PERSPECTIVES

phase 0 trial is widely evaluated, we expect
that pharmacodynamic-driven early
therapeutic studies, as was the case for
pharmacokinetic monitoring nearly 20 years
ago21, will become a routine part of future
early-phase oncological drug development.
Robert Kinders, Larry Rubinstein, Ralph E. Parchment,
Anthony J. Murgo, Jerry Collins, Oxana Pickeral,
Jennifer Low, Sherry Yang, Joseph E. Tomaszewski and
James H. Doroshow are at the Division of Cancer
Treatment and Diagnosis, National Cancer Institute,
Bethesda, Maryland, USA.
Shivaani Kummar, Seth M. Steinberg, Martin Gutierrez,
Lee Helman, Robert Wiltrout and James H. Doroshow
are at the Center for Cancer Research, SAIC-Frederick,
Inc., NCI-Frederick, Frederick, Maryland USA.
Correspondence to J.H.D.
e-mail doroshoj@mail.nih.gov
18. Sun, H. et al. Imaging the pharmacokinetics of
[F-18]FAU in patients with tumors: PET studies.
Cancer Chemother. Pharmacol. 57, 343–348
(2006).
19. Liu, G. et al. Dynamic contrast-enhanced magnetic
resonance imaging as a pharmacodynamic measure of
response after acute dosing of AG-013736, an oral
angiogenesis inhibitor, in patients with advanced solid
tumors: results from a phase I study. J. Clin. Oncol. 23,
5464–5473 (2005).
20. Collins, J. M. Imaging and other biomarkers in early
clinical studies: one step at a time or re-engineering
drug development? J. Clin. Oncol. 23, 5417–5419
(2005).
21. Collins, J. M., Grieshaber, C. K. & Chabner, B. A.
Pharmacologically guided phase I clinical trials based
upon preclinical drug development. J. Natl. Cancer Inst.
82, 1321–1326 (1990).
Acknowledgements
This project has been funded in whole or in part with fed-
eral funds from the US National Cancer Institute, National
Institutes of Health. The content of this publication does
not necessarily reflect the views or policies of the US
Department of Health and Human Services, nor does any
mention of trade names, commercial products or organiza-
tions imply endorsement by the US Government. This
research was supported by the Division of Cancer Treatment
and Diagnosis and the Center for Cancer Research of the
National Cancer Institute.
Competing interests statement
The authors declare no competing financial interests.
FURTHER INFORMATION
National Cancer Institute: http://www.cancer.gov
Division of Cancer Treatment and Diagnosis: http://www.
cancer.gov/dctd
Center for Cancer Research, National Cancer Institute:
http://ccr.cancer.gov
Cancer Therapy and Evaluation Program, National Cancer
Institute Guidelines for Correlative Studies in Clinical
Trials: http://ctep.info.nih.gov/guidelines/index.html
Office of Biorepositories and Biospecimen Research,
National Cancer Institute: http://biospecimens.cancer.gov
Steps for pharmacodynamic assay development:
http://dtp.nci.nih.gov/docs/phase0/PharmacoDynamicAssay
Develoment.html
Access to this links box is available online.

doi:10.1038/nrc2066

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12. Parulekar, W. R., Eisenhauer, E. A. Phase I trial design tions about the nature of cancer and how to the immediate microenvironment within a
for solid tumor studies of targeted, non-cytotoxic
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control it. Directly bearing on this, there has developing tumour become as important as
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Eggermont A. M. M. Integration of translational
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12–9566 in patients with advanced or metastatic dendritic cells. All these cells can participate genesis and carcinomas as phenomena that
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PERSPECTIVES

a Acute inflammation b Carcinogenesis there might be molecular lesions in cells of

the microenvironment and in epithelial cells
Stimulus (injury, infection) Epithelia themselves. Although there are many excel-
lent recent reviews on the tumour microen-
Basal lamina vironment, and it has recently been proposed
Mast cells
as a target for therapy4,5, the application of
Stroma
chemoprevention to control the tumour
ECM microenvironment during the early stages
Neutrophils of carcinogenesis has so far not received
Mutagenesis
Proliferation concerted attention.
Inflammation This Perspective is not intended to
Macrophages be a comprehensive review; rather, it
attempts to indicate new directions and to
highlight new priorities for future research.
Although the microenvironment is also
involved in the genesis of leukaemias and
Effector
immune cells Hyperplasia sarcomas, this Perspective deals only with
Dysplasia carcinomas (the most common forms of
Further mutagenesis
Inflammation malignancy), which originate in epithelia
and their associated stroma.
