Upload cancer.csv

cancer.csv

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+,passage,passage_token
+0,"Why Haven’t We Cured Cancer?
+Seventy years since the first reported use of cancer chemotherapy, malignancies are the second most common cause of
+death among children and adults. So why are the headlines
+rarely punctuated with cancer success stories? One explanation
+is that, although classifying cancers is relatively straightforward,
+understanding the basis of cancer heterogeneity is complex.
+Over the years, we have become quite proficient at cataloging
+cancer according to patterns of epidemiology and pathology.
+Each cancer is recognized to occur at a particular age, to occur
+more frequently in one sex than another, and to have a particular
+morphology—usually resembling the originating tissue.
+Advances in imaging and histology have enabled us to further
+segregate cancer diagnoses into distinct stages and grades
+that predict different treatment responses and prognoses.
+Despite this exhaustive work, our attempts to understand the
+processes that generate the different forms of cancer have
+proved far less fruitful, hamstringing efforts to advance therapy
+in the clinic. Failure to determine the biological basis of histologically similar but clinically and molecularly distinct cancers (intertumoral heterogeneity) has proved especially limiting, preventing
+the development of preclinical models of the full spectrum of
+human cancers and fostering a clinical trials culture that accepts
+‘‘all comers’’ with only the broadest categories of histological
+criteria to filter eligibility.
+Our failure to define the origins of cancer subtypes is not for
+want of trying. However, our relatively crude understanding of
+what drives cancers, coupled with uncertainty about initiating
+cell types, has prevented investigators from making the jump
+from correlative observation to functional understanding.
+Recently, a string of publications suggest that the genomic revolution may provide a route through this impasse. Microarray
+technologies have transformed the depth with which we can
+interrogate cancers like leukemias (Ross et al., 2004), breast
+cancers (Sotiriou et al., 2003), and brain tumors (Gibson et al.,
+2010; Johnson et al., 2010; Northcott et al., 2010; Cancer
+Genome Atlas Research Network, 2008), partitioning these
+diseases into robust subgroups according to genome-wide
+patterns of gene expression, copy number alteration, and mutation. These genomic profiles correlate with long-recognized
+epidemiological, pathological, and clinical characteristics;
+provide fundamental biological insights; and detect molecular
+echoes of tumor origins.
+Lessons from Leukemia
+Different types of chromosomal translocations—the principal
+oncogenic mutations in the blood—have long been associated
+with specific subtypes of leukemia. Genomic, stem cell, and
+cancer assays have taught us important lessons about the basis
+of this ‘‘matching.’’ First, the different forms of leukemia appear
+to arise from distinct points in the hematopoietic lineage that
+are susceptible to specific translocations. For example, the
+BCR-ABL translocation seen in human chronic myeloid
+leukemia (CML) only initiates CML in uncommitted hematopoietic stem cells (HSCs) (Huntly et al., 2004), whereas translocations involving the mixed-lineage leukemia (MLL) gene can
+initiate acute leukemias in both HSCs and committed
+progenitor cells (Barabe´ et al., 2007; Chen et al., 2008; Krivtsov
+et al., 2006).
+What is the biology behind this translocation-lineage stage
+matching? Comparative gene expression profiling suggests
+that the answer might lie in the capacity of translocations to
+activate key leukemogenic programs. Extensive self-renewal is
+considered a requisite feature of leukemic stem cells. When
+committed, nonself-renewing granulocyte macrophage progenitors (GMP) are transduced with MLL-AF9, they generate AML.
+The leukemic stem cells in this model retain a GMP-like gene
+expression profile, but they also acquire an aberrant self-renewal
+signature and self-renewal capacity, normally seen only in HSCs
+(Krivtsov et al., 2006). Because BCR-ABL does not appear to
+activate self-renewal, but rather enhanced cell proliferation and
+survival, its leukemogenic potential might be restricted to
+HSCs that already possess the capacity to self-renew (Huntly
+et al., 2004; Schemionek et al., 2010). Further probing of gene
+expression profile differences between normal and transformed
+hematopoietic cells has also highlighted new therapeutic opportunities. The transcriptome of MLL-AF9 transformed GMPs
+encodes a reactivated b-catenin (Ctnnb1) signal that drives
+leukemogenic self-renewal and that might be blocked for therapeutic gain (Wang et al., 2010).
+Although it is intuitive that cancers arise from specific combinations of mutations and susceptible cell types, these landmark
+studies of leukemia demonstrate the power of genomic technologies to decipher this process. Importantly, these data demonstrate that mutations can activate oncogenic signals without
+globally reprogramming the initiating cell. As we shall see, the
+legacy of the initiating cell transcriptome within cancer cells
+Cell 145, April 1, 2011 ª2011 Elsevier Inc. 25
+can provide crucial clues to tumor origins as well as unmask
+novel therapeutic targets.
+Charting Cancer Origins in Solid Tissues
+The availability of assays for each stage in the hematopoietic
+lineage, as well as the liquidity of blood, has accelerated understanding of leukemogenesis beyond that of solid tumorigenesis.
+But studies of solid cancers are catching up. The rigid anatomical organization of solid tissues has allowed investigators to
+map cells that express transcriptomes similar to those seen in
+cancers, and improved techniques to isolate and culture cells
+in solid tissue hierarchies have advanced the study of these populations. These studies have identified cells in solid tissues that
+share the transcriptomes of solid tumors and might therefore
+initiate cancer (Figure 1).
+Like most solid tissues, those of the central nervous system
+(CNS) give rise to a variety of cancers classified according to
+patterns of histology. Intracranial ependymomas are the third
+most common brain tumor of children and carry a much worse
+prognosis than spinal forms of the disease that predominate in
+adults. Ependymomas contain transcriptomes and DNA
+Figure 1. Cross-Species Genomics
+Matches Cells in Developing and Adult
+Mouse Tissues with Human Tumor
+Subgroups
+Matching of developing mouse tissues with
+childhood cancers (left). Different cell stages in an
+embryonic mouse tissue hierarchy are colored
+according to differentiation stage. Expression
+profiling segregates these cells according to
+transcriptome (upper-left). Histologically similar
+but clinically distinct tumors from the corresponding childhood tissue express different transcriptomes driven by different mutations (mut1–3)
+(lower-left). Cross-species genomics matches
+human tumors with their candidate cells of origin in
+the corresponding developing mouse tissue. As
+development proceeds (right), the spectrum of
+normal cell types (upper-right) and cancers (lowerright) changes. The same approach shown for
+childhood cancers can match tumors with candidate cells of origin in adult tissues.
