 cells to expand in a new region and/or in the environment of = different supporting cells (i.e., an alternate niche).=20 Alternatively, mutant stem cells may have acquired the = ability to=20 induce the proliferation of niche cells to allow for = expansion of=20 the niche to accommodate the mutant stem cells. C, = mutations=20 within the stem cells may enable them to proliferate in the = absence=20 of a niche, but they would require additional mutations to = undergo=20 self-renewal (D). A related possibility is that = mutated stem=20 cells undergo a differentiation program but retain = proliferative=20 potential. Acquisition of additional mutations in the = proliferative=20 progenitors would then be required to enable them to = self-renew.=20 E, normal stem cells may be exposed to a niche that = has=20 itself undergone modifications. Self-renewing divisions in = the=20 aberrant niche may then select for specific types of = mutations=20 within the stem cells, which are the precursors of cancer. = The=20 cancer shown is composed of a heterogeneous cell population = that=20 could be generated by the self-renewing divisions of the = mutated=20 cancer stem cell along with its "differentiated" cell types = that=20 comprise the tumor. Various mutated proliferative = progenitors could=20 also contribute to the tumor along with the self-renewing,=20 differentiation competent progenitor that is the cancer stem = cell.=20 Both models are compatible with clonal origin of most tumors = as all=20 cells shown derive from a common stem cell ancestor. =

 = ;
Normal=20 tissue stem cells are dependent on interactions with adjacent = stromal=20 cells that comprise a specialized microenvironment or niche, = which is=20 necessary for the maintenance of stem cell identity and = self-renewal=20 capacity (Fig.=20 1). Similarly, in some malignancies, tumor growth is also = thought=20 to depend on a dynamic interaction with adjacent stromal = cells that=20 compromise the tumor niche. As tumors grow, the niche may = change. It=20 is reasonable to surmise that the stem cells of a tumor may = also=20 evolve with changing cues in their microenvironment, = including=20 infiltration of immune cells and activation of inflammatory=20 responses. In addition, from studies of the Drosophila = germ=20 cell niche shown at the Workshop, it is possible that cancer = stem=20 cells will signal to their niche to allow it to expand as the = cancer=20 stem cells proliferate.

Cancer Stem Cell Assays

One of the most frequent errors made in defining stem cells = is=20 generalizing results obtained in studies of stem cells in one = organ.=20 Although stem cells in different adult tissues share the = fundamental=20 properties of self-renewal and the ability to differentiate = into a=20 diversity of mature cell types, stem cells in different = organs can=20 differ significantly from one another. Thus, properties that = are=20 useful for the identification and characterization of stem = cells in=20 one tissue are frequently not shared with the stem cells in a = different organ. This is likely to also be true for cancer = stem cells=20 isolated from different tumor types.

Self-renewal and lineage capacity are the hallmarks of any stem=20 cell. Therefore, as with normal stem cells, assays for cancer = stem cell activity need to be evaluated for their potential = to=20 show both self-renewal and tumor propagation. The gold standard = assay=20 that fulfills these criteria is serial transplantation in = animal=20 models, which, although imperfect, is regarded as the best = functional=20 assay for these two critical criteria.

In transplantation assays, cells are xenografted into an = orthotopic=20 site of immunocompromised (typically NOD/SCID) mice that are=20 assayed at various time points for tumor formation. To show=20 self-renewal, cells then must be isolated from the tumors and = grafted into a second recipient animal. Issues complicating=20 transplantation assays include potential effects of the = grafting=20 site. It is known that normal stem cells can be highly = dependent=20 on signals from the surrounding stroma for function, and it = is=20 not clear what the effect may be on separating cancer stem = cells from=20 any supporting cells during the course of the assay. = Experiments=20 using mixed populations of normal and breast tumor cells in = mice have=20 shown that combining tumor cells with normal fibroblasts = increases=20 latency and decreases tumor take, whereas combining them with = carcinoma-associated fibroblasts has the opposite effect. = Conversely,=20 nontumor cells placed next to tumor stroma can become = independently=20 tumorigenic, possibly due to stroma-induced genetic or = epigenetic=20 instability. The number of cells needed to form a tumor can = also be=20 affected by the addition of irradiated feeder cells or the = use of=20 Matrigel; for feeder cells, by orders of magnitude. =