Angiogenesis
New insights
The concept that the microenvironment of
a developing tumour is a crucial regulator
Fibroblasts Angiogenesis of carcinogenesis was originally proposed
and fibrosis Uncontrolled growth by Paget in his famous ‘seed and soil’
Progression
hypothesis. Recent data indicate that car-
cinogenesis and tumour angiogenesis result
not only from the interaction of cancer
Tissue remodelling cells with endothelial cells of various origin
(vascular or lymphatic), but that surround-
Figure 1 | Correlations and contrasts between acute inflammation and carcinogenesis. a | The
ing ‘normal’ stromal and inflammatory cells
sequence of events in acute inflammation and tissue repair (see REF. 9 for a more detailed descrip-
tion). The process of inflammation initiates a series of catabolic and anabolic processes that occur in and tissue also have a crucial role in direct-
a defined order, first eliminating foreign pathogens and then remodelling tissue, thereby establishing ing the formation of the blood vessels that
homeostasis. Shown in this figure are: first, the activation of resident cells (mast cells, resident mac- nourish a developing tumour. This newer
rophages and dendritic cells) and rapid entry of granulocytes in response to injury; second, further version of an old hypothesis now enables
recruitment of macrophages; third, infiltration of effector immune cells (lymphocytes) to enable us to consider that stromal cells and their
specific immune responses; fourth, the recruitment and activation of mesenchymal cells such as associated matrix, as well as cells of the
endothelial cells and fibroblasts to form new blood vessels and a collagenous matrix; and fifth, tissue immune system, have important roles in
remodelling. In its initial stages, inflammation is an aggressive state that can destroy both exogenous tumour angiogenesis and carcinogenesis6–9.
pathogens and host tissues; this is followed by a switch to a state that promotes cell survival and There is a discrete order of events in phys-
tissue regeneration. b | Carcinogenesis as the chaotic disorganization of inflammation and repair. In
iologically acute inflammation and repair10
contrast to the orderly series of events shown in part a, during chronic unresolved inflammation and
(FIG. 1a). However, these events become
carcinogenesis these events are chaotically disorganized and homeostasis is not achieved. During
carcinogenesis, both epithelial and stromal elements might initially undergo alterations that promote chaotically disorganized during chronic
epithelial cell proliferation and mutation. This alteration in tissue homeostasis can in turn lead to an unresolved inflammation and carcinogenesis
inflammatory response, which then further promotes tumour growth through the activation of the (FIG. 1b). This chaotic local microenvironment
surrounding stroma, especially neovascularization. Continued hyperplasia and dysplasia eventually has led to the suggestion that tumours are
lead to an invasive neoplastic state. The process shown here has been described with the metaphor ‘wounds that do not heal’11. The constant
that “tumours are wounds that do not heal”11. Both epithelial cells and cells of the microenvironment disruption of homeostasis by proliferating
are targets for chemopreventive agents at all the steps shown. Chemopreventive agents might be epithelial cells produces a chronic inflamma-
anti-mutagenic, anti-proliferative, anti-inflammatory or anti-angiogenic, therefore restoring tissue tory reaction, which is an abortive attempt
homeostasis that has been disrupted during carcinogenesis. Early genetic or epigenetic changes in
to re-establish homeostasis through tissue
epithelia or stroma are shown in yellow. ECM, extracellular matrix.
remodelling12. However, the classic players
in acute inflammation (granulocytes, mac-
Therefore, it is necessary to consider the targeted to the tumour microenvironment rophages, endothelial cells and fibroblasts)
microenvironment of a cancer and its associ- to control the process of carcinogenesis and that ordinarily lead to the resolution of a
ated abnormal epithelium as a functional prevent cancer. The implementation of this wound through an orderly series of events,
whole. In addition to existing preventive new approach, in addition to the accepted instead react paradoxically to the presence of
efforts directed at dysfunctional epithe- approach of targeting dysfunctional epithelial dysfunctional epithelial cells by promoting
lium, we propose that it is now essential to cells, becomes increasingly important as their survival and replication12. This proc-
develop new chemopreventive measures new data, summarized below, indicate that ess includes inflammatory angiogenesis.

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© 2007 Nature Publishing Group

Continuing angiogenesis driven by myeloid
inflammatory cells is well recognized as an
important component of chronic inflamma-
tory disorders such as rheumatoid arthritis13;
recent data indicate that it can also have a key
role in the progression of cancer12,14,15.
Epithelial cells can become dysfunctional
if their microenvironment is severely
perturbed. This control of epithelia by their
stroma is a default condition in normal
tissues, as adult organs do not change
composition, size or shape by uncontrolled
remodelling. Therefore, rather than being
a passive reaction to the cancer cell, the
microenvironment might be a primary
active factor in determining whether dys-
functional epithelial cells will continue to
grow and invade in a particular local milieu
or, alternatively, merely become an indolent
micro-hyperplasia or even be eliminated.
Recent observations suggest that paracrine
control in a developing tumour depends
not so much on the intrinsic identity of its
cellular components, but on the phenotypic
expression of specific factors that either pro-
mote or suppress carcinogenesis. For
example, the phenotype of tumour-
associated macrophages (termed M2) might
be quite different compared with normal
macrophages (termed M1)16, and additional
subsets based on microenvironmental cues
have been proposed17. M2 macrophages
might also directly influence tumour cells
themselves and promote aggressiveness; for
example, macrophages might have a key
role in freeing prostate cancer cells from
androgen dependence18, a crucial step in
malignant progression.