+copy number alterations that correlate
+with tumor location (Johnson et al.,
+2010; Taylor et al., 2005). Similarly, gene
+expression profiles of medulloblastomas—the most common malignant
+pediatric brain tumor—carve these
+cancers into clinically and molecularly
+distinct subgroups, including the Sonic
+Hedgehog (SHH) subtype driven by aberrant SHH signaling and the highly curable
+WNT subtype containing mutations in
+CTNNB1 (Northcott et al., 2010).
+To uncover the cellular origins of these
+diverse brain tumors, investigators tested
+the hypothesis that brain tumor subtypes
+inherit significant portions of their transcriptome from initiating CNS cells. Initial
+in situ hybridization analyses showed that the subventricular zone
+of the embryonic lateral ventricle and peri-canal region of the
+adult spine express the transcriptomes of human cerebral and
+spinal ependymoma, respectively (Taylor et al., 2005). Because
+these regions house neural stem cells (NSCs), the investigators
+looked for transcriptomic similarities between regionally and
+developmentally discrete mouse NSCs and human ependymomas (Johnson et al., 2010). Using a powerful new cross-species
+genomics algorithm, the investigators pinpointed embryonic
+cerebral and adult spinal NSCs as candidate cells of origin of
+cerebral and spinal ependymomas, respectively.
+This approach has also provided clues to the origins of
+medulloblastomas, yielding the surprising insight that some of
+these tumors might arise outside of the cerebellum (Gibson
+et al., 2010). SHH subtype medulloblastomas have been shown
+to arise from committed cerebellar granule neuron precursor
+cells (GNPCs) (Schu¨ ller et al., 2008; Yang et al., 2008). Not
+surprisingly, therefore, in situ hybridization and cross-species
+genomics revealed a close match between SHH subtype
+medulloblastomas and GNPC transcriptomes (Gibson et al.,
+2010). In stark contrast, the transcriptome of WNT subtype
+26 Cell 145, April 1, 2011 ª2011 Elsevier Inc.
+medulloblastoma matched that of neural precursor cells of the
+lower rhombic lip and embryonic dorsal brainstem (Gibson
+et al., 2010). Remarkably, magnetic resonance imaging demonstrated that, whereas human SHH subtype medulloblastomas
+are confined to the cerebellum, WNT subtype tumors invariably
+involve the dorsal brainstem, supporting further the notion that
+these different tumor types have distinct cellular origins (Gibson
+et al., 2010).
+Clues to cancer origins are not just present in the transcriptomes of leukemias and brain tumors, but have also been uncovered through comparative profiling of breast cancers and the
+normal mammary gland. The ducts and lobules of the human
+breast are lined by two cell layers: an inner luminal cell population
+and a heterogeneous outer cell layer that includes basal progenitor cells. Basal-like breast cancers, so called for their basal cell
+immunophenotype (cytokeratins 5/6, 14, and 17), are aggressive
+tumors, particularly prevalent among women with germline
+mutations in BRCA1. It seemed intuitive that basal-like tumors
+would arise from basal progenitor cells; however, recent data
+suggest these cancers actually arise from luminal progenitors.
+The preneoplastic breasts of BRCA1 mutant woman contain
+an expanded population of aberrant luminal progenitor cells,
+and the transcriptomes of BRCA1 mutant breast tissue and
+basal-type breast cancers are more like that of luminal progenitors than other normal breast cell types (Lim et al., 2009).
+Transcriptome Mapping Identifies Solid
+Tumor-Initiating Cells
+Although the transcriptomes of certain normal and malignant
+solid tissue cells correlate, does this pinpoint cancer origins?
+Studies of mammary tissue have delineated a cellular hierarchy
+on which to frame this question in the breast. Cell transplant
+studies have identified a Lin
CD29hiCD24+ mammary stem cell
+(MaSC) that is capable of reconstituting the entire breast via
+lineage-committed progenitors (e.g., Lin
CD29loCD24+ luminal
+progenitors) (Shackleton et al., 2006; Stingl et al., 2006). Initial
+studies indicate that different cells in the mammary hierarchy
+are susceptible to different mutations. For example, transgenic
+expression of Wnt1 via the MMTV promoter generates heterogeneous breast cancers in mice that are preceded by the accumulation of aberrantly self-renewing MaSCs (Shackleton et al.,
+2006). In contrast, the mammary glands of MMTV-neu mice
+contain normal numbers of MaSCs and develop luminal breast
+cancers, whereas forced expression of Notch1 in MaSCs
+expands the luminal progenitor population, leading to basallike breast cancers (Bouras et al., 2008).
+Targeting tumor type-specific mutations to transcriptomematched normal cells has provided direct evidence that comparative gene expression profiling can identify cancer origins
+(Figure 2). In the breast, conditional deletion of Brca1 from
+mouse luminal progenitors, but not basal progenitors, produced
+tumors that mimic the histology and transcriptome of human
+BRCA1 mutant and sporadic basal-type breast cancers, thus
+confirming comparative gene expression profile predictions
+(Lim et al., 2009; Molyneux et al., 2010). Similarly, embryonic
+cerebral NSCs that were predicted by transcriptome mapping
+to initiate cerebral ependymomas generated these tumors
+when challenged with mutations found exclusively in this form
+of the human disease (Johnson et al., 2010). Further, mouse
+models have validated the surprising prediction that WNT
+subtype medulloblastomas likely arise from progenitor cells in
+the dorsal brainstem (Gibson et al., 2010). Mutation of
+Ctnnb1—an invariable feature of WNT subtype medulloblastoma—had little impact on progenitor cell populations in the
+cerebellum but caused the abnormal accumulation of neuron
+precursor cells in the dorsal brainstem that progressed to form
+medulloblastomas that recapitulate the anatomy and gene
+expression profiles of human WNT subtype medulloblastoma.
+Further study will doubtless reveal significant exceptions and
+nuances in the relationship between the transcriptomes of
+normal cells and their malignant offspring. Nevertheless, integrated genomic and stem cell studies have provided a useful
+framework for investigating the origin of cancer subtypes.
+In the Right Place at the Wrong Time
+Tissues have been viewed largely as passive players in cancer
+pathogenesis—their risk of malignant transformation being
+dictated by heritable mutations and environmental exposures.
+But if cancers arise from preordained combinations of specific
+cell types and matched mutations, then the availability of either
+of these factors could dictate the epidemiology of cancer. In its
+broadest terms, this concept is not new. The very different
+cancer types observed in children and adults have long
+been suspected to have their roots in development (Figure 1).
+Figure 2. Modeling Cancer Heterogeneity
+Subgroups of the childhood cancer shown in Figure 1 can be modeled
+accurately when transcriptome-matched normal cell types are challenged with
+mutations found in the corresponding cancer. These models should prove
+extremely useful for developing new therapies for specific cancer subgroups.