Interpretation of transplantation assays is also complicated = by=20 the possibility that the cells that can recapitulate the = tumor might=20 have a greater ability to survive in the host; the = extraordinarily=20 high level of genetic and epigenetic changes that take place = within=20 most cancer cells, in some cases, as high as 1,000 daily, may = allow=20 some cells to generate diverse cell types not because they = are stem=20 cells per se but because of their genetic/epigenetic = instability.=20 Still, although serial transplantation assays remain the best = developed method to date for identifying cells with the = properties=20 expected of cancer stem cells, more sophisticated, precise, = and=20 simpler assays are likely to emerge as the field = develops.=20

In vivo assays are the gold standard for identifying stem = cells;=20 however, as serial transplantation experiments with animal = models=20 can take 6 months or more, high-throughput screens for lead=20 compounds will be difficult, if not impossible, using animal=20 models. Therefore, the development of reliable surrogate = assays=20 would significantly enhance drug development.

An ideal in vitro assay would be (a) quantitative; = (b)=20 highly specific, measuring only the cells of interest; = (c)=20 sufficiently sensitive to measure candidate stem cells when = present=20 at low frequency; and (d) rapid. Several in = vitro=20 assays have been used to identify stem cells, including = sphere=20 assays, serial colony-forming unit (CFU) assays (replating = assays),=20 and label-retention assays. Studies have also been done with = the goal=20 of determining genetic signatures that define cancer stem = cells.=20 However, each of these methods has potential pitfalls that = complicate=20 interpretation of the results. All three groups reporting the = isolation of normal breast stem cells indicated that = individual=20 breast stem cells do not form spheres by themselves using = conditions=20 that are permissive for the formation of neurospheres or=20 mammospheres. Furthermore, the rapidity of sphere development = in many=20 systems makes it unlikely that they arose from single cells = solely=20 through clonal expansion. The difficulty of distinguishing = the=20 relative contributions of aggregation and proliferation in = sphere=20 formation poses a major impediment to their use to construct = lineage=20 maps. Serial CFU assays have been used to identify cells with = increased proliferative potential, but their activity must be = confirmed by a clonal in vivo assay. Indeed, in the=20 hematopoietic system, selecting for CFU in semisolid medium = usually=20 identifies progenitors and not stem cells. This may be due to = the=20 need for the niche to provide the requisite signals for both=20 self-renewal and proliferation.

Additional technical issues make stem cell isolation and = functional=20 assays challenging. Although flow cytometry offers a = sensitive,=20 specific, and robust method of cell isolation and = purification,=20 some of its technical limitations make its application to = stem=20 cell purification challenging. For example, even when using=20 advanced sorting techniques to distinguish single cells from=20 aggregates, doublets (cells sticking to one another) can = still=20 occasionally sort together and need to be eliminated. Thus,=20 microscopy is needed to show that single cells were indeed = isolated.=20 It is very difficult to make viable single-cell suspensions = of=20 solid tissues, such as brain and epithelial tissues cells. = Thus,=20 techniques for dissociating cells must be carefully developed. = Most=20 flow cytometers are typically set up to sort blood components = using=20 small diameter streams at high pressures. These conditions = are often=20 not tolerated by larger, more fragile cells found in many = organs.=20 Therefore, diameters of the liquid stream and sorting = pressures=20 frequently must be optimized for cells isolated from solid = tissues.=20 In addition, although phenotypes based on markers often use = terms,=20 such as high, middle, low, and nonexpression, to describe the = properties of the sorted cells for each marker, these terms = are=20 subjective and can vary depending on the method used for cell = preparation, how the gates are set, and the antibody = preparation=20 used. Thus, cells marked as one phenotype by one group may = exhibit=20 another phenotype in other hands. This could be remedied by=20 availability of standardized antibodies and by consistent = calibration=20 of each batch of fluorescently labeled antibodies. At this = point in=20 time, such quality control needs to be done by the individual = investigator. Because of these technical challenges, it takes = the=20 typical neophyte several months of training in an experienced = stem=20 cell laboratory to even begin to master flow cytometry = isolation of=20 cancer stem cells.

