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Nature Reviews Cancer | AOP, published online 13 June 2013; doi:10.1038/nrc3536
OPINION
The evolution of the cancer niche
during multistage carcinogenesis
Mary Helen Barcellos-Hoff, David Lyden and Timothy C. Wang
Abstract | The concept of the tumour microenvironment recognizes that the
interplay between cancer cells and stromal cells is a crucial determinant of cancer
growth. In this Perspectives article, we propose the novel concept that the tumour
microenvironment is built through rate-limiting steps during multistage
carcinogenesis. Construction of a ‘precancer niche’ is a necessary and early step
that is required for initiated cells to survive and evolve; subsequent niche
expansion and maturation accompany tumour promotion and progression,
respectively. As such, cancer niches represent an emergent property of a tumour
that could be a robust target for cancer prevention and therapy.
The paradigm that cancer is a cellular disease that is defined only by events within
the genomes of cancer cells has given way
in recent years to one in which cancer is
viewed as an ecological disease involving a
dynamic interplay between malignant and
non-malignant cells. This shift redirects
attention to the tumour microenvironment
(TME), which encompasses signals, proteins and cells (such as immune cells and
fibroblasts) present in the tumour mass that
are necessary for tumour growth and progression. The contribution of the TME to
malignant behaviours, treatment response
and metastasis is an area of active research.
The importance of the TME has been further underlined by the identification of
the premetastatic niche1. This concept is
based on evidence from mouse models that
established tumours release factors that
can act on cells in distant organs to recruit
bone-marrow-derived cells (BMDCs) that
create an environment that is conducive
to the survival and proliferation of newly
arrived metastatic cells2. Yet, is the generation of a hospitable environment restricted
to metastasis? In this Perspectives article,
we propose a broader concept: that the
construction of a ‘cancer niche’ is an early
and necessary step that is required for neoplastic cells to evolve towards a clinically
relevant cancer. We are not suggesting that
such niches pre-exist to facilitate cancer
development and are somehow dormant
or inactive in healthy individuals; rather,
we propose that de novo cancer niche
formation is the earliest stage at which
non-malignant cells can be stimulated by
the initiating carcinogenic insult and can
support the survival of an initiated clone.
In short, the development of a cancer niche
is a prerequisite for tumorigenesis.
This Perspectives article uses the classical
framework of initiation, promotion and
progression to divide the stages of carcinogenesis3. We propose that the evolution of the
cancer niche can be divided into three phases:
construction, expansion and maturation
(FIG. 1). In brief, niche construction is a spontaneous interaction between activated stromal
cells and normal cells that enables initiated
(or transformed) clone survival. Niche expansion, which could be viewed as a ‘micromicroenvironment’, generates secreted factors
(such as chemokines, cytokines and exosomes)
that remodel local tissue concurrent with
initiated clone expansion and parallels tumour
promotion (that is, the stage before
tumour invasion). Recruitment of BMDCs as
well as of resident cells (fibroblasts in particular) drives niche maturation from a nascent
to an established TME, the composition of
which is currently under intense research.
We propose that this concept of a dynamic
and evolving cancer niche fundamentally
changes how we view cancer. Our model postulates that cancer is as much a function of the
successful construction of the niche as it is of
the natural selection for specific mutations that
enable cancer cell survival and proliferation.
Consequently, tumour cell evolution in the
context of a niche results in both normal and
malignant phenotypes that cannot be understood solely in terms of epigenetic or genetic
changes. Instead, these phenotypes represent
an emergent property that requires comprehensive analysis of cell–cell interactions in the
context of the entire construct.
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The need for a cancer niche
In contrast to a physiological niche, such as
the niche that functions to control haemato­
poietic stem cell (HSC) proliferation and
survival4–6, a cancer niche would, by definition, evolve through steps that result in cancer
cell survival, proliferation and gain of malignant potential. Is there any evidence of the
need for such a process in carcino­genesis?
Experiments in which cancer cells are
exposed to a normal microenvironment —
such as those by Barry Pierce7, who injected
carcinoma cells into developing embryos
— resulted in the loss of malignant behaviour, which indicates that the environment
in which cancer cells exist influences their
behaviour, despite the presence of genetic and
epigenetic alterations. Likewise, combining
cancer cells with normal mesenchyme results
in varying degrees of cancer cell differentiation8,9, and cancer cells can form muscle cells
when transplanted into normal muscle10.