+Cell 145, April 1, 2011 ª2011 Elsevier Inc. 27
+However, evidence is emerging that more subtle shifts in the
+makeup of cell hierarchies might account for changes in cancer
+incidence. For example, it is tempting to speculate that the
+expanded population of aberrant luminal progenitors seen in
+the breasts of cancer-free patients carrying the BRCA1 mutation
+provides a source of cells that are susceptible to additional
+transforming mutations and thereby an increased risk of developing basal-type cancers (Lim et al., 2009; Molyneux et al.,
+2010).
+Shifts in cell hierarchies might also explain the association
+between certain physiological states and cancer. For example,
+if the massive progesterone-induced increases in mouse MaSCs
+prove to occur in humans, then this may explain why breast
+cancer is associated with early menarche, late menopause,
+and the inclusion of progestin in hormone replacement therapy
+(Joshi et al., 2010).
+As genomic and stem cell technologies allow further dissection of cancer subgroups and their origins, it will be interesting
+to see whether these studies provide answers to other key questions about cancer epidemiology. For example, do temporal
+changes in the GNPC lineage explain why SHH subtype medulloblastoma incidence peaks in both early childhood and later life
+(Northcott et al., 2010)? And might the close matching of adult
+spinal NSC and spinal ependymoma transcriptomes explain
+why these tumors occur almost exclusively in adults (Johnson
+et al., 2010)?
+Toward Cancer Cures
+Most biomedical discoveries rarely translate rapidly into
+improved patient care. However, recent discoveries that
+genomic tools can identify robust cancer subgroups, and point
+to the origins of these cancers, have immediate clinical relevance. This promise lies in the profound implications that this
+information holds for the full spectrum of cancer research.
+Nonspecific cytotoxic treatments remain the mainstay of
+cancer therapy. Efforts to introduce more directed treatments
+that target mutant proteins in cancers have met with mixed
+results. The inefficiency of this process results, in part, from prior
+failures to adequately capture the heterogeneity of cancers in
+preclinical models. The integration of stem cell biology and
+genomics outlined in this Minireview is producing multiple, highly
+accurate models of human cancer subgroups (Gibson et al.,
+2010; Johnson et al., 2010; Molyneux et al., 2010; Yang et al.,
+2008). Preclinical drug development using these models should
+allow investigators to better predict which forms of leukemias
+and solid cancers are most likely to respond to certain treatments (Figure 2). Such preclinical data could then be used to
+design genomic metrics that would direct treatments to the
+most appropriate patients in early clinical trials.
+Cancer models built from specific cells of origin offer an additional advantage to drug developers. Therapies that cripple critical processes in cancer cells carry significant risks of damaging
+normal cell hierarchies. Understanding the origin of cancers
+might therefore allow the development of effective drugs with
+fewer side effects. For example, evidence that Ctnnb1-mediated
+self-renewal driven by MLL-AF9 in AML is not required by adult
+HSCs suggests that CTNNB1 might be targeted therapeutically
+in this disease without incurring significant hematological toxicity
+(Wang et al., 2010).
+Finally, the approaches outlined here promise to shed light on
+one of the greatest contemporary controversies in cancer
+research: the cancer stem cell hypothesis. Evidence that
+cancers are propagated and maintained by subpopulations of
+stem-like cancer cells has come largely from studies of human
+cancer xenografts in mice. But these systems do not allow
+lineage tracing of cancer development, and their interpretation
+is complicated by species differences. New mouse models of
+human tumors initiated from predefined and selected cells are
+enabling investigators to track tumorigenesis with much greater
+precision. Comparative genomic studies of initiating and
+daughter cancer cells should provide a more comprehensive
+view of the processes that cause and propagate cancer.","['Why', 'Haven’t', 'We', 'Cured', 'Cancer', '?', 'Seventy', 'years', 'since', 'the', 'first', 'reported', 'use', 'of', 'cancer', 'chemotherapy', ',', 'malignancies', 'are', 'the', 'second', 'most', 'common', 'cause', 'of', 'death', 'among', 'children', 'and', 'adults', '.', 'So', 'why', 'are', 'the', 'headlines', 'rarely', 'punctuated', 'with', 'cancer', 'success', 'stories', '?', 'One', 'explanation', 'is', 'that', ',', 'although', 'classifying', 'cancers', 'is', 'relatively', 'straightforward', ',', 'understanding', 'the', 'basis', 'of', 'cancer', 'heterogeneity', 'is', 'complex', '.', 'Over', 'the', 'years', ',', 'we', 'have', 'become', 'quite', 'proficient', 'at', 'cataloging', 'cancer', 'according', 'to', 'patterns', 'of', 'epidemiology', 'and', 'pathology', '.', 'Each', 'cancer', 'is', 'recognized', 'to', 'occur', 'at', 'a', 'particular', 'age', ',', 'to', 'occur', 'more', 'frequently', 'in', 'one', 'sex', 'than', 'another', ',', 'and', 'to', 'have', 'a', 'particular', 'morphologyâ€', '”', 'usually', 'resembling', 'the', 'originating', 'tissue', '.', 'Advances', 'in', 'imaging', 'and', 'histology', 'have', 'enabled', 