Cancer Stem Cell Markers

It is clearly not sufficient to define a stem cell based solely = on=20 surface markers in the absence of linking marker expression = to a=20 self-renewal assay. None of the markers used to isolate stem = cells in=20 various normal and cancerous tissues is expressed exclusively = by stem=20 cells. For example, CD133 was used to successfully enrich for = brain=20 tumor stem cells, but it is also present on normal brain stem = cells=20 and on many nonstem cells in various tumors and tissues. The = same is=20 true for other commonly used markers, such as CD44, Sca1, and = Thy1.=20 In fact, the vast majority of cells that express these = markers are=20 not stem cells. In addition, markers used to identify stem = cells from=20 one organ are frequently not useful for identifying stem = cells in=20 other tissues: Sca-1 is useful for the identification of = murine blood=20 stem cells, but it is not consistently expressed by murine = mammary=20 duct stem cells. Furthermore, just because a marker can be = used=20 to identify stem cells from a particular organ does not mean = it=20 will work in all other contexts. For example, placing stem = cells=20 in culture can drastically alter their marker expression. = Thus,=20 describing the markers presently used to identify stem cells=20 from one tissue as a "stemness" marker when investigating a=20 potential stem cell population in a different tissue is = misleading.=20 The marker may or may not be useful for identifying stem = cells=20 from the other organ or tumor type.

Another phenotype used to distinguish cells is their presence=20 within the SP fraction defined by Hoechst dye efflux = properties.=20 However, as with cell surface markers, possession of a SP = phenotype=20 is not a universal property of stem cells, and in some = tissues,=20 the SP fraction may not contain the stem cells. Experiments=20 that identified normal breast stem cells by their ability to=20 generate mammary glands in cleared fat pads showed that the=20 majority of these cells are not included within the SP = fraction.=20 Possible toxicity of the dye to cells that do not exclude it=20 should also be considered as a caveat to interpreting = functional=20 assays of SP cells. As with other markers used to identify = certain=20 types of stem cells, marker expression must be linked with a=20 functional assay. Because of this complicating factor, it is=20 safer to first isolate stem cells using other methods and = then=20 ask whether that particular stem cell population is indeed = included=20 within the SP.

Label retention (bromodeoxyuridine incorporation) studies have=20 also been proposed as way of identifying stem cells. This = method=20 is based on the assumption that normal or cancer stem cells=20 either spend long periods not cycling or undergo an "immortal = strand" DNA replication and therefore preserve the labeled = state=20 for an extended period. However, neither event is the case = for=20 stem cells in every organ or tissue. In fact, both normal and = malignant breast stem cells appear to be cycling and so much=20 more needs to be known about the regulation of cancer stem = cell=20 cycling behavior before assays based on this property can be=20 relied on for purposes of identifying stem cells. = Furthermore,=20 it is known that not all stem cells are label retaining and = not=20 all label-retaining cells are stem cells. Thus, as with any = other=20 potential stem cell marker, one must link the property with a = stem=20 cell functional assay. In other words, label-retaining cells = must be=20 shown to regenerate the tissue in vivo.

Genetic and Epigenetic Signatures of=20 "Stemness"

Work has begun in several systems to develop genetic signatures=20 that typify stem cells. Several genes and signaling pathways, = including Bmi-1, Tie-2, Shh, Notch, and = Wnt/=DF-catenin,=20 have been shown to have important regulatory functions for = some=20 stem cells. However, as these genes frequently operate in = other=20 cell types, they cannot be called "stemness" genes. = Microarray=20 and genome-wide techniques can be applied to detect trends in = genetic and epigenetic "blueprints" for cancer stem cells, = but=20 to identify true signatures, pure populations are necessary.=20 This is especially true for cells expected to be rare, such = as=20 cancer stem cells, whose expression signature would be swamped = by the=20 majority of nonstem cells in a whole tumor sample. Even after = a=20 cancer stem cell signature from a particular type of tumor is = identified, one cannot assume that a given signature is = useful for=20 identifying cancer stem cells in a different tumor type = unless=20 validated by a functional assay (such as an in vivo=20 self-renewal assay as it is the most definitive at this point = in time).

The development of in vitro assays, although critical, is = at=20 an early stage, and the results of all in vitro work must = be=20 examined rigorously and ultimately validated in vivo.=20 Therefore, any method used to identify putative stem cells = must be=20 verified and followed by functional assays, preferably a gold = standard in vivo assay, before claims about "stemness" = can be=20 made. It should be a goal of the field to develop cell = surface=20 marker and gene activity profiles that can be used reliably = to=20 identify cancer stem cells. At this time, the presence of=20 particular markers or gene expression signatures associated = with=20 other stem cell populations, normal or cancer derived, is not = sufficient to label a given population of cells as cancer = stem cells=20 without confirmation by functional assays. In addition, = analysis=20 and interpretation of these data are limited by the purity of = the cell population in a given system; results from a mixed=20 population constitute an average and not a specific = signature.=20 Furthermore, use of gene inactivation to eliminate "stemness" = or gene=20 activation to engender "stemness" would be required to = functionally=20 link any marker to stem cell identity. Although the isolation = of=20 markers correlated with stem cells can aide in stem cell = isolation,=20 the identification and isolation of genes that are = functionally=20 significant for "stemness" would constitute an important step = forward and could provide valuable targets for drug = development.=20