Moreover, G.H. Smith and colleagues11,12
provided a striking demonstration of the
capacity of normal tissue to revert a malignant phenotype. Pluripotent human embryonal carcinoma cells and human metastatic,
non-metastatic and metastasis-suppressed
breast cancer cells produced normal epithelial
progeny without tumour formation when
injected into a regenerating mammary gland
microenvironment in vivo11,12. These experiments and others13,14 show that cancer cells
carrying sufficient mutations to confer neoplastic potential can be suppressed by normal
tissue. Therefore, one can infer that mutations
in cancer cells alone are not able to induce
tumour growth, and that active changes in the
surrounding tissue cells must be essential for
the clinical development of cancer.
Consistent with this idea, the initiation
of tumorigenesis by the expression of an
oncogene or deletion of a tumour suppressor gene in mouse tissues is remarkably
inefficient at generating cancers. From a
cancer genome perspective, this is often
attributed to the need for additional sporadic genetic alterations. Considering the
host stroma as a necessary participant provides another explanation for this apparent
inefficiency: the juxtaposition of initiated
cells with host cells that favour survival,
proliferation and genomic evolution is stochastic and rare, which limits the further
evolution of transformed cells. Thus, in a
young, healthy individual, a cancer niche
develops by chance, not by intrinsic capacity. It is conceivable that, occasionally, the
initial transforming event might result in
signals that actively recruit a compatible
host cell partner. But more often than not,
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Niche construction
Stress
Niche expansion
Tumour cell
Epithelial
cell
Basement
membrane
Fibroblast
IMC
CAF
Bone-marrowderived cell
Blood vessel
Endothelial cell
Premetastatic niche
Niche maturation
Exosomes
Tumour microenvironment
Figure 1 | The dynamic cancer niche. A cartoon depiction of niche
construction engendered from local or systemically recruited cells that
initially improve cell survival and then promote malignancy as the niche
expands and matures into the tumour microenvironment. This expansion
is able to initiate new microenvironments, such as the premetastatic
host processes (such as ageing and chronic
inflammation) that are associated with cancer development increase the likelihood of
such events coinciding.
Construction of a cancer niche
How are normal cells involved in the earliest steps of cancer development, when we
argue that the cancer niche is formed? Here,
we consider evidence that carcinogenesis is
initiated when interactions between a genetically initiated cell and particular host cells in
the developing niche facilitate survival and
malignant behaviour.
One example of niche construction that
is induced by oncogene expression is
that of transgenic KRAS mutations; the
key downstream targets of many of these
mutations are cytokines and chemokines15.
In particular, crucial events are likely to
be the upregulation of chemokines, such
as interleukin 8 (IL‑8)16 and CXCL1, and
cytokines, such as granulocyte–macrophage
colony-stimulating factor (GM‑CSF) and
IL‑6. They in turn activate and remodel
stromal cells that promote progression to
niche, at a distance. Particular cytokines, such as transforming growth
factor‑β, interleukin 6 and stromal-derived factor 1, can be produced by
bone-marrow-derived cells, cancer-associated fibroblasts (CAFs) or
Nature Reviews | Cancer
tumour cells, and seem to support niche expansion
and maturation. IMC,
immature myeloid cell.
dysplasia17. In this case, the products of the
initiating mutation elicit the construction
of a precancer niche.
A second example comes from experimental models of chemical carcinogenesis.
In skin carcinogenesis, initiation with
7,12‑dimethylbenz(α)anthracene (DMBA)
is followed by 12‑O‑tetradecanoyl-phorbol13‑acetate (TPA), whereas in colorectal
carcino­genesis, initiation with azoxymethane
(AOM) is followed by dextran sodium sulphate (DSS)18. A key piece of the two-stage
carcinogenesis strategy is that each exposure
alone is insufficient to generate tumours.
Carcinogens are clearly capable of initiating — presumably by genomic change — the
target cells, which remain ‘latent’ until the
tissue is treated with a promoter. Classically,
this requirement for a tumour promoter is
explained by invoking the need for proliferation, which then expands the initiated
cells. We propose an alternative explanation:
chemical promoters recruit or induce host
stromal cells that can partner with the initiated cell, forming a precancer niche. One
action that is common among chemical
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promoters is that they induce substantial
inflammation, either primary inflammation
as occurs with TPA treatment, or inflammation that is secondary to injury as occurs
with DSS treatment; thus, this tumour
promotion can usually be blocked with antiinflammatory therapies. These experimental
models reflect the clinical observation that
cancer often arises in the setting of repeated
injury (such as tobacco carcinogens) or
chronic inflammation (such as that induced
by chronic Helicobacter pylori-mediated
gastritis)19. We speculate that chemical promoters enable niche construction, which
supports the proliferation of the initiated
clone. This hypothesis is experimentally testable by using strategies to silence or block
particular stromal phenotypes.