'us', 'to', 'further', 'segregate', 'cancer', 'diagnoses', 'into', 'distinct', 'stages', 'and', 'grades', 'that', 'predict', 'different', 'treatment', 'responses', 'and', 'prognoses', '.', 'Despite', 'this', 'exhaustive', 'work', ',', 'our', 'attempts', 'to', 'understand', 'the', 'processes', 'that', 'generate', 'the', 'different', 'forms', 'of', 'cancer', 'have', 'proved', 'far', 'less', 'fruitful', ',', 'hamstringing', 'efforts', 'to', 'advance', 'therapy', 'in', 'the', 'clinic', '.', 'Failure', 'to', 'determine', 'the', 'biological', 'basis', 'of', 'histologically', 'similar', 'but', 'clinically', 'and', 'molecularly', 'distinct', 'cancers', '(', 'intertumoral', 'heterogeneity', ')', 'has', 'proved', 'especially', 'limiting', ',', 'preventing', 'the', 'development', 'of', 'preclinical', 'models', 'of', 'the', 'full', 'spectrum', 'of', 'human', 'cancers', 'and', 'fostering', 'a', 'clinical', 'trials', 'culture', 'that', 'accepts', '‘‘all', 'comers’’', 'with', 'only', 'the', 'broadest', 'categories', 'of', 'histological', 'criteria', 'to', 'filter', 'eligibility', '.', 'Our', 'failure', 'to', 'define', 'the', 'origins', 'of', 'cancer', 'subtypes', 'is', 'not', 'for', 'want', 'of', 'trying', '.', 'However', ',', 'our', 'relatively', 'crude', 'understanding', 'of', 'what', 'drives', 'cancers', ',', 'coupled', 'with', 'uncertainty', 'about', 'initiating', 'cell', 'types', ',', 'has', 'prevented', 'investigators', 'from', 'making', 'the', 'jump', 'from', 'correlative', 'observation', 'to', 'functional', 'understanding', '.', 'Recently', ',', 'a', 'string', 'of', 'publications', 'suggest', 'that', 'the', 'genomic', 'revolution', 'may', 'provide', 'a', 'route', 'through', 'this', 'impasse', '.', 'Microarray', 'technologies', 'have', 'transformed', 'the', 'depth', 'with', 'which', 'we', 'can', 'interrogate', 'cancers', 'like', 'leukemias', '(', 'Ross', 'et', 'al.', ',', '2004', ')', ',', 'breast', 'cancers', '(', 'Sotiriou', 'et', 'al.', ',', '2003', ')', ',', 'and', 'brain', 'tumors', '(', 'Gibson', 'et', 'al.', ',', '2010', ';', 'Johnson', 'et', 'al.', ',', '2010', ';', 'Northcott', 'et', 'al.', ',', '2010', ';', 'Cancer', 'Genome', 'Atlas', 'Research', 'Network', ',', '2008', ')', ',', 'partitioning', 'these', 'diseases', 'into', 'robust', 'subgroups', 'according', 'to', 'genome-wide', 'patterns', 'of', 'gene', 'expression', ',', 'copy', 'number', 'alteration', ',', 'and', 'mutation', '.', 'These', 'genomic', 'profiles', 'correlate', 'with', 'long-recognized', 'epidemiological', ',', 'pathological', ',', 'and', 'clinical', 'characteristics', ';', 'provide', 'fundamental', 'biological', 'insights', ';', 'and', 'detect', 'molecular', 'echoes', 'of', 'tumor', 'origins', '.', 'Lessons', 'from', 'Leukemia', 'Different', 'types', 'of', 'chromosomal', 'translocationsâ€', '”', 'the', 'principal', 'oncogenic', 'mutations', 'in', 'the', 'bloodâ€', '”', 'have', 'long', 'been', 'associated', 'with', 'specific', 'subtypes', 'of', 'leukemia', '.', 'Genomic', ',', 'stem', 'cell', ',', 'and', 'cancer', 'assays', 'have', 'taught', 'us', 'important', 'lessons', 'about', 'the', 'basis', 'of', 'this', '‘‘matching.’’', 'First', ',', 'the', 'different', 'forms', 'of', 'leukemia', 'appear', 'to', 'arise', 'from', 'distinct', 'points', 'in', 'the', 'hematopoietic', 'lineage', 'that', 'are', 'susceptible', 'to', 'specific', 'translocations', '.', 'For', 'example', ',', 'the', 'BCR-ABL', 'translocation', 'seen', 'in', 'human', 'chronic', 'myeloid', 'leukemia', '(', 'CML', ')', 'only', 'initiates', 'CML', 'in', 'uncommitted', 'hematopoietic', 'stem', 'cells', '(', 'HSCs', ')', '(', 'Huntly', 'et', 'al.', ',', '2004', ')', ',', 'whereas', 'translocations', 'involving', 'the', 'mixed-lineage', 'leukemia', '(', 'MLL', ')', 'gene', 'can', 'initiate', 'acute', 'leukemias', 'in', 'both', 'HSCs', 'and', 'committed', 'progenitor', 'cells', '(', 'Barabe´', 'et', 'al.', ',', '2007', ';', 'Chen', 'et', 'al.', ',', '2008', ';', 'Krivtsov', 'et', 'al.', ',', '2006', ')', '.', 'What', 'is', 'the', 'biology', 'behind', 'this', 'translocation-lineage', 'stage', 'matching', '?', 'Comparative', 'gene', 'expression', 'profiling', 'suggests', 'that', 'the', 'answer', 'might', 'lie', 'in', 'the', 'capacity', 'of', 'translocations', 'to', 'activate', 'key', 'leukemogenic', 'programs', '.', 'Extensive', 'self-renewal', 'is', 'considered', 'a', 'requisite', 'feature', 'of', 'leukemic', 'stem', 'cells', '.', 'When', 'committed', ',', 'nonself-renewing', 'granulocyte', 'macrophage', 'progenitors', '(', 'GMP', ')', 'are', 'transduced', 'with', 'MLL-AF9', ',', 'they', 'generate', 'AML', '.', 'The', 'leukemic', 'stem', 'cells', 'in', 'this', 'model', 'retain', 'a', 'GMP-like', 'gene', 'expression', 'profile', ',', 'but', 'they', 'also', 'acquire', 'an', 'aberrant', 'self-renewal', 'signature', 'and', 'self-renewal', 'capacity', ',', 'normally', 'seen', 'only', 'in', 'HSCs', '(', 'Krivtsov', 'et', 'al.', ',', '2006', ')', '.', 'Because', 'BCR-ABL', 'does', 'not', 'appear', 'to', 'activate', 'self-renewal', ',', 'but', 'rather', 'enhanced', 'cell', 'proliferation', 'and', 'survival', ',', 'its', 'leukemogenic', 'potential', 'might', 'be', 'restricted', 'to', 'HSCs', 'that', 'already', 'possess', 'the', 'capacity', 'to', 'self-renew', '(', 'Huntly', 'et', 'al.', ',', '2004', ';', 'Schemionek', 'et', 'al.', ',', '2010', ')', '.', 