Implications for Cancer Therapy: = Opportunities and=20 Challenges

The cancer stem cell hypothesis posits that cancer stem cells = are=20 a minority population of self-renewing cancer cells that fuel = tumor=20 growth and remain in patients after conventional therapy has = been=20 completed. The hypothesis predicts that effective tumor = eradication=20 will require obtaining agents that can target cancer stem = cells while=20 sparing normal stem cells. Experimental evidence in human AML = suggests that, compared with the bulk population of leukemic = blasts,=20 the leukemia stem cells are relatively resistant to = conventional=20 chemotherapeutic agents. Although it has been speculated in = solid=20 tumors that conventional agents kill the nontumorigenic = cancer cells=20 while sparing the cancer stem cells, this has not been = proven. There=20 are other models of drug resistance consistent with the = existence of=20 cancer stem cells that could explain relapse, including the = classic=20 view of mutation and selection.

The moving target nature of cancer stem cells may present a=20 challenge in the clinic. To achieve effective implementation = of=20 new therapies, physicians will require methods of determining = the=20 type (or types) of cancer stem cells present in a given = patient's=20 tumor. Work involving 150 CML patient peripheral blood and = bone=20 marrow samples is encouraging in that patients in blast = crisis all=20 exhibited an expansion of the granulocyte-macrophage = progenitor=20 population, which included the fraction displaying stem cell=20 properties. Therefore, it seems reasonable to expect that = tumors=20 sharing a similar pathology may also share common features in = their=20 cancer stem cell populations, which would facilitate = diagnosis and=20 the application of appropriate treatments. This point, = however, needs=20 to be borne out by further study.

It is important that agents directed against cancer stem cells=20 discriminate between cancer stem cells and normal stem cells. = This will require identification of realistic drug targets = unique=20 to cancer stem cells. The identification of such targets and=20 the development of anticancer agents will require a fuller=20 understanding of normal stem cell biology as well as the = genetics and=20 epigenetics of tumor progression. There is some indication = that such=20 an approach can be successful. For example, stem cells = isolated=20 from AML patients display differences from normal = hematopoietic=20 stem cells.

There has also been some success identifying agents effective=20 against leukemia stem cells. Conventional anthracycline = agents=20 show synergy with proteasome inhibitors against AML stem = cells,=20 reducing viability in vitro dramatically. The novel agent=20 parthenolide, isolated from Mexican medicinal plants and = shown to be=20 a potent nuclear factor-3D{kappa}=20B = inhibitor,=20 promotes apoptosis of AML stem cells and inhibits tumor = development=20 in NOD/SCID mice. Mutation of the Janus-activated kinase 2 = (JAK2)=20 kinase is found in many patients with the blood disorder = Polycythemia=20 Vera, and JAK2 inhibitors display efficacy against the cancer = stem=20 cells from these patients, although individual responses vary = significantly.

Summary and Future Directions

Participants in the AACR Workshop agreed that, to move the = cancer=20 stem cell field forward, multiple assays need to be validated = for as many putative stem cell populations as possible. Cells = should be interrogated by multiple methods, including = functional=20 assays, marker analysis, and analysis of genetic and = epigenetic=20 signatures. More accurate and standardized reagents are = needed,=20 particularly for the cell surface markers used for sorting. =

Participants also expressed the frequent difficulties in = obtaining=20 sufficient quantities of patient tissues. It was noted that=20 patients are often willing to supply tissue, but the current=20 regulatory climate presents an obstacle for many. Joint = efforts=20 by the research and patient advocacy communities are needed = to=20 overcome these regulatory barriers.

Clearly, there is much excitement and momentum in this important = field. Investigation of cancer stem cells offers the = possibility=20 of generating novel targets that could overcome issues of = drug=20 resistance, improve therapeutic efficacy, and make cancer = treatment=20 more successful and perhaps even curative while obviating = systemic=20 toxicity. The AACR will form a task force to discuss = developments=20 in this field to help identify and eliminate bottlenecks and = to=20 expedite progress in this promising area through focused = scientific=20 meetings and other mechanisms.