A third example is that of physiological
conditions that may also modulate the
frequency with which initiated cells can
construct a permissive stromal environment.
Tlsty and colleagues20 investigated the association of high mammographic density with
increased risk of breast cancer. They found
that stromal tissue from women with dense
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breast tissue on a mammogram is characterized by a loss of CD36 expression and a
gene expression profile that is similar to that
found in patients with breast cancer, suggesting that it is primed for niche construction.
Studies from Schedin and collaborators21,22
showed that breast involution after pregnancy leaves a stroma that is conducive to
malignant growth21. Conversely, tamoxifen
treatment results in a breast tissue that is
suppressive of tumour growth22. Thus, the
composition of tissue at the time of initiation
could have dramatic effects on whether cancer ensues. Recent studies suggest that host
biology also strongly influences the intrinsic
subtype of cancer 23,24.
Ageing is a special case of physiological
status. Most cancers increase in incidence in
older individuals. This is generally attributed
to the idea that multiple oncogenic mutations are necessary before cancer is clinically
established, and that these mutations accumulate over the lifetime of an individual25.
An alternative explanation, based on our
concept of the dynamic cancer niche, is
that ageing promotes niche construction
and expansion. An emerging theme is that
the deterioration of immune and inflammatory control systems as a function of
age is strongly associated with age-related
diseases, including cancer 26. Cellular alterations accompanying ageing may be better
suited to cooperate with initiated cells, or
ageing may simply result in more-abundant
partners. Another possibility is that ageassociated senescent cells, which have a proinflammatory secretory phenotype, stimulate
niche construction in a manner that is
similar to the action of chemical initiation
and promoters; that is, sporadically initiated
cells accumulate over time but fail to recruit
the necessary partners for niche construction until systemic low-grade inflammatory
activity increases in older individuals.
The last example is that of complete carcinogens, such as ionizing radiation or infection of animals with H. pylori or Helicobacter
felis 27,28, which both induce the upregulation
of inflammatory cytokines and promote the
development of cancer. The carcinogenic
action of ionizing radiation is classically
ascribed to the mutagenic consequences of
DNA damage, but ionizing radiation could
also affect early niche dynamics, stimulating niche construction and expansion.
Ionizing radiation activates transforming
growth factor‑β (TGFβ) and leads to rapid
extracellular matrix remodelling 29, which
elicits myofibroblast differentiation30.
Mice that have been irradiated and subsequently transplanted with non-irradiated,
oncogenically primed mammary epithelial
cells develop aggressive tumours with a
shorter latency than recipient mice that have
not been irradiated31. Given that the mammary epithelium was not irradiated in these
experiments, the acceleration of tumori­
genesis results from direct radiation effects
on the microenvironment. This acceleration
depends on TGFβ1 (REF. 31), through either
stromal remodelling or low-grade inflammation. Similar effects have been noted
in muscle: tumour cells transplanted into
normal muscle differentiate into functional
muscle, but give rise to tumours when transplanted into irradiated muscle10. Likewise,
irradiating mice that have neuronal-specific
mutations in the Hedgehog receptor,
patched homologue 1 (Ptch1), increases the
incidence of medulloblastoma, even when
the brain is shielded from ionizing radiation32. In each of these studies, the cells giving rise to the cancer were not irradiated,
so only the irradiated stroma is modulating
tumour incidence. These observations are
consistent with the notion that complete
carcinogens increase niche construction.
One mechanism might be through the
contribution of immune cell phenotypes to
cancer niche construction24,31–35. An intriguing example that was shown by Wright and
colleagues36,37 is that macrophages in irradiated mice produce signals that include CD95
ligand, tumour necrosis factor‑α (TNFα),
nitric oxide and superoxide. Interactions
between these irradiated macrophages and
non-irradiated bone marrow cells generates
DNA damage, as shown by chromosomal
instability in target cells36,37. The juxtaposition of activated macrophages and initiated
cells, each induced by radiation, could lead
to increased DNA damage and genomic
instability, independently of mutations that
already exist in the initiated cells38.
Potential signals. Essential signals in these
early stages of the cancer niche are currently unknown but probably include both
stromal-cell-derived factor 1 (SDF1, also
known as CXCL12) and TGFβ39. TGFβ
seems to be an important mediator of niche
remodelling throughout cancer progression. TGFβ polymorphisms that affect its
activity are associated with cancer susceptibility in a complex manner 40. Conditional
inactivation of the TGFβ type II receptor
gene in a subset of fibroblasts that express
fibroblast-specific protein 1 (FSP1)41 leads
to the rapid development of neoplasia in
the prostate and forestomach. Conditional
deletion of this receptor also results in defective mammary ductal development and
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accelerated neoplastic progression, in part
owing to increased stromal production of
hepatocyte growth factor (HGF)42. As mentioned above, ionizing radiation increases
cancer frequency through effects on the
stroma that are mediated in part by TGFβ24.