'Further', 'probing', 'of', 'gene', 'expression', 'profile', 'differences', 'between', 'normal', 'and', 'transformed', 'hematopoietic', 'cells', 'has', 'also', 'highlighted', 'new', 'therapeutic', 'opportunities', '.', 'The', 'transcriptome', 'of', 'MLL-AF9', 'transformed', 'GMPs', 'encodes', 'a', 'reactivated', 'b-catenin', '(', 'Ctnnb1', ')', 'signal', 'that', 'drives', 'leukemogenic', 'self-renewal', 'and', 'that', 'might', 'be', 'blocked', 'for', 'therapeutic', 'gain', '(', 'Wang', 'et', 'al.', ',', '2010', ')', '.', 'Although', 'it', 'is', 'intuitive', 'that', 'cancers', 'arise', 'from', 'specific', 'combinations', 'of', 'mutations', 'and', 'susceptible', 'cell', 'types', ',', 'these', 'landmark', 'studies', 'of', 'leukemia', 'demonstrate', 'the', 'power', 'of', 'genomic', 'technologies', 'to', 'decipher', 'this', 'process', '.', 'Importantly', ',', 'these', 'data', 'demonstrate', 'that', 'mutations', 'can', 'activate', 'oncogenic', 'signals', 'without', 'globally', 'reprogramming', 'the', 'initiating', 'cell', '.', 'As', 'we', 'shall', 'see', ',', 'the', 'legacy', 'of', 'the', 'initiating', 'cell', 'transcriptome', 'within', 'cancer', 'cells', 'Cell', '145', ',', 'April', '1', ',', '2011', 'ª2011', 'Elsevier', 'Inc.', '25', 'can', 'provide', 'crucial', 'clues', 'to', 'tumor', 'origins', 'as', 'well', 'as', 'unmask', 'novel', 'therapeutic', 'targets', '.', 'Charting', 'Cancer', 'Origins', 'in', 'Solid', 'Tissues', 'The', 'availability', 'of', 'assays', 'for', 'each', 'stage', 'in', 'the', 'hematopoietic', 'lineage', ',', 'as', 'well', 'as', 'the', 'liquidity', 'of', 'blood', ',', 'has', 'accelerated', 'understanding', 'of', 'leukemogenesis', 'beyond', 'that', 'of', 'solid', 'tumorigenesis', '.', 'But', 'studies', 'of', 'solid', 'cancers', 'are', 'catching', 'up', '.', 'The', 'rigid', 'anatomical', 'organization', 'of', 'solid', 'tissues', 'has', 'allowed', 'investigators', 'to', 'map', 'cells', 'that', 'express', 'transcriptomes', 'similar', 'to', 'those', 'seen', 'in', 'cancers', ',', 'and', 'improved', 'techniques', 'to', 'isolate', 'and', 'culture', 'cells', 'in', 'solid', 'tissue', 'hierarchies', 'have', 'advanced', 'the', 'study', 'of', 'these', 'populations', '.', 'These', 'studies', 'have', 'identified', 'cells', 'in', 'solid', 'tissues', 'that', 'share', 'the', 'transcriptomes', 'of', 'solid', 'tumors', 'and', 'might', 'therefore', 'initiate', 'cancer', '(', 'Figure', '1', ')', '.', 'Like', 'most', 'solid', 'tissues', ',', 'those', 'of', 'the', 'central', 'nervous', 'system', '(', 'CNS', ')', 'give', 'rise', 'to', 'a', 'variety', 'of', 'cancers', 'classified', 'according', 'to', 'patterns', 'of', 'histology', '.', 'Intracranial', 'ependymomas', 'are', 'the', 'third', 'most', 'common', 'brain', 'tumor', 'of', 'children', 'and', 'carry', 'a', 'much', 'worse', 'prognosis', 'than', 'spinal', 'forms', 'of', 'the', 'disease', 'that', 'predominate', 'in', 'adults', '.', 'Ependymomas', 'contain', 'transcriptomes', 'and', 'DNA', 'Figure', '1', '.', 'Cross-Species', 'Genomics', 'Matches', 'Cells', 'in', 'Developing', 'and', 'Adult', 'Mouse', 'Tissues', 'with', 'Human', 'Tumor', 'Subgroups', 'Matching', 'of', 'developing', 'mouse', 'tissues', 'with', 'childhood', 'cancers', '(', 'left', ')', '.', 'Different', 'cell', 'stages', 'in', 'an', 'embryonic', 'mouse', 'tissue', 'hierarchy', 'are', 'colored', 'according', 'to', 'differentiation', 'stage', '.', 'Expression', 'profiling', 'segregates', 'these', 'cells', 'according', 'to', 'transcriptome', '(', 'upper-left', ')', '.', 'Histologically', 'similar', 'but', 'clinically', 'distinct', 'tumors', 'from', 'the', 'corresponding', 'childhood', 'tissue', 'express', 'different', 'transcriptomes', 'driven', 'by', 'different', 'mutations', '(', 'mut1â€', '“', '3', ')', '(', 'lower-left', ')', '.', 'Cross-species', 'genomics', 'matches', 'human', 'tumors', 'with', 'their', 'candidate', 'cells', 'of', 'origin', 'in', 'the', 'corresponding', 'developing', 'mouse', 'tissue', '.', 'As', 'development', 'proceeds', '(', 'right', ')', ',', 'the', 'spectrum', 'of', 'normal', 'cell', 'types', '(', 'upper-right', ')', 'and', 'cancers', '(', 'lowerright', ')', 'changes', '.', 'The', 'same', 'approach', 'shown', 'for', 'childhood', 'cancers', 'can', 'match', 'tumors', 'with', 'candidate', 'cells', 'of', 'origin', 'in', 'adult', 'tissues', '.', 'copy', 'number', 'alterations', 'that', 'correlate', 'with', 'tumor', 'location', '(', 'Johnson', 'et', 'al.', ',', '2010', ';', 'Taylor', 'et', 'al.', ',', '2005', ')', '.', 'Similarly', ',', 'gene', 'expression', 'profiles', 'of', 'medulloblastomasâ€', '”', 'the', 'most', 'common', 'malignant', 'pediatric', 'brain', 'tumorâ€', '”', 'carve', 'these', 'cancers', 'into', 'clinically', 'and', 'molecularly', 'distinct', 'subgroups', ',', 'including', 'the', 'Sonic', 'Hedgehog', '(', 'SHH', ')', 'subtype', 'driven', 'by', 'aberrant', 'SHH', 'signaling', 'and', 'the', 'highly', 'curable', 'WNT', 'subtype', 'containing', 'mutations', 'in', 'CTNNB1', '(', 'Northcott', 'et', 'al.', ',', '2010', ')', '.', 'To', 'uncover', 'the', 'cellular', 'origins', 'of', 'these', 'diverse', 'brain', 'tumors', ',', 'investigators', 'tested', 'the', 'hypothesis', 'that', 'brain', 'tumor', 'subtypes', 'inherit', 'significant', 'portions', 'of', 'their', 'transcriptome', 'from', 'initiating', 'CNS', 'cells', '.', 'Initial', 