Appendix A. Participant list


Dr. Stephen B. Baylin, Johns = Hopkins=20 University, Baltimore, Maryland Dr. Michael F. Clarke, Stanford = University=20 School of Medicine, Stanford, = California
Dr. Bayard D. Clarkson, = Memorial=20 Sloan-Kettering Cancer Center, New York, New York Dr. John E. Dick, = University=20 Health Network, Toronto, Ontario, Canada
Dr. Peter B. Dirks, = University=20 of Toronto, Hospital for Sick Children, Toronto, = Ontario,=20 Canada Dr. Connie J. Eaves, Terry Fox=20 Laboratory, BC Cancer Research Center, Vancouver, = British=20 Columbia, Canada
Dr. Dong Fang, Celera = Genomics,=20 Rockville, Maryland Dr. Dwight Gary = Gilliland,=20 Harvard Medical School, Boston, Massachusetts
Dr. John A. Hassell, = McMaster=20 University, Hamilton, Ontario, Canada Dr. Lothar = Hennighausen,=20 National Institutes of Diabetes, Digestive and = Kidney=20 Diseases/NIH, Bethesda, Maryland
Dr. Catriona H.M. = Jamieson,=20 Moores University of California San Diego Cancer = Center,=20 La Jolla, California Dr. D. Leanne Jones, The Salk=20 Institute for Biological Studies, San Diego,=20 California
Dr. Peter A. Jones, = University=20 of Southern California, Norris Comprehensive = Cancer=20 Center, Keck School of Medicine, Los Angeles, = California Dr. Craig T. Jordan, = University=20 of Rochester School of Medicine, Rochester, New=20 York
Dr. Diane Krause, Yale = University=20 School of Medicine, New Haven, Connecticut Dr. Ihor R. Lemischka, = Princeton=20 University, Princeton, New Jersey
Dr. Hiromitsu Nakauchi,=20 University of Tokyo, Institute of Medical Science, = Tokyo,=20 Japan Dr. Larry Norton, = Memorial=20 Sloan-Kettering Cancer Center, New York, New = York
Dr. Stuart H. Orkin, Dana-Farber = Cancer=20 Institute, Boston, Massachusetts Dr. Kornelia Polyak, Dana-Farber = Cancer Institute, Boston, Massachusetts
Dr. Tannishtha Reya, Duke=20 University, Medical Center, Durham, North = Carolina Dr. Guy Sauvageau, = Institut de=20 Recherche en Immunologie et en = Cancerologie/Universit=E9 de=20 Montr=E9al, Montr=E9al, Quebec, Canada
Dr. Saul J. Sharkis, = Sidney=20 Kimmel Comprehensive Cancer Center, Baltimore,=20 Maryland Dr. Jerry W. Shay, University of = Texas=20 Southwestern Medical Center, Dallas, = Texas
Dr. James L. Sherley, = Massachusetts=20 Institute of Technology, Cambridge, Massachusetts Dr. Gilbert H. Smith = National=20 Cancer Institute (NCI), Bethesda, Maryland
Dr. Patricia S. = Steeg, National=20 Cancer Institute (NCI), Bethesda, Maryland Dr. Toshio Suda, Keio = University, Tokyo,=20 Japan
Dr. Dean G. Tang, The = University of Texas M. D. Anderson Cancer Center, = Smithville, Texas Dr. Thea Dorothy Tlsty, = University=20 of California School of Medicine, San Francisco,=20 California
Dr. Maarten van = Lohuizen, The=20 Netherlands Cancer Institute, Amsterdam, The=20 Netherlands Dr. Jane Visvader, Walter & = Eliza Hall=20 Institute Parkville, Victoria, = Australia
Dr. Amy Wagers, Harvard = Medical=20 School, Joslin Diabetes Center, Boston, = Massachusetts Dr. Geoffrey M. Wahl, = The Salk=20 Institute for Biological Studies, La Jolla,=20 California
Dr. Roberto Weinmann, = Bristol-Myers Squibb=20 Co., Princeton, New Jersey Dr. Irving L. Weissman, Stanford = University Medical Center, Palo Alto,=20 California

Acknowledgments

The costs of publication of this article were defrayed in part = by=20 the payment of page charges. This article must therefore be = hereby=20 marked advertisement in accordance with 18 U.S.C. = Section 1734=20 solely to indicate this fact.