Neutrophils are another important cell in
the microenvironment. They can promote
tumour destruction, but might also have an
opposite effect and increase the growth of
tumour cells12,19. Several chemokines that
act on the CXCR2 receptor (also known
as the interleukin 8 receptor, β) are known
to be angiogenic factors produced within
tumours, and this seems to involve the
neutrophil-dependent release of vascular
endothelial growth factor A (VEGFA)20,21. A
cascade of events that includes neutrophil
recruitment followed by VEGF and matrix
metalloproteinase 9 (MMP9) release is
induced by these chemokines, which subse-
quently leads to endothelial cell invasion and
vessel formation19. Experimentally, events
such as Ras transformation have been shown
to enhance this cascade15.
Furthermore, fibroblasts in a tumour
can also promote tumorigenesis22. These
include, among others, tumour fibroblasts
such as carcinoma-associated fibroblasts
NATURE REVIEWS | CANCER
PERSPECTIVES
Table 1 | Molecular targets and chemopreventive agents in the microenvironment
Molecular targets Chemopreventive agents
Oestrogen receptors Tamoxifen; raloxifene; arzoxifene
Akt and NFκB Curcumin; N-acetyl cysteine; silibinin; xanthohumol;
deguelin; EGCG; resveratrol
NRF2–KEAP1 Sulphoraphane; oltipraz
COX2 Rofecoxib; celecoxib; EGCG
COX1/2 Aspirin and other NSAIDs
Histone deacetylases Sulphoraphane
TGFβ pathway CDDO-Imidazolide
HIF1α EGCG; resveratrol; apigenin; sulphoraphane
STATs CDDO-Imidazolide
VEGF Sulphoraphane; EGCG; fenretinide
This is not intended as a comprehensive list, but only to show specific targets in the microenvironment, and
indicate specific agents that interact with these targets, as discussed in the text. CDDO, 2-cyano-3,12-
dioxooleana-1,9-dien-28-oic acid; COX2, cyclooxygenase 2; EGCG, epigallocatechin-3-gallate; HIF1α, hypoxia-
inducible factor 1α; KEAP1, kelch-like ECH-associated protein 1; NFκB, nuclear factor κB; NSAIDs, non-steroidal
anti-inflammatory drugs; STATs, signal transducers and activators of transcription; TGFβ, transforming growth
factor-β; VEGF, vascular endothelial growth factor.
(CAFs) that increase tumour growth and specific cytokines (the adipokines leptin,
angiogenesis through the expression of adiponectin, resistin and visfatin), as well as
CXCL1223. CXCL12, a chemokine ligand matrix metalloproteinases that promote the
for the widely distributed chemokine inflammatory process and angiogenesis28.
receptor CXCR4, promotes angiogenesis by A key question remains: which comes
recruiting marrow-derived precursors that first, the dysfunction of epithelial cells or the
contribute to vessel development. Similar to dysfunction of their microenvironment29?
tumour macrophages, CAFs have a distinct There is no intrinsic reason to postulate that
phenotype compared with normal fibrob- carcinogenesis necessarily begins with epi-
lasts22, which neither produce CXCL12 nor thelial dysfunction, especially because under-
induce angiogenesis, and only marginally lying mesenchymal cells control epithelial
contribute to tumour growth23. differentiation during embryogenesis30,31.
Another important mesenchymal cell is Genetic changes in stromal cells adjacent
the myofibroblast, which has different func- to breast cancer cells have been described
tions in different organs. Myofibroblasts in many publications, although these might
abut on epithelial or glandular cells and not always be present (see REF. 32 for further
produce several growth factors, cytokines, data). Most recently, new studies on clinical
chemokines and extracellular matrix com- material derived from both breast and colon
ponents. They express many receptors and carcinomas indicate that genetic changes
are a source and target of soluble media- occur in the stroma during the earliest stages
tors24. Myofibroblasts are activated when of human carcinogenesis33,34, and suggest that
tissue integrity is compromised and might a genetically unstable stroma might facilitate
actively increase tumour growth and expan- further genetic instability in the overlying
sion once tissue invasion begins, especially epithelium33,34. Clinical histopathology data,
in the colon and liver25. which show lymphoma-specific genetic
Finally, adipocytes have also been recog- abnormalities in the microvascular endothe-
nized recently as important components of lial cells in B-cell lymphomas, support these
the tumour microenvironment. The explo- findings35. Furthermore, animal studies
sion of concern about obesity in the United have found cytogenetic abnormalities in the
States has heightened awareness about the endothelium of lung tumours36, although
relationship between fat cells and cancer. the primacy of these endothelial lesions is
Obesity constitutes an independent risk fac- still uncertain. However, given the exposed
tor for several types of cancer26,27, especially anatomic location of capillaries in the alveoli
those with a strong inflammatory compo- of the lung, it would not be surprising, for
nent. Adipocytes are important producers example, if alveolar capillary endothelial
of various biologically active molecules that cells in smokers were mutagenized by
influence inflammation and angiogenesis, tobacco carcinogens. Furthermore, recent
and adipose tissue is an authentic endocrine murine studies, which are discussed more
and paracrine organ that secretes several below, have shown that initial genetic lesions
VOLUME 7 | FEBRUARY 2007 | 141
© 2007 Nature Publishing Group
PERSPECTIVES

Hyperplastic and dysplastic foci Macrophages are crucial partners for

tumour cell migration, invasion and metas-
tasis. These contextually responsive cells of
the microenvironment can either promote
the formation of extracellular matrix or
Macrophage
Neutrophil speed up its destruction, and are primary
sources of gaseous signalling molecules such
ECM Fibroblast as reactive oxygen and nitrogen species that
can be mutagenic and carcinogenic, as well
Angioprevention Angiogenesis
as prostaglandins that regulate inflamma-
tion. As such, they have become targets for
many pharmacological agents that include
Apoptotic suppressors of nitric oxide synthase (iNOS)
cell synthesis and function and suppressors of
cyclooxygenase 2 (COX2) synthesis and
function, in addition to the antagonists of
Apoptosis = proliferation Uncontrolled growth the cytokines they produce. There is a vast
Limited inflammation Progression amount of literature on this topic44–48.