'in', 'situ', 'hybridization', 'analyses', 'showed', 'that', 'the', 'subventricular', 'zone', 'of', 'the', 'embryonic', 'lateral', 'ventricle', 'and', 'peri-canal', 'region', 'of', 'the', 'adult', 'spine', 'express', 'the', 'transcriptomes', 'of', 'human', 'cerebral', 'and', 'spinal', 'ependymoma', ',', 'respectively', '(', 'Taylor', 'et', 'al.', ',', '2005', ')', '.', 'Because', 'these', 'regions', 'house', 'neural', 'stem', 'cells', '(', 'NSCs', ')', ',', 'the', 'investigators', 'looked', 'for', 'transcriptomic', 'similarities', 'between', 'regionally', 'and', 'developmentally', 'discrete', 'mouse', 'NSCs', 'and', 'human', 'ependymomas', '(', 'Johnson', 'et', 'al.', ',', '2010', ')', '.', 'Using', 'a', 'powerful', 'new', 'cross-species', 'genomics', 'algorithm', ',', 'the', 'investigators', 'pinpointed', 'embryonic', 'cerebral', 'and', 'adult', 'spinal', 'NSCs', 'as', 'candidate', 'cells', 'of', 'origin', 'of', 'cerebral', 'and', 'spinal', 'ependymomas', ',', 'respectively', '.', 'This', 'approach', 'has', 'also', 'provided', 'clues', 'to', 'the', 'origins', 'of', 'medulloblastomas', ',', 'yielding', 'the', 'surprising', 'insight', 'that', 'some', 'of', 'these', 'tumors', 'might', 'arise', 'outside', 'of', 'the', 'cerebellum', '(', 'Gibson', 'et', 'al.', ',', '2010', ')', '.', 'SHH', 'subtype', 'medulloblastomas', 'have', 'been', 'shown', 'to', 'arise', 'from', 'committed', 'cerebellar', 'granule', 'neuron', 'precursor', 'cells', '(', 'GNPCs', ')', '(', 'Schu¨', 'ller', 'et', 'al.', ',', '2008', ';', 'Yang', 'et', 'al.', ',', '2008', ')', '.', 'Not', 'surprisingly', ',', 'therefore', ',', 'in', 'situ', 'hybridization', 'and', 'cross-species', 'genomics', 'revealed', 'a', 'close', 'match', 'between', 'SHH', 'subtype', 'medulloblastomas', 'and', 'GNPC', 'transcriptomes', '(', 'Gibson', 'et', 'al.', ',', '2010', ')', '.', 'In', 'stark', 'contrast', ',', 'the', 'transcriptome', 'of', 'WNT', 'subtype', '26', 'Cell', '145', ',', 'April', '1', ',', '2011', 'ª2011', 'Elsevier', 'Inc.', 'medulloblastoma', 'matched', 'that', 'of', 'neural', 'precursor', 'cells', 'of', 'the', 'lower', 'rhombic', 'lip', 'and', 'embryonic', 'dorsal', 'brainstem', '(', 'Gibson', 'et', 'al.', ',', '2010', ')', '.', 'Remarkably', ',', 'magnetic', 'resonance', 'imaging', 'demonstrated', 'that', ',', 'whereas', 'human', 'SHH', 'subtype', 'medulloblastomas', 'are', 'confined', 'to', 'the', 'cerebellum', ',', 'WNT', 'subtype', 'tumors', 'invariably', 'involve', 'the', 'dorsal', 'brainstem', ',', 'supporting', 'further', 'the', 'notion', 'that', 'these', 'different', 'tumor', 'types', 'have', 'distinct', 'cellular', 'origins', '(', 'Gibson', 'et', 'al.', ',', '2010', ')', '.', 'Clues', 'to', 'cancer', 'origins', 'are', 'not', 'just', 'present', 'in', 'the', 'transcriptomes', 'of', 'leukemias', 'and', 'brain', 'tumors', ',', 'but', 'have', 'also', 'been', 'uncovered', 'through', 'comparative', 'profiling', 'of', 'breast', 'cancers', 'and', 'the', 'normal', 'mammary', 'gland', '.', 'The', 'ducts', 'and', 'lobules', 'of', 'the', 'human', 'breast', 'are', 'lined', 'by', 'two', 'cell', 'layers', ':', 'an', 'inner', 'luminal', 'cell', 'population', 'and', 'a', 'heterogeneous', 'outer', 'cell', 'layer', 'that', 'includes', 'basal', 'progenitor', 'cells', '.', 'Basal-like', 'breast', 'cancers', ',', 'so', 'called', 'for', 'their', 'basal', 'cell', 'immunophenotype', '(', 'cytokeratins', '5/6', ',', '14', ',', 'and', '17', ')', ',', 'are', 'aggressive', 'tumors', ',', 'particularly', 'prevalent', 'among', 'women', 'with', 'germline', 'mutations', 'in', 'BRCA1', '.', 'It', 'seemed', 'intuitive', 'that', 'basal-like', 'tumors', 'would', 'arise', 'from', 'basal', 'progenitor', 'cells', ';', 'however', ',', 'recent', 'data', 'suggest', 'these', 'cancers', 'actually', 'arise', 'from', 'luminal', 'progenitors', '.', 'The', 'preneoplastic', 'breasts', 'of', 'BRCA1', 'mutant', 'woman', 'contain', 'an', 'expanded', 'population', 'of', 'aberrant', 'luminal', 'progenitor', 'cells', ',', 'and', 'the', 'transcriptomes', 'of', 'BRCA1', 'mutant', 'breast', 'tissue', 'and', 'basal-type', 'breast', 'cancers', 'are', 'more', 'like', 'that', 'of', 'luminal', 'progenitors', 'than', 'other', 'normal', 'breast', 'cell', 'types', '(', 'Lim', 'et', 'al.', ',', '2009', ')', '.', 'Transcriptome', 'Mapping', 'Identifies', 'Solid', 'Tumor-Initiating', 'Cells', 'Although', 'the', 'transcriptomes', 'of', 'certain', 'normal', 'and', 'malignant', 'solid', 'tissue', 'cells', 'correlate', ',', 'does', 'this', 'pinpoint', 'cancer', 'origins', '?', 'Studies', 'of', 'mammary', 'tissue', 'have', 'delineated', 'a', 'cellular', 'hierarchy', 'on', 'which', 'to', 'frame', 'this', 'question', 'in', 'the', 'breast', '.', 'Cell', 'transplant', 'studies', 'have', 'identified', 'a', 'Lin\x01CD29hiCD24+', 'mammary', 'stem', 'cell', '(', 'MaSC', ')', 'that', 'is', 'capable', 'of', 'reconstituting', 'the', 'entire', 'breast', 'via', 'lineage-committed', 'progenitors', '(', 'e.g.', ',', 'Lin\x01CD29loCD24+', 'luminal', 'progenitors', ')', '(', 'Shackleton', 'et', 'al.', ',', '2006', ';', 'Stingl', 'et', 'al.', ',', '2006', ')', '.', 'Initial', 'studies', 'indicate', 'that', 'different', 'cells', 'in', 'the', 'mammary', 'hierarchy', 'are', 'susceptible', 'to', 'different', 'mutations', '.', 'For', 'example', ',', 'transgenic', 'expression', 'of', 'Wnt1', 'via', 