Footnotes

Note: The AACR Cancer Stem Cells = Workshop=20 was held on February 2-4, 2006 in Lansdowne, Virginia. =

Received 8/23/06. Accepted 8/23/06.




This article has been cited by other=20 articles: (Search Google Scholar for Other Citing Articles)=20

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Opera = requires=0A= the Sun Java Runtime Environment .=0A= =0A= by Andrew Gregory=0A= http://www.scss.com.au/family/andrew/webdesign/xmlhttprequest/=0A= =0A= This work is licensed under the Creative Commons Attribution License. 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; // = 0=3Duninitialized,1=3Dloading,2=3Dloaded,3=3Dinteractive,4=3Dcomplete=0A= this.status =3D 0; // HTTP status codes=0A= this.statusText =3D '';=0A= this._headers =3D [];=0A= this._aborted =3D false;=0A= this._async =3D true;=0A= this._defaultCharset =3D 'ISO-8859-1';=0A= this._getCharset =3D function() {=0A= var charset =3D _defaultCharset;=0A= var contentType =3D = this.getResponseHeader('Content-type').toUpperCase();=0A= val =3D contentType.indexOf('CHARSET=3D');=0A= if (val !=3D -1) {=0A= charset =3D contentType.substring(val);=0A= }=0A= val =3D charset.indexOf(';');=0A= if (val !=3D -1) {=0A= charset =3D charset.substring(0, val);=0A= }=0A= val =3D charset.indexOf(',');=0A= if (val !=3D -1) {=0A= charset =3D charset.substring(0, val);=0A= }=0A= return charset;=0A= };=0A= this.abort =3D function() {=0A= this._aborted =3D true;=0A= };=0A= this.getAllResponseHeaders =3D function() {=0A= return this.getAllResponseHeader('*');=0A= };=0A= this.getAllResponseHeader =3D function(header) {=0A= var ret =3D '';=0A= for (var i =3D 0; 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_0000_01C72F25.891D9060 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= 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quoted-printable Content-Location: http://cancerres.aacrjournals.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. 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}=0A= else {=0A= if (iq=3D=3D-1 && ih=3D=3D-1) f.action+=3D"?"+p;=0A= else if (ih=3D=3D-1) f.action+=3D"&"+p;=0A= else if (iq=3D=3D-1) = f.action=3Df.action.substring(0,ih-1)+"?"+p+f.action.substring(ih);=0A= else = f.action=3Df.action.substring(0,ih-1)+"&"+p+f.action.substring(ih);=0A= }=0A= }=0A= return;=0A= }=0A= function __utmSetVar(v) {=0A= if (!v || v=3D=3D"") return;=0A= if (!_udo || _udo =3D=3D "") {=0A= _udh=3D_uDomain();=0A= if (_udn && _udn!=3D"") { _udo=3D" domain=3D"+_udn+";"; }=0A= }=0A= if (!_uVG()) return;=0A= var r=3DMath.round(Math.random() * 2147483647);=0A= _ubd.cookie=3D"__utmv=3D"+_udh+"."+_uES(v)+"; path=3D"+_utcp+"; = expires=3DSun, 18 Jan 2038 00:00:00 GMT;"+_udo;=0A= var s=3D"&utmt=3Dvar&utmn=3D"+r;=0A= if ((_userv=3D=3D0 || _userv=3D=3D2) && _uSP()) {=0A= var i=3Dnew Image(1,1);=0A= i.src=3D_ugifpath+"?"+"utmwv=3D"+_uwv+s;=0A= i.onload=3Dfunction() { _uVoid(); }=0A= }=0A= if ((_userv=3D=3D1 || _userv=3D=3D2) && _uSP()) {=0A= var i2=3Dnew Image(1,1);=0A= = i2.src=3D_ugifpath2+"?"