Slow progression Invasion Less attention has been given to lym-
Chronic or subclinical disease Metastasis
phocytes as targets for chemoprevention.
Figure 2 | Angioprevention as a strategy for chemoprevention. The foci of hyperplastic and However, recent studies on the role of Smad
dysplastic cells are microscopic, non-invasive lesions. It is known that people might have many such
signalling (the key signal transduction
lesions in different organs but still be asymptomatic. These silent lesions will usually not progress
until an “angiogenic switch” occurs, which enables significant neovascularization that results in the pathway for transforming growth factor-β
progression of the tumour, invasion and metastasis108. Angioprevention seeks to interrupt this (TGFβ)) in T cells, and its importance for
sequence of events by blocking the formation of new blood vessels. Many chemopreventive drugs the suppression of gastrointestinal cancer,
function by various mechanisms to suppress tumour angiogenesis, as discussed in the text. If hyper- now show that the selective loss of SMAD4-
plastic and dysplastic foci do not become vascularized, then a steady state might be achieved in dependent signalling in stromal T cells leads
which programmed cell death (apoptosis) and proliferation are in balance, resulting in lesions that to spontaneous epithelial cancers throughout
are continually asymptomatic and never life-threatening22. ECM, extracellular matrix. the gastrointestinal tract of mice, whereas
deletion of the Smad4 gene in the epithelium
only does not37. Loss of TGFβ signalling
confined to the stromal compartment of All of these targets should now be investi- is a frequent occurrence in early stages of
the gastrointestinal tract are sufficient to gated for their use in chemoprevention. The gastrointestinal cancer in humans, and these
induce epithelial carcinomas37. A recent and overall topic of chemoprevention has been new studies therefore suggest that increased
provocative hypothesis suggests that chronic reviewed at length many times39–43, and we stromal TGFβ signalling could be chemopre-
tissue hypoxia within the tumour microenvi- will not do this here. Rather, we will briefly ventive during the early stages of carcinogen-
ronment might favour stromal mutagenesis, summarize recent progress that indicates esis. New synthetic triterpenoids, such as the
which subsequently promotes further that the effects of chemopreventive agents oleanolic acid derivatives CDDO (2-cyano-
mutagenesis and genetic instability in the on the microenvironment are an important 3,12-dioxooleana-1,9-dien-28-oic acid) and
adjacent epithelium38. All of these findings aspect of their preventive action, and that its imidazolide derivative, have been shown to
require a re-evaluation of previous notions many classes of agents previously shown to facilitate Smad signalling and to increase the
that the stroma has only a secondary role in have significant chemopreventive actions expression of TGFβ-dependent genes, such
the genesis of carcinomas. on epithelia also have similar useful actions as plasminogen activator inhibitor-1 (PAI1)
on the microenvironment. We will discuss and the TGFβ type 2 receptor itself 49. Further
Approaches to control selected examples of important cellular and studies on the possible use of these agents to
As the microenvironment has such a crucial molecular targets in the microenvironment, prevent cancer in appropriate mouse models
role in carcinogenesis and metastasis, it rep- and the drugs that interact with these targets. of carcinogenesis seem to be warranted.
resents a crucial target not only for cancer
therapy but also for preventive strategies. Cellular targets for chemoprevention in Molecular targets for chemoprevention
The rationale for chemoprevention is simple the microenvironment. During the earliest in the microenvironment and agents that
and straightforward: it is preferable to fix stages of carcinogenesis, all of the cells in the regulate these targets. There are many
something in its early stages of dysfunction, microenvironment are targets for chemo- molecular targets in the microenviron-
before it is beyond repair. The microenviron- prevention, because dysfunctional cytokine ment, and many drugs that are known
ment of a developing carcinoma is an obvi- networks that promote carcinogenesis are to interact with these targets (TABLE 1).
ous target for chemoprevention, although in established in these cells. Chemopreventive Transcription factors and their associated
the past, most attention in cancer research agents can be directed towards regulating regulatory proteins, by virtue of their
has been given to controlling the dysfunc- and normalizing the function of macro- pleiotropic actions on many genes, are an
tional epithelium. There is already a wealth phages, granulocytes, lymphocytes, endothe- obvious target for chemoprevention, espe-
of information about specific cells and mol- lial cells and their associated pericytes, as cially as carcinogenesis typically involves
ecules in the tumour microenvironment that well as fibroblasts. Owing to space limita- the dysfunction of several genes. Although
are targets for cancer therapy at present4,5. tions only selected examples are cited. this is contrary to conventional approaches

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© 2007 Nature Publishing Group

to finding monofunctional ‘magic bullets’,
it represents a more realistic approach to
the actualities of carcinogenesis and the
increasing problem of emerging resistance
to monofunctional agents42.