'the', 'MMTV', 'promoter', 'generates', 'heterogeneous', 'breast', 'cancers', 'in', 'mice', 'that', 'are', 'preceded', 'by', 'the', 'accumulation', 'of', 'aberrantly', 'self-renewing', 'MaSCs', '(', 'Shackleton', 'et', 'al.', ',', '2006', ')', '.', 'In', 'contrast', ',', 'the', 'mammary', 'glands', 'of', 'MMTV-neu', 'mice', 'contain', 'normal', 'numbers', 'of', 'MaSCs', 'and', 'develop', 'luminal', 'breast', 'cancers', ',', 'whereas', 'forced', 'expression', 'of', 'Notch1', 'in', 'MaSCs', 'expands', 'the', 'luminal', 'progenitor', 'population', ',', 'leading', 'to', 'basallike', 'breast', 'cancers', '(', 'Bouras', 'et', 'al.', ',', '2008', ')', '.', 'Targeting', 'tumor', 'type-specific', 'mutations', 'to', 'transcriptomematched', 'normal', 'cells', 'has', 'provided', 'direct', 'evidence', 'that', 'comparative', 'gene', 'expression', 'profiling', 'can', 'identify', 'cancer', 'origins', '(', 'Figure', '2', ')', '.', 'In', 'the', 'breast', ',', 'conditional', 'deletion', 'of', 'Brca1', 'from', 'mouse', 'luminal', 'progenitors', ',', 'but', 'not', 'basal', 'progenitors', ',', 'produced', 'tumors', 'that', 'mimic', 'the', 'histology', 'and', 'transcriptome', 'of', 'human', 'BRCA1', 'mutant', 'and', 'sporadic', 'basal-type', 'breast', 'cancers', ',', 'thus', 'confirming', 'comparative', 'gene', 'expression', 'profile', 'predictions', '(', 'Lim', 'et', 'al.', ',', '2009', ';', 'Molyneux', 'et', 'al.', ',', '2010', ')', '.', 'Similarly', ',', 'embryonic', 'cerebral', 'NSCs', 'that', 'were', 'predicted', 'by', 'transcriptome', 'mapping', 'to', 'initiate', 'cerebral', 'ependymomas', 'generated', 'these', 'tumors', 'when', 'challenged', 'with', 'mutations', 'found', 'exclusively', 'in', 'this', 'form', 'of', 'the', 'human', 'disease', '(', 'Johnson', 'et', 'al.', ',', '2010', ')', '.', 'Further', ',', 'mouse', 'models', 'have', 'validated', 'the', 'surprising', 'prediction', 'that', 'WNT', 'subtype', 'medulloblastomas', 'likely', 'arise', 'from', 'progenitor', 'cells', 'in', 'the', 'dorsal', 'brainstem', '(', 'Gibson', 'et', 'al.', ',', '2010', ')', '.', 'Mutation', 'of', 'Ctnnb1â€', '”', 'an', 'invariable', 'feature', 'of', 'WNT', 'subtype', 'medulloblastomaâ€', '”', 'had', 'little', 'impact', 'on', 'progenitor', 'cell', 'populations', 'in', 'the', 'cerebellum', 'but', 'caused', 'the', 'abnormal', 'accumulation', 'of', 'neuron', 'precursor', 'cells', 'in', 'the', 'dorsal', 'brainstem', 'that', 'progressed', 'to', 'form', 'medulloblastomas', 'that', 'recapitulate', 'the', 'anatomy', 'and', 'gene', 'expression', 'profiles', 'of', 'human', 'WNT', 'subtype', 'medulloblastoma', '.', 'Further', 'study', 'will', 'doubtless', 'reveal', 'significant', 'exceptions', 'and', 'nuances', 'in', 'the', 'relationship', 'between', 'the', 'transcriptomes', 'of', 'normal', 'cells', 'and', 'their', 'malignant', 'offspring', '.', 'Nevertheless', ',', 'integrated', 'genomic', 'and', 'stem', 'cell', 'studies', 'have', 'provided', 'a', 'useful', 'framework', 'for', 'investigating', 'the', 'origin', 'of', 'cancer', 'subtypes', '.', 'In', 'the', 'Right', 'Place', 'at', 'the', 'Wrong', 'Time', 'Tissues', 'have', 'been', 'viewed', 'largely', 'as', 'passive', 'players', 'in', 'cancer', 'pathogenesisâ€', '”', 'their', 'risk', 'of', 'malignant', 'transformation', 'being', 'dictated', 'by', 'heritable', 'mutations', 'and', 'environmental', 'exposures', '.', 'But', 'if', 'cancers', 'arise', 'from', 'preordained', 'combinations', 'of', 'specific', 'cell', 'types', 'and', 'matched', 'mutations', ',', 'then', 'the', 'availability', 'of', 'either', 'of', 'these', 'factors', 'could', 'dictate', 'the', 'epidemiology', 'of', 'cancer', '.', 'In', 'its', 'broadest', 'terms', ',', 'this', 'concept', 'is', 'not', 'new', '.', 'The', 'very', 'different', 'cancer', 'types', 'observed', 'in', 'children', 'and', 'adults', 'have', 'long', 'been', 'suspected', 'to', 'have', 'their', 'roots', 'in', 'development', '(', 'Figure', '1', ')', '.', 'Figure', '2', '.', 'Modeling', 'Cancer', 'Heterogeneity', 'Subgroups', 'of', 'the', 'childhood', 'cancer', 'shown', 'in', 'Figure', '1', 'can', 'be', 'modeled', 'accurately', 'when', 'transcriptome-matched', 'normal', 'cell', 'types', 'are', 'challenged', 'with', 'mutations', 'found', 'in', 'the', 'corresponding', 'cancer', '.', 'These', 'models', 'should', 'prove', 'extremely', 'useful', 'for', 'developing', 'new', 'therapies', 'for', 'specific', 'cancer', 'subgroups', '.', 'Cell', '145', ',', 'April', '1', ',', '2011', 'ª2011', 'Elsevier', 'Inc.', '27', 'However', ',', 'evidence', 'is', 'emerging', 'that', 'more', 'subtle', 'shifts', 'in', 'the', 'makeup', 'of', 'cell', 'hierarchies', 'might', 'account', 'for', 'changes', 'in', 'cancer', 'incidence', '.', 'For', 'example', ',', 'it', 'is', 'tempting', 'to', 'speculate', 'that', 'the', 'expanded', 'population', 'of', 'aberrant', 'luminal', 'progenitors', 'seen', 'in', 'the', 'breasts', 'of', 'cancer-free', 'patients', 'carrying', 'the', 'BRCA1', 'mutation', 'provides', 'a', 'source', 'of', 'cells', 'that', 'are', 'susceptible', 'to', 'additional', 'transforming', 'mutations', 'and', 'thereby', 'an', 'increased', 'risk', 'of', 'developing', 'basal-type', 'cancers', '(', 'Lim', 'et', 'al.', ',', '2009', ';', 'Molyneux', 'et', 'al.', ',', '2010', ')', '.', 'Shifts', 'in', 'cell', 'hierarchies', 'might', 'also', 'explain', 'the', 'association', 