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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 LinCD29hiCD24+ mammary stem cell
(MaSC) that is capable of reconstituting the entire breast via
lineage-committed progenitors (e.g., LinCD29loCD24+ 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. | [
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".",
"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\u0001CD29hiCD24+",
"mammary",
"stem",
"cell",
"(",
"MaSC",
")",
"that",
"is",
"capable",
"of",
"reconstituting",
"the",
"entire",
"breast",
"via",
"lineage-committed",
"progenitors",
"(",
"e.g.",
",",
"Lin\u0001CD29loCD24+",
"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",
"."
] |
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