Consistent with this, human fibroblasts
that have been engineered to overexpress
TGFβ or HGF promote the development
of histologically dysplastic lesions from
normal human mammary epithelial cells
when co‑implanted into mouse mammary
glands43. Together, these studies underscore
the importance of TGFβ in modulating the
stromal–epithelial interface during the earliest
stages of oncogenesis44.
Recent findings on tumour-generated
exosomes — which are 30–90 nm vesicles
that are released from the cell when multi­
vesicular bodies fuse with the plasma
membrane — have changed how we view
communication between tumours and
organs45,46. Importantly, exosomes, which
contain proteins and nucleic acids that can
dramatically modify the recipient cells,
can clearly act systemically and seem to
have a major role in the crosstalk between
initiated cells and host tissues. In fact,
increasing evidence demonstrates that
tumour-secreted exosomes profoundly
regulate the immune response and the
haematopoietic system in general, including lineage-specific differentiation of
bone marrow precursors, dendritic
cell function and transference of mole­
cules47–53. Altered exosome production or
composition can alter the fate of nearby
cells and thus could contribute to early cancer niche formation by mobilizing potential
niche partners. Exosomes are implicated
in stress responses to injury, which have
long been associated with cancer development. Several studies have linked TGFβ in
exosomes to immune modulation48,54, but
a recent study also reported that TGFβ in
exosomes contributes to remodelling of the
TME by stimulating the differentiation of
fibroblasts into myofibroblasts55, which
we speculate could contribute to niche
construction or expansion.
Niche expansion
As the initiated clone expands and acquires
more mutations, the activation of oncogenic signalling pathways might also trigger niche expansion, thus leading to the
recruitment of additional inflammatory
cells and reprogramming of the stroma.
Initiated cells are not readily identified
in situ, but further progression to the
stage of dysplasia, which is the earliest
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histological evidence of neoplastic potential, produces systemic signals that lead to
profound reprogramming of the bone marrow stroma and mobilization of cells that
can expand the cancer niche. Signals from
the nascent niche can act both systemically
and locally to expand the niche during
progression from dysplasia to carcinoma
in situ.
Immune cells. Tumour-promoting agents,
such as TPA, stimulate the recruitment of
immature myeloid cells (IMCs) to incipient
tumour sites in chemical-carcinogen-treated
skin. After a single TPA application, IMCs
are mobilized from the bone marrow and
increase ~3.5‑fold in number in the peripheral blood, followed by recruitment to the
skin, and these cells persist in models of
two-stage carcinogenesis18. In addition,
these IMCs induce a greater recruitment of
α-smooth-muscle-actin-positive (αSMA+)
fibroblasts, 20% of which are bone-marrowderived. These bone-marrow-derived cells
are mainly derived from the mesenchymal
stem cell (MSC) lineage. MSCs normally
generate αSMA+ myofibroblasts in order to
maintain their own niche within the bone
marrow: both cell types are recruited to
tumours27,28. During tumorigenesis, both
the MSCs and the αSMA+ daughter cells are
recruited to the expanding tumour niche,
which promotes further tumour growth
and malignant progression. Thus, the
second phase of niche evolution, niche
expansion, involves the recruitment of
bone-marrow-derived myeloid cells, MSCs
and myofibroblasts that together probably
enable progression. Interestingly, MSCs
in the precancer niche may be recapitulating their physiological role to establish the
haematopoietic stem cell niche, in part by
reciprocal regulation by myofibroblasts28.
A study from Lyden and colleagues56 first
identified myeloid progenitor cells as necessary components of the TME in 2001, and
recent studies have shown that they also participate in the formation of a premetastatic
niche57–61. Studies of many carcinogenesis
models have clarified that innate immune
responses, particularly the recruitment of
IMCs, are crucial during the initial steps
of cancer. IMCs are defined as a hetero­
geneous population of CD11b+GR1+ cells
that include both granulocytic and monocytic precursors and constitute a large proportion (>30%) of nucleated bone marrow
cells62. Typically, they are less abundant in
the circulation and rare in most peripheral
tissues and organs. However, their numbers
are markedly increased in cancers, where
they also acquire immune-suppressive
properties and thus have been described
by some as myeloid-derived suppressor
cells (MDSCs). In many models of carcino­
genesis, IMCs are among the first cell types
that are recruited to a nascent TME. For
example, IMC levels are increased in the skin
within 6 hours of exposure of the skin to
TPA18. In mouse models of colorectal cancer,
repeated doses of AOM (that is, >3 doses)
are needed to both recruit IMCs to the colon
and induce colon tumours, thus indicating
a tight link between these two processes.