'between', 'certain', 'physiological', 'states', 'and', 'cancer', '.', 'For', 'example', ',', 'if', 'the', 'massive', 'progesterone-induced', 'increases', 'in', 'mouse', 'MaSCs', 'prove', 'to', 'occur', 'in', 'humans', ',', 'then', 'this', 'may', 'explain', 'why', 'breast', 'cancer', 'is', 'associated', 'with', 'early', 'menarche', ',', 'late', 'menopause', ',', 'and', 'the', 'inclusion', 'of', 'progestin', 'in', 'hormone', 'replacement', 'therapy', '(', 'Joshi', 'et', 'al.', ',', '2010', ')', '.', 'As', 'genomic', 'and', 'stem', 'cell', 'technologies', 'allow', 'further', 'dissection', 'of', 'cancer', 'subgroups', 'and', 'their', 'origins', ',', 'it', 'will', 'be', 'interesting', 'to', 'see', 'whether', 'these', 'studies', 'provide', 'answers', 'to', 'other', 'key', 'questions', 'about', 'cancer', 'epidemiology', '.', 'For', 'example', ',', 'do', 'temporal', 'changes', 'in', 'the', 'GNPC', 'lineage', 'explain', 'why', 'SHH', 'subtype', 'medulloblastoma', 'incidence', 'peaks', 'in', 'both', 'early', 'childhood', 'and', 'later', 'life', '(', 'Northcott', 'et', 'al.', ',', '2010', ')', '?', 'And', 'might', 'the', 'close', 'matching', 'of', 'adult', 'spinal', 'NSC', 'and', 'spinal', 'ependymoma', 'transcriptomes', 'explain', 'why', 'these', 'tumors', 'occur', 'almost', 'exclusively', 'in', 'adults', '(', 'Johnson', 'et', 'al.', ',', '2010', ')', '?', 'Toward', 'Cancer', 'Cures', 'Most', 'biomedical', 'discoveries', 'rarely', 'translate', 'rapidly', 'into', 'improved', 'patient', 'care', '.', 'However', ',', 'recent', 'discoveries', 'that', 'genomic', 'tools', 'can', 'identify', 'robust', 'cancer', 'subgroups', ',', 'and', 'point', 'to', 'the', 'origins', 'of', 'these', 'cancers', ',', 'have', 'immediate', 'clinical', 'relevance', '.', 'This', 'promise', 'lies', 'in', 'the', 'profound', 'implications', 'that', 'this', 'information', 'holds', 'for', 'the', 'full', 'spectrum', 'of', 'cancer', 'research', '.', 'Nonspecific', 'cytotoxic', 'treatments', 'remain', 'the', 'mainstay', 'of', 'cancer', 'therapy', '.', 'Efforts', 'to', 'introduce', 'more', 'directed', 'treatments', 'that', 'target', 'mutant', 'proteins', 'in', 'cancers', 'have', 'met', 'with', 'mixed', 'results', '.', 'The', 'inefficiency', 'of', 'this', 'process', 'results', ',', 'in', 'part', ',', 'from', 'prior', 'failures', 'to', 'adequately', 'capture', 'the', 'heterogeneity', 'of', 'cancers', 'in', 'preclinical', 'models', '.', 'The', 'integration', 'of', 'stem', 'cell', 'biology', 'and', 'genomics', 'outlined', 'in', 'this', 'Minireview', 'is', 'producing', 'multiple', ',', 'highly', 'accurate', 'models', 'of', 'human', 'cancer', 'subgroups', '(', 'Gibson', 'et', 'al.', ',', '2010', ';', 'Johnson', 'et', 'al.', ',', '2010', ';', 'Molyneux', 'et', 'al.', ',', '2010', ';', 'Yang', 'et', 'al.', ',', '2008', ')', '.', 'Preclinical', 'drug', 'development', 'using', 'these', 'models', 'should', 'allow', 'investigators', 'to', 'better', 'predict', 'which', 'forms', 'of', 'leukemias', 'and', 'solid', 'cancers', 'are', 'most', 'likely', 'to', 'respond', 'to', 'certain', 'treatments', '(', 'Figure', '2', ')', '.', 'Such', 'preclinical', 'data', 'could', 'then', 'be', 'used', 'to', 'design', 'genomic', 'metrics', 'that', 'would', 'direct', 'treatments', 'to', 'the', 'most', 'appropriate', 'patients', 'in', 'early', 'clinical', 'trials', '.', 'Cancer', 'models', 'built', 'from', 'specific', 'cells', 'of', 'origin', 'offer', 'an', 'additional', 'advantage', 'to', 'drug', 'developers', '.', 'Therapies', 'that', 'cripple', 'critical', 'processes', 'in', 'cancer', 'cells', 'carry', 'significant', 'risks', 'of', 'damaging', 'normal', 'cell', 'hierarchies', '.', 'Understanding', 'the', 'origin', 'of', 'cancers', 'might', 'therefore', 'allow', 'the', 'development', 'of', 'effective', 'drugs', 'with', 'fewer', 'side', 'effects', '.', 'For', 'example', ',', 'evidence', 'that', 'Ctnnb1-mediated', 'self-renewal', 'driven', 'by', 'MLL-AF9', 'in', 'AML', 'is', 'not', 'required', 'by', 'adult', 'HSCs', 'suggests', 'that', 'CTNNB1', 'might', 'be', 'targeted', 'therapeutically', 'in', 'this', 'disease', 'without', 'incurring', 'significant', 'hematological', 'toxicity', '(', 'Wang', 'et', 'al.', ',', '2010', ')', '.', 'Finally', ',', 'the', 'approaches', 'outlined', 'here', 'promise', 'to', 'shed', 'light', 'on', 'one', 'of', 'the', 'greatest', 'contemporary', 'controversies', 'in', 'cancer', 'research', ':', 'the', 'cancer', 'stem', 'cell', 'hypothesis', '.', 'Evidence', 'that', 'cancers', 'are', 'propagated', 'and', 'maintained', 'by', 'subpopulations', 'of', 'stem-like', 'cancer', 'cells', 'has', 'come', 'largely', 'from', 'studies', 'of', 'human', 'cancer', 'xenografts', 'in', 'mice', '.', 'But', 'these', 'systems', 'do', 'not', 'allow', 'lineage', 'tracing', 'of', 'cancer', 'development', ',', 'and', 'their', 'interpretation', 'is', 'complicated', 'by', 'species', 'differences', '.', 'New', 'mouse', 'models', 'of', 'human', 'tumors', 'initiated', 'from', 'predefined', 'and', 'selected', 'cells', 'are', 'enabling', 'investigators', 'to', 'track', 'tumorigenesis', 'with', 'much', 'greater', 'precision', '.', 'Comparative', 'genomic', 'studies', 'of', 'initiating', 'and', 'daughter', 'cancer', 'cells', 'should', 'provide', 'a', 'more', 'comprehensive', 'view', 'of', 'the', 'processes', 'that', 'cause', 'and', 'propagate', 'cancer', '.']"