+"utmwv=3D"+_uwv+s+"&utmac=3D"+_uacct+"&utmcc=3D"+= _uGCS();=0A= i2.onload=3Dfunction() { _uVoid(); 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return 1; }=0A= if (_udn=3D=3D"auto") {=0A= var d=3D_ubd.domain;=0A= if (d.substring(0,4)=3D=3D"www.") {=0A= d=3Dd.substring(4,d.length);=0A= }=0A= _udn=3Dd;=0A= }=0A= if (_uhash=3D=3D"off") return 1;=0A= return _uHash(_udn);=0A= }=0A= function _uHash(d) {=0A= if (!d || d=3D=3D"") return 1;=0A= var h=3D0,g=3D0;=0A= for (var i=3Dd.length-1;i>=3D0;i--) {=0A= var c=3DparseInt(d.charCodeAt(i));=0A= h=3D((h << 6) & 0xfffffff) + c + (c << 14);=0A= if ((g=3Dh & 0xfe00000)!=3D0) h=3D(h ^ (g >> 21));=0A= }=0A= return h;=0A= }=0A= function _uFixA(c,s,t) {=0A= if (!c || c=3D=3D"" || !s || s=3D=3D"" || !t || t=3D=3D"") return "-";=0A= var a=3D_uGC(c,"__utma=3D"+_udh,s);=0A= var lt=3D0,i=3D0;=0A= if ((i=3Da.lastIndexOf(".")) > 9) {=0A= _uns=3Da.substring(i+1,a.length);=0A= _uns=3D(_uns*1)+1;=0A= a=3Da.substring(0,i);=0A= if ((i=3Da.lastIndexOf(".")) > 7) {=0A= lt=3Da.substring(i+1,a.length);=0A= a=3Da.substring(0,i);=0A= }=0A= if ((i=3Da.lastIndexOf(".")) > 5) {=0A= a=3Da.substring(0,i);=0A= }=0A= a+=3D"."+lt+"."+t+"."+_uns;=0A= }=0A= return a;=0A= }=0A= function _uTrim(s) {=0A= if (!s || s=3D=3D"") return "";=0A= while ((s.charAt(0)=3D=3D' ') || (s.charAt(0)=3D=3D'\n') || = (s.charAt(0,1)=3D=3D'\r')) s=3Ds.substring(1,s.length);=0A= while ((s.charAt(s.length-1)=3D=3D' ') || = (s.charAt(s.length-1)=3D=3D'\n') || (s.charAt(s.length-1)=3D=3D'\r')) = s=3Ds.substring(0,s.length-1);=0A= return s;=0A= }=0A= function _uEC(s) {=0A= var n=3D"";=0A= if (!s || s=3D=3D"") return "";=0A= for (var i=3D0;i0) r=3Da.substring(i+1,i2); else return = ""; =0A= if ((i=3Da.indexOf(".",i2+1))>0) t=3Da.substring(i2+1,i); else return = ""; =0A= if (f) {=0A= return r;=0A= } else {=0A= var c=3Dnew = Array('A','B','C','D','E','F','G','H','J','K','L','M','N','P','R','S','T'= ,'U','V','W','X','Y','Z','1','2','3','4','5','6','7','8','9');=0A= return = c[r>>28&m]+c[r>>23&m]+c[r>>18&m]+c[r>>13&m]+"-"+c[r>>8&m]+c[r>>3&m]+c[((r= &7)<<2)+(t>>30&3)]+c[t>>25&m]+c[t>>20&m]+"-"+c[t>>15&m]+c[t>>10&m]+c[t>>5= &m]+c[t&m];=0A= }=0A= }=0A= function _uIN(n) {=0A= if (!n) return false;=0A= for (var i=3D0;i"9") && (c!=3D".")) return false;=0A= }=0A= return true;=0A= }=0A= function _uES(s,u) {=0A= if (typeof(encodeURIComponent) =3D=3D 'function') {=0A= if (u) return encodeURI(s);=0A= else return encodeURIComponent(s);=0A= } else {=0A= return escape(s);=0A= }=0A= }=0A= function _uUES(s) {=0A= if (typeof(decodeURIComponent) =3D=3D 'function') {=0A= return decodeURIComponent(s);=0A= } else {=0A= return unescape(s);=0A= }=0A= }=0A= function _uVG() {=0A= if((_udn.indexOf("www.google.") =3D=3D 0 || _udn.indexOf(".google.") = =3D=3D 0 || _udn.indexOf("google.") =3D=3D 0) && _utcp=3D=3D'/') {=0A= return false;=0A= }=0A= return true;=0A= }=0A= function _uSP() {=0A= var s=3D100;=0A= if (_usample) s=3D_usample;=0A= if(s>=3D100 || s<=3D0) return true;=0A= return ((__utmVisitorCode(1)%10000)<(s*100));=0A= }=0A= ------=_NextPart_000_0000_01C72F25.891D9060--