With respect to the microenvironment,
signal transducers and activators of tran-
scription (STATs), nuclear factor κB (NFκB)
and hypoxia-inducible factor 1α (HIF1α)
are particularly attractive targets, as these
three transcription factors are known to be
intimately involved in regulating inflam-
mation, wound healing and angiogenesis.
STATs are constitutively overexpressed in
many cancers; their phosphorylation, which
is required for transcriptional activity, is
regulated by a set of kinases (JAKs), phos-
phatases and binding proteins, all of which
are targets for drug development50. Synthetic
triterpenoids, which have recently been
shown to be potent agents for the chemo-
prevention of adenocarcinoma of the lung
in mice (K. Liby, unpublished observations),
have also been shown to be highly active in
regulating the phosphorylation of STAT3
and STAT5 (REF. 51). Gene-array studies have
shown that STAT3 is a potent inducer of
many genes involved in wound healing and
repair52. Particularly striking is the ability of
STAT3 to increase the expression of fibrino-
gen genes in lung cancer cells; fibrinogen can
increase tumour cell growth and metastasis
by controlling cell adhesion, invasion, ang-
iogenesis and chemotaxis52,53. Similarly, the
transcriptional activity of STAT3 is markedly
upregulated in vivo in the mouse lung dur-
ing chronic inflammation, and the activation
of STAT3 is found at the leading edge of
human lung cancers, again suggesting a role
for STAT3 in stromal invasion52. Therefore,
STATs regulate processes that are crucial for
carcinogenesis in the microenvironment,
and are ideal targets for the development of
new chemopreventive agents.
The crucial role of NFκB and its associ-
ated proteins in many aspects of inflamma-
tion47,54 indicates that it, too, is an important
target for chemoprevention directed at the
microenvironment. The NFκB family of
transcription factors and the various kinases
that regulate NFκB (such as phosphati-
dylinositol 3-kinase (PI3K)–Akt), besides
participating in the regulation of many
genes required for cell growth, survival
and invasion, are strongly pro-inflamma-
tory up-stream of COX2. Although these
effects have been extensively documented in
tumour cells, it is now apparent that they are
also exerted on components of the micro-
environment. Chemopreventive agents,
some of which are under investigation in
NATURE REVIEWS | CANCER
PERSPECTIVES
IGF1 HGF VEGF
IGF1R MET VEGFR
RAC1
Endothelial cell
PI3K GRB2
NADPH SOS
Akt
oxidase ROS
Ras
mTOR
Raf
NFκB IκB
p70S6K
MEK
MMPs
HIF1α HIF1α ERK
VEGF IL-8
HIF1β AP1 NFκB
MET E-selectin
Figure 3 | Molecular targets for chemoprevention of angiogenesis (angioprevention). Growth
factors and their kinase receptors are frequent targets for cancer chemotherapy. These targets exist
in the cells of the tumour microenvironment and epithelial cells, and they are targets for chemopre-
ventive agents. The endothelial cell is shown here as an example of this strategy, with possible
chemoprevention targets shown in red. Several growth factors, such as insulin-like growth factor 1
(IGF1), hepatocyte growth factor (HGF) and vascular endothelial growth factor (VEGF), stimulate
the proliferation of otherwise quiescent endothelial cells through the activation of their cognate
receptors. These cytokines activate paracrine or autocrine loops in the endothelial cells, resulting
in neovascularization of the tumour. Several chemopreventive agents have also been shown to
target signalling molecules or cascades that are downstream of the original receptors, such as
phosphatidylinositol-3 kinase (PI3K), Akt–mammalian target of rapamycin (mTOR) and nuclear fac-
tor κB (NFκB), as well as the generation of reactive oxygen species (ROS) and hypoxia-inducible
factor 1α (HIF1α). The activation of NFκB or HIF1α, which are transcription factors, leads to the
synthesis of pro-inflammatory and angiogenic factors. NFκB regulates many inflammatory genes;
HIF1α is a master regulator of VEGF and is induced by hypoxic conditions. Other potential targets
downstream of the growth-factor receptors are Ras and extracellular signal-regulated kinase (ERK).