Transgenic models of gastric cancer (mice
that overexpress H+/K+‑ATPase and IL‑1β)27
or oesophageal cancer (conditional p120
catenin knockout mice)63 are also notable for
the early recruitment of IMCs to the incipient tumour sites, before any other changes
in the mucosa. Genetic alterations, such as
knockout of histidine decarboxylase18, that
led to an increase in circulating IMCs also led
to a more rapid induction and growth of
cancer cells at multiple sites (such as the
colon, skin and stomach) in response to
carcinogens. Thus, the recruitment of IMCs
to the precancer niche is probably one of the
earliest changes of cancer formation.
Although IMCs are probably necessary,
they are not sufficient for cancer: exposure
of the skin to TPA alone does not induce
skin cancer, neither is DSS-induced colitis
sufficient for colon cancer initiation. Unlike
resident tissue macrophages (which are
not bone-marrow-derived)64, IMCs are
short-lived and typically mature to monocytes and neutrophils and then seem to
diminish. Thus, a long-lasting, and possibly
permanent, effect of niche formation may
be required to stabilize the IMC phenotype
locally. With a complete carcinogen, such as
infection by Helicobacter species, levels of
myeloid cells remain increased in the circulation and at the tumour site. Eventually these
IMCs result in the recruitment of fibroblasts
and the induction of angiogenesis18; together
these events establish a TME that further
promotes tumour cell proliferation and
progression.
Interactions between adaptive immune
cells and transformed cells also determine
cancer progression. To examine the link
between chronic inflammation and skin
cancer, Coussens and colleagues65 used a
transgenic mouse model that expresses the
human papillomavirus type 16 (HPV16)
early region genes under the control of
the keratin 14 (K14) promoter. In this
study, B lymphocytes did not infiltrate skin
tumours, but were required for tumour
development because of their production
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of immunoglobulins. Indeed, crossing the
K14–HPV16 mice with Rag1−/− mice, which
lack mature B and T cells, blocked leukocyte recruitment and chronic inflammation
that generate pro-angiogenic factors, an
activated vasculature and hyperproliferation of oncogene-expressing keratinocytes.
Transfer of either B lymphocytes or serum
from K14–HPV16 mice effectively restored
the chronic inflammation and malignant
progression in K14–HPV16;Rag1−/− mice.
Importantly, all of these changes occurred
in the premalignant phase of tumour
development.
MSC and fibroblast contributions. Several
studies suggest that abnormal fibroblasts
can induce tumour promotion66–71. One of
the earliest indications that abnormal fibroblasts could promote cancer came from
the laboratory of Seth and Ana Schor 72,
who showed that fibroblasts from tumours
had a fetal phenotype, characterized by
the production of migration-stimulatory
factor (MSF), which was also expressed by
normal-appearing fibroblasts from cancer
patients with a familial history of cancer.
MSF is a truncated form of the oncofetal
isoform of fibronectin73, which is proposed
to contribute to carcinoma development by
altering cellular adhesion early in carcino­
genesis74,75. This aberrant stromal phenotype might also contribute to a genetic
predisposition to cancer by promoting
niche formation.
Fibroblasts are extremely heterogeneous
and are also crucial sources of proteolytic
enzymes, growth factors and cytokines76.
Fibroblasts are responsible for the production and deposition of the bulk of the
extracellular matrix proteins, such as coll­
agen I and fibronectin, as well as matrix
metalloproteinases. Although prominent
in all tissues, it is not likely that normal
fibroblasts participate in precancer niche
formation; rather, a subset of activated
myofibroblasts that are αSMA+ are strongly
implicated. Some myofibroblasts originate
from bone-marrow-derived MSCs, which
are a self-renewing population of cells that
have been shown to regulate cancer stem
cells through cytokine networks77, whereas
other myofibroblasts are derived from tissue
MSCs or are reprogrammed cells from local
sources28,78. As mentioned above, various
studies provide compelling evidence that
aberrant fibroblast signalling promotes cancer 41,42,79. A model in which Pten is deleted
in stromal fibroblasts is characterized by an
expansion of the stroma and the initiation
of mammary tumorigenesis80. In support of
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fibroblast niche-forming potential, investigations led by Leland Chung 81 showed that
co‑injection of transformed fibroblasts (rat
NBF‑1 or mouse NIH3T3 cells) induced a
normally non-tumorigenic cell line to form
tumours. Consistent with niche expansion,
Cunha and co-workers82 demonstrated that
fibroblasts derived from prostate tumours
stimulated tumour progression of prostate
epithelial cells immortalized with the simian
virus (SV40) T antigen. Such studies suggest
that fibroblasts, rather than being innocent
bystanders in the tumorigenic process,
can convert from tumour-suppressive to
tumour-promoting agents.
Detailed studies of early events in
gastric cancer induced by infection with
Helicobacter species supports the contention that dynamic interactions mediated by
MSCs begin very early in the carcinogenic
process28. As discussed above, this model
leads to chronic inflammation and eventual
dysplastic lesions. αSMA+ myofibroblasts,
generated from MSCs, contribute to both
the normal bone marrow niche and MSC
self-renewal. During chronic inflammation leading to carcinogenesis, these
αSMA+ bone marrow niche cells increase
in a TGFβ-dependent manner, possibly facilitating niche construction. The
CXCR4–SDF1‑dependent recruitment of
αSMA+ bone marrow cells to sites of dysplasia, together with Gremlin-1‑expressing
MSCs, act in concert to expand the cancer
niche that promotes and sustains tumour
progression83. Notably, inhibition of TGFβ or
CXCR4 prevents niche expansion, and significantly reduces dysplasia. Once the TME
is established, a biologically distinct cellular
phenotype — cancer-associated fibroblasts
(CAFs) — is identifiable and functionally
active, and is often derived from different
cell types, including MSCs.
The maturing cancer niche
In order for cancer to evolve from carcinoma
in situ into invasive cancer, further changes in
both the initiated cell and the niche are
required. In this third stage of niche development, selection forces at work on the tumour
would seem to favour interactions between
cancer cells and stromal cells that increase
the availability or variety of growth-inducing
signals or immune-suppressive signals.
Changes in bone marrow, such as cell
activation and mobilization, in response
to tumour development are likely to be
integral in niche maturation. The nature of
these systemic signals is not fully defined,
but could involve TGFβ, SDF1, and possibly exosomes. TGFβ seems to have a
major role in the conversion of MSCs into
CAFs, and treatment with a TGFβ inhibitor blocks the expansion of CAFs at the
tumour site28. In addition, TGFβ induces
the production of CAFs through an
SDF1–CXCR4 axis, and SDF1 is essential
for the recruitment of MSCs and CAFs to
the tumour site. Overexpression of SDF1
leads to a greater recruitment of MSCs and
CAFs84, whereas SDF1 antagonism blocks
the production of CAFs in the bone marrow, as well as the recruitment of CAFs to
the tumour site28.
Recent reports suggest that circulating
exosomes produced by established primary
tumours have an effect on bone marrow progenitors through the horizontal transfer of
molecules, such as proteins and microRNAs84.
Tumour-derived exosomes alter bone marrow progenitors and recruit BMDCs through
the upregulation of pro-inflammatory mole­
cules at premetastatic sites. As noted above,
tumour cell exosomes also activate CAFs in
the local stroma, recruit MSCs and alter
T cell function48,54,55.
at some point, a successful
niche evolves and matures into a
dynamic feedback system
Oncogenic changes in tumour cells can
moderate angiogenesis and so influence
the maturation of the cancer niche into the
TME. For example, sustained activity of
the transcription factor MYC in the presence
of the anti-apoptotic protein BCL‑XL in the
islets of the mouse pancreas drives the proliferation of β‑islet cells, but also indirectly
increases the proliferation of endothelial
cells85. The cytokine IL‑1β produced by the
proliferating β‑islet cells was shown to be
necessary and sufficient for the angiogenic
effects of MYC activity. IL‑1β expression
mediated the activation and redistribution
of the angiogenic factor vascular endothelial
growth factor A (VEGFA) from the extra­
cellular matrix. Thus, the production of IL‑1β
induced by MYC in the proliferating β‑islet
cells serves as a paracrine trigger to modify
the microenvironment. Inhibition of IL‑1β
delayed tumour growth, thus indicating the
importance of the effects on the TME.
In a model of breast cancer, enhanced
infiltration of macrophages and other myeloid cells was found to always precede the
angiogenic switch, which is necessary for
the transition between dysplastic and early
carcinoma stages86. Genetic depletion of
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myeloid cells by homozygous deletion of
the macrophage growth factor, colonystimulating factor 1 (CSF1), delays both
the angiogenic switch and malignant progression of mammary cells expressing the
polyoma middle T oncoprotein, suggesting
that myeloid cells regulate angiogenesis.
Overexpression of CSF1 from the mouse
mammary tumour virus promoter resulted
in an especially early recruitment of macro­
phages and other leukocytes to hyperplastic
lesions in the mammary gland and the
extensive development of blood vessels.