See REFS 11,12,56,58–61,63,68,70,71,80,91,92 for details. AP1, activator protein 1; GRB2, growth
factor receptor-bound protein 2; IL8, interleukin 8; MMP, matrix metalloproteinase.
clinical trials, such as curcumin55, N-acetyl and NFκB activation are associated with the
cysteine56, EGCG (epigallocatechin-3-gallate) downstream upregulation of survivin, an
from green tea56, silibinin57, xanthohumol58 apoptosis inhibitor, in tumour cells64; this
and deguelin59 all regulate Akt and NFκB in has been correlated with angiogenic poten-
endothelial cells. Many of these agents have tial. This observation also relates to the
also been found to be potent inhibitors of inhibition of the Akt–NFκB–survivin axis
angiogenesis, and the repression of angiogen- in endothelial cells, as previously suggested
esis seems to be a key mechanism for the inhi- in chemoprevention studies57. Survivin is
bition of tumour growth in animal models12. upregulated in endothelial cells in response
The anti-angiogenic effects of sulphoraphane60 to VEGF65,66, and vaccination against
have been linked to the inhibition of NFκB61. survivin inhibits angiogenesis67. Therefore,
Endothelial NFκB activity correlates with targeting a restricted signalling pathway can
angiogenesis62, whereas its inhibition is associ- repress inflammatory angiogenesis, a proc-
ated with the suppression of angiogenesis56,58,63. ess we have called ‘angioprevention’68 (FIG. 2).
New drug discovery directed at regulating It remains to be determined if the NFκB
NFκB function is a highly active field of inves- pathway can also target other host compo-
tigation, and will undoubtedly generate newer nents: can it switch macrophage phenotypes
agents for chemoprevention. away from the carcinogenic M2 profile, or
Angiogenesis dependent on inflamma- can it suppress the aggressive CAF pheno-
tion seems to be a central force in tumour type? Could chronic inhibition of the NFκB
growth and expansion12, a concept that is pathway repress the colonization of distant
reinforced by evidence that the inhibition sites by bone marrow precursor cell clusters
of inflammation prevents angiogenesis. Akt and therefore prevent metastasis?
VOLUME 7 | FEBRUARY 2007 | 143
© 2007 Nature Publishing Group
PERSPECTIVES
Similarly, HIF1 — a master regulator in
the control of tissue homeostasis, crucial
in adaptive responses to tissue oxygenation
including energy status, glucose and iron
metabolism as well as growth factor signal-
ling69,70 — is a key target for the prevention
and treatment of cancer. Although HIF1
contributes to an invasive, lethal phenotype
in the cancer cell71, in the microenviron-
ment, metabolic responses activated by
HIF1 are required for the infiltration of
myeloid cells at early stages of inflamma-
tion72. The HIF1α subunit is currently the
target of significant drug development for
therapy. Recent studies with many agents
indicate that HIF1α is an important target
for chemoprevention. For example, the
potent chemopreventive agent sulphora-
phane controls HIF1 function in endothelial
cells by inhibiting expression of HIF1α and
HIF1-regulated genes60. Sulphoraphane is
also a histone deacetylase inhibitor73. In
addition to being promising chemopreven-
tive agents74, histone deacetylase inhibitors
also inhibit HIF independent of the direct
acetylation of HIF1α by promoting HIF1α
degradation75,76. Recent data indicate that
other chemopreventive agents, including
green-tea extracts and purified EGCG77,
resveratrol78 and apigenin79, also target
HIF1α. HIF1α is therefore at the crossroads
of the main signalling pathways involved
in oncogenic tissue remodelling, as its
activation promotes both angiogenesis and
inflammation80. However, a word of caution
needs to be introduced here, as in some con-
texts the inhibition of either HIF1α or the
related factor HIF2α can promote tumour
growth81,82. These bifunctional actions of
HIFs seem to depend on the context of the
microenvironment of tumour cells81,82.
The transcription factor NRF2, together
with its associated inhibitor kelch-like
ECH-associated protein 1 (KEAP1), are
other factors that are targets for chemo-
preventive agents. This system is a primary
sensor of oxidative or electrophilic stress,
both of which have important roles in the
microenvironment83. NRF2 upregulates the
transcription of an entire battery of ‘phase
2’ enzymes that protect both epithelium
and stroma from oxidative and electrophilic
stress, and serve to exert an inhibitory tone
on mutagenic activity and the inflammatory
process. Some of these phase 2 enzymes
include glutathione transferases, which
detoxify mutagenic electrophiles, as well as
superoxide dismutases and catalase, which
deactivate reactive oxygen species. Heme
oxygenase-1, which is strongly anti-inflam-
matory84, is another important phase 2
144 | FEBRUARY 2007 | VOLUME 7
Table 2 | Two ‘scorecards’ for risk assessment for cardiovascular disease or cancer
Established scorecard for Proposed new scorecard for
cardiovascular risk (European cancer risk
Society of Cardiology)
Personal Age and sex Age and sex
and lifestyle
Smoking Smoking
components
Exercise
Dietary habits
Obesity
Reproductive history
Use of drugs such as NSAIDs
Genetic Family history Family history
analysis
Oncogene and/or tumour-suppressor
mutations
Metabolic activity polymorphisms
Laboratory Mean LDL cholesterol DNA adducts
measurements
Mean HDL cholesterol/LDL:HDL ratio DNA oxidative damage score
Mean systolic blood pressure Proteomics score: tissue proteomics;
serum proteomics
Indications of diabetes Microbiopsy dysplasia score
Hormone status
Chronic infection (for example,
Helicobacter pylori)
Any new biochemical markers that
are developed
The scorecard of the European Society of Cardiology109 uses 5 principal factors: age, sex, smoking status, serum
cholesterol and blood pressure, although indirect consideration is also given to diet, exercise and obesity. For the
proposed cancer risk scorecard, there will be a very wide range of risk factors, which will unquestionably vary from
one form of cancer to another. Some of the risk factors related to personal lifestyle might be difficult to quantify at
the present time, although there are clearly good data at present regarding the risk attendant on most of the other
factors, such as specific genetic lesions. There is now a crucial need for algorithms to integrate the relative weight
that should be attached to each of these individual risks, with the realization that the algorithm might be different
for cancers at different organ sites. HDL, high-density lipoprotein; LDL, low-density lipoprotein; NSAIDs, non-
steroidal anti-inflammatory drugs.