Thus, premature myeloid cell recruitment
was sufficient to stimulate a degree of angiogenesis that is more common in late-stage
carcinomas, thus indicating that angiogenic
activity is not necessarily a response to
enhanced tumour size (and hypoxia), but is
controlled by cells that are recruited to the
TME, independently of tumour stage.
Just as the ability of a tumour to generate premetastatic niches is likely to be a
major factor that determines metastatic
spread (reviewed in REF. 87), we speculate
that niche-forming interactions affect which
transformed cells survive, expand and progress to clinical disease, and thus determine
cancer incidence. The multiple cellular candidates that might establish a cancer niche early
in carcinogenesis all serve the same purpose:
to provide a suitable environment for survival
of the cancer cells. Resident, circulating and
bone-marrow-derived stromal cells stabilize
initiated clones, which secrete factors and
exosomes that refine tumour-associated
stromal cell phenotypes, elicit angiogenesis
and evade immune surveillance. The initial
stromal cell interactions with the transformed clone may be adventitious, and thus
rate limiting, but at some point, a successful
niche evolves and matures into a dynamic
feedback system (FIG. 2).
Eliminating the cancer niche
Considering the new insights into the interplay between cancer cells and stromal cells,
one might recall Stephen Paget’s theory of
“seed and soil” in metastatic disease88. Indeed,
recent studies suggest that the early use of
systemic therapies targeted to the metastatic
microenvironment may be beneficial, perhaps
even as an adjunct to the initial treatment of
the primary tumour (reviewed in REF. 87).
Yet, the ‘soil’ is prepared long before metastatic growth. We suggest that greater attention should be paid to the niche when
designing therapies to prevent and treat cancer. If cancer is initiated in part by carcino­
genic effects on the stroma, as suggested
by the responses of experimental models
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Malignant cell
Initiation
Niche
Stochastic
Basement
membrane
Epithelial
cell
Construction
Fibroblast
IMC
Tumour cell
Promotion
Expansion
CAF
Progression
Bone-marrowderived cell
Maturation
Cancer and tumour microenvironment
Figure 2 | Schematic of niche construction, expansion and maturation. This cartoon
the
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| Cancer
interdependent processes that might occur in a developing niche that parallel the classic multistep
carcinogenesis model of initiation, promotion and progression. Niche construction by normal cells
ratchets up malignant potential by improving the survival of initiated cells. Niche expansion supports
the tumour cell diversity and probably accompanies angiogenesis, and eventually matures into the
tumour microenvironment. CAF, cancer-associated fibroblast; IMC, immature myeloid cell.
to radiation and chemical carcinogens,
then chemopreventive agents aimed at the
stroma to avert niche expansion would be a
reasonable strategy to reduce risk or inhibit
cancer progression to clinical disease. Antiinflammatory agents, particularly those
directed to chronic ‘smouldering’ inflammation (as opposed to acute inflammation)
might be effective. Alternatively, activated
phenotypes in macrophages and fibroblasts
might be suppressed by inactivating or dampening epigenetic switches, as has been experimentally achieved using differentiating agents
such as 5‑azacytidine.
As niches are by nature highly localized,
and incipient cancer is undetected, ideas for
targeting the precancer niche may be inferred
from the factors that augment carcinogen
efficiency or from studying tissue samples
from individuals who have a high risk of
developing cancer. Of special interest is ageing: could the higher risk of cancer in older
individuals be reduced by eliminating the
potentially ‘permissive’ microenvironment?
The observation that only 4% of people aged
over 100 years die of cancer in comparison to
40% of those aged 50–69 (REF. 26), indicates
that this is physiologically achievable and
might be emulated pharmaceutically if it was
better understood. Those who live to be quite
old seem to have an immune system that efficiently resolves acute inflammation and suppresses chronic inflammation. This duality is
evident in the chemical carcinogenesis model
of skin cancer, in which the genetic control of
a strong acute inflammatory response to TPA
is associated with a reduced incidence of skin
tumours, whereas a chronic inflammation
response is strongly associated with cancer
susceptibility 89.
Strategies to personalize cancer medicine
by using agents that interrupt aberrant
signalling in cancer cells are typically shortlived because of resistance. Therapeutic success should include not only the eradication
of malignant tissues, but also therapies that
may provide long-term control of cancer by
reverting a hospitable niche. For example,
α‑interferon treatment in chronic myeloid
leukaemia re‑establishes the interaction
between haematopoietic progenitor cells and
the bone marrow stroma and thereby reduces
6 | ADVANCE ONLINE PUBLICATION
proliferation90,91. That some therapeutic
agents may already act through effects on
the microenvironment provides support for
turning attention to even earlier events in the
cancer niche.
Conclusions
Recent initiatives to understand the biology
of stromal cells that contribute to tumour
growth and survival have produced new
strategies to control cancer. We think that
understanding the carcinogenic process as
being a balanced partnership of stromal and
cancer cells will not only provide keys to
controlling cancer, but will also be crucial for
cancer prevention.
Several authors have described cancer in
terms of evolution, ecology and emergent
properties92–94, frequently focusing on two
important concepts: the impact of selection
at different levels of organization and the role
of fitness in cancer cell dynamics. However,
fitness is only relative to the particular microenvironment of those cells. This implies that
there are two sides to the coin of somatic
evolution: changes in the neoplastic cells and
changes in their environment that alter the
selective pressures on the neoplastic cells.
Here we propose the concept of a dynamic
niche that expands on these concepts. We
speculate that niche construction, like initiation, is often stochastic, and thus not subject
to evolutionary selection at the level of the
organism; however, once a cooperative interaction is established, evolutionary processes
would act to select the most productive
pheno­types of both malignant and normal
cells. In other words, these novel ecological
relationships may be due to an unfortunate
convergence, but construction of a niche
results in successful co‑evolution that promotes cancer progression. Indeed, fortuitous
interactions between initiated cells and
specific stromal cells result in an emergent
property in which both stromal and tumour
cell participants of a niche are necessary for
survival, that is, fitness. A cancer prevention
strategy might disable the niche, which has
a relatively limited phenotypic repertoire
within and between individuals, or re‑educate its normal cell constituents. The next
stage of carcinogenesis, promotion, parallels
niche expansion through tissue remodelling and the recruitment of stromal cells and
BMDCs. The maturation of the niche supports progression to clinically evident
cancer and produces the TME that actively
contributes to invasion and metastasis.
New models and methods are needed
to study the dynamic changes in stromal
cells that enable initiated cells to survive and
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PERSPECTIVES
progress, and to test cancer prevention strategies that tip the balance towards tumour
suppression. In contrast to the tools that are
available for studying an established TME,
niche formation results from rare, stochastic
cell interactions that create specialized micromicroenvironments for presumably undetectable initiated cells; therefore, defining crucial
parameters of niche formation requires different approaches. Tissue studies of rare events
using a combination of in situ localization,
informative biomarkers and statistical modelling will identify specific patterns. Dynamic
modelling using complex in vitro models will
be important for demonstrating instructive
interactions, identifying crucial pathways and
finding control points that are susceptible to
therapy. For example, quantitative modelling of the angiogenic switch predicted that a
potential growth plateau that results from a
dynamic balance between angiogenic stimulation and inhibition is a possible therapeutic
target95. When the distinctive behaviours
of stromal cells under the influence of cancer cells are better understood, we suggest
that they can be targeted without harming
immune, inflammatory or stromal cells elsewhere in the body. Such strategies may provide the long sought means to control a root
cause of cancer: the corruption of local and
systemic environments.
Mary Helen Barcellos-Hoff is at The Department of
Radiation Oncology, New York University
School of Medicine, 566 First Avenue, New York,
New York 10016, USA.
David Lyden is at The Children’s Cancer and Blood
Foundation Laboratories, Departments of Pediatrics,
Cell and Developmental Biology, Weill Cornell Medical
College, New York, New York 10021, USA; and
Champalimaud Metastasis Centre, Lisbon, Portugal.
Timothy C. Wang is at The Department of Medicine
and Irving Cancer Research Center, Columbia
University Medical Center, 130 St. Nicholas Avenue,
New York, New York 10032–3802, USA.
e-mails: [email protected];
[email protected]; [email protected]
doi:10.1038/nrc3536
Published online 13 June 2013
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Acknowledgements
The authors thank C. Maley for helpful discussions and apologize to those whose work was not cited owing to space limitations. M.H.B.H. is supported by the US National Aeronautics
and Space Administration (NASA) Specialized Center for
Research in Radiation Health Effects, grant NNX09AM52G.
D.L. is supported by the Hartwell Foundation, the Children’s
Cancer and Blood Foundation and the Champalimaud
Foundation.
Competing interests statement
The authors declare no competing financial interests.
FURTHER INFORMATION
Mary Helen Barcellos-Hoff’s homepage:
http://www.med.nyu.edu/biosketch/barcem01
David Lyden’s homepage:
http://weill.cornell.edu/research/dclyden/index.html
Timothy C. Wang’s homepage: http://asp.cpmc.columbia.
edu/facdb/profile_list.asp?uni=tcw21&DepAffil=Medicine
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