enzyme. Many chemopreventive agents that observation that angiogenesis is a key target
promote NRF2 function and phase 2 activity of chemopreventive agents has led us to look
have been described85,86. for common molecular mechanisms. Some
Ligands that bind to members of the clues come from the findings that non-
nuclear receptor superfamily are important steroidal anti-inflammatory drugs (NSAIDs),
chemopreventive agents in clinical medi- COX2 inhibitors in particular, are effective
cine, and some of their actions might be chemopreventive agents, both in animals and
mediated by the tumour microenvironment. in people48,93,94. The suppression of COX2
Thus, the interaction of tamoxifen with the is now a crucial target for the control of
oestrogen receptor is anti-angiogenic by tumours associated with chronic inflamma-
virtue of its suppression of VEGF synthe- tion. Indeed, the first report to indicate that
sis87,88. Similarly, bexarotene, a ligand for the COX2 can have a significant role in colon
retinoid x receptors, has also recently been polyp formation presciently noted that COX2
reported to have anti-angiogenic activity89. expression in polyps occurred in the stromal
cells, rather than in the epithelium of the
Angiogenesis as a key target for chemopre- polyp95. COX2 modulates angiogenesis96 and
vention. Although we have reviewed many seems to be upstream of VEGF, but is down-
cellular and molecular targets in the micro- stream of inflammatory signals activated by
environment for chemoprevention, angio- NFκB. There are many other molecular tar-
prevention seems to be particularly attractive gets in the angiogenic cascade. For example,
(FIG. 3). Controlling angiogenesis is clearly all of the transcription factors discussed above
an important strategy for the treatment of affect angiogenesis, and they will continue to
invasive cancers90–92. It is now essential to be important targets for chemoprevention.
apply this same strategy for prevention. The Interestingly, many anti-angiogenic agents
www.nature.com/reviews/cancer
© 2007 Nature Publishing Group

also have marked anti-inflammatory activity;
good examples are EGCG97, angiostatin20
and fenretinide98,99, which has been clinically
effective for the prevention of breast cancer in
premenopausal women100.
Translation into effective prevention
In the United States, about one in three peo-
ple will eventually develop cancer, and one in
four will die from it. Every chronic disease has
a latency period, during which pathogenesis
proceeds before symptoms and subjective
feelings of pain can be detected. The common
misconception that people are ‘healthy’ dur-
ing this latency period is the greatest single
impediment to the effective implementation
of chemoprevention42. However, clinical data
on chronic drug use for conditions other
than cancer, such as the use of statins for
cardiovascular disease or NSAIDs for chronic
inflammatory diseases, suggest that preven-
tion has enormous potential to reduce cancer
incidence. Statins reduce cancer incidence,
and it has been suggested that possible
mechanisms for this effect involve the sup-
pression of inflammation and angiogenesis in
the microenvironment101. Recent studies have
now shown that the chronic use of NSAIDs,
which is already known to reduce colon
cancer48, is also associated with a striking
reduction in the risk of breast cancer94. This
study found an approximately 50% reduction
in breast cancer risk with aspirin use, and
relative risk dropped to 0.29 with specific
COX2 inhibitors. These data further confirm
the importance of the microenvironment as a
target for chemoprevention.
NSAIDs are the most widely used
medications in the world, and the broad
use of these drugs has confirmed their
effectiveness and relative safety. The well-
recognized gastrointestinal complications of
many NSAIDs led to the search for selective
COX2 enzyme inhibitors. However, selective
COX2 inhibitors have not found clinical
acceptance for chemoprevention because
of increased cardiovascular risk associated
with chronic use, particularly at high doses.
For example, recent findings indicate that
although celecoxib is an effective agent for
the prevention of colorectal adenomas, it
cannot be routinely recommended for this
indication at present because of potential
cardiovascular events102–104. In colon cancer
prevention studies, celecoxib at 200 mg or
400 mg twice a day showed a 1.3 to nearly
2-fold increased cardiovascular risk. The
trend for a dose-related increase in cardio-
vascular events raises the possibility that
lower doses or alternative dose scheduling
(such as the use of rest periods, rather than
NATURE REVIEWS | CANCER
the constant administration of drug) might
be associated with less cardiovascular risk.
Close examination of the current use of
these drugs will give more exact indications
of the risks associated with their use and of
potential strategies to circumvent the nega-
tive side effects encountered.
It is essential to appreciate that everyone
has some finite, measurable potential risk
of developing cancer. As there are now new
methods to quantify that risk, we need to
do so, realizing that, for many people, total
risk factors might be miniscule. Sceptics
maintain that in cancer we do not have
adequate simple markers of risk, such as
elevated cholesterol or high blood pressure as
indicators for cardiovascular disease. This is
indeed true, but the problem might be able to
be overcome if we adopt a more sophisticated
approach and develop a new ‘integrated
personal risk index’ for the development of
cancer (TABLE 2). Although none of the items
shown in TABLE 2 are themselves guarantors
of future clinically manifest disease (in the
same way that neither high serum cholesterol
nor high blood pressure necessarily lead to
a cardiovascular incident), as an ensemble
they might be empirically useful to indicate
who might be the best candidates for
chemoprevention. Cancer risk tools for the
evaluation of specific cancers at specific organ
sites, such as the Gail model for breast cancer,
have been extremely useful in the design and
interpretation of clinical chemoprevention
studies105–107. We now suggest that a risk index
that translates across various cancer types
might also be useful, although such an index
would require a whole new set of parameters
and more effective ways of analysing many
markers that predispose to cancer risk.
Clearly, the risks are different for cancers at
different organ sites, but nevertheless, there
is a widespread public desire to have some
overall assessment of personal cancer risk.
What connection do any of the indicators
in TABLE 2 have with the microenvironment?
As there are now intensive efforts to develop
new biomarkers for assessing cancer risk, we
suggest that some of the cellular or biochemi-
cal measurements now be directed towards
evaluating abnormalities in the stromal
microenvironment. In the past, almost all of
the efforts in evaluating exfoliative cytology
have been directed toward epithelial changes.
In the future, it should be possible, with
microbiopsy techniques, to assess cellular or
molecular changes in the microenvironment
of a developing carcinoma. Furthermore, as
we have discussed above, chemopreventive
agents such as the widely used NSAIDs affect
the microenvironment and clearly have a
© 2007 Nature Publishing Group
PERSPECTIVES
significant effect on the risk of developing
some cancers.
An absence of symptoms is not a sign
of health; everyone is at some finite risk.
Ultimately, personal risk should not be
regarded in a ‘benefit versus risk’ evaluation,
but rather in a ‘risk versus risk’ paradigm,
which compares the risk of using an inter-
ventional agent with the risk of doing noth-
ing. The risk of doing nothing is the 25% risk
of eventually dying of cancer. Therefore, we
suggest that an index for selection for cancer
chemoprevention is feasible — if an individ-
ual has a score above a threshold value (to be
defined) then that individual is a candidate
for chemoprevention (just as blood pressure
determines whether someone should receive
anti-hypertensive medication, or low-density
lipoprotein (LDL) cholesterol levels indicate
whether someone is a candidate for statins).
These markers have been most useful in
the control of cardiovascular disease with
chemo-preventive drugs. The control of can-
cer with new chemopreventive agents should
be next. At the same time, we must be fully
aware of assuring the long-term safety of any
drug to be used for chemoprevention. Safety
is always a paramount concern in chemo-
prevention; clearly the risks associated with
the use of chemopreventive agents must be
driven as close to zero as possible. Although
transcription factors are attractive targets for
chemoprevention (and have been clinically
useful targets), the multifunctional nature of
transcription factors also has attendant risks.
However, if used judiciously, chemopreven-
tion should ultimately facilitate the preserva-
tion of health and improve the quality of life
of many people.
Conclusion
Chemoprevention directed towards the
control of carcinogenesis in its early stages
should ultimately provide a higher quality of
life for people than waiting to treat end-stage
disease. If we are to provide effective and safe
chemoprevention, we need to understand the
primary role of the tumour microenviron-
ment in determining the fate of putative
cancer cells and controlling their incipient
malignant behaviour. In a holistic view of
carcinogenesis, one might now consider
that the microenvironment is an essential,
intrinsic part of the tumour itself. The data
we have summarized here clearly show a pri-
mary role for the microenvironment during
carcinogenesis. These data further indicate
that the use of chemopreventive agents to
control the function and behaviour of cells in
the microenvironment will be an important
approach to the overall control of cancer.
VOLUME 7 | FEBRUARY 2007 | 145
PERSPECTIVES
Adriana Albini is at the IRCCS Multimedica Science
and Technology Park, Viale Fantoli 15/16,
Milan, 20138, Italy.
Michael B. Sporn is at the Dartmouth Medical School,
Department of Pharmacology, Hanover,
New Hampshire 03755, USA.
Correspondence to M.B.S. and A.A.
e-mails: michael.sporn@dartmouth.edu;
adriana.albini@multimedica.it
doi:10.1038/nrc2067
Published online 12 January 2007
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