You are on page 1of 9

PERSPECTIVES

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

doi:10.1038/nrc2066

1. US Food and Drug Administration. Guidance for


Industry, Investigators, and Reviewers. US Food and
Drug Administration [online], http://www.fda.gov/cder/ TUMOUR MICROENVIRONMENT — OPINION
guidance/7086fnl.pdf (2006).
2. Kola, I., Landis, J. Can the pharmaceutical industry

3.
reduce attrition rates? Nature Rev. Drug Discov. 3,
711–715 (2004).
Johnson, J. I. et al. Relationships between drug activity
The tumour microenvironment as a
4.
in NCI preclinical in vitro and in vivo models and early
clinical trials. Br. J. Cancer 84, 1424–1431 (2001).
Olson, H., Betton, G., Robinson D. et al. Concordance
target for chemoprevention
of the toxicity of pharmaceuticals in humans and in
animals. Regul. Toxicol. Pharmacol. 32, 56–67
(2000). Adriana Albini and Michael B. Sporn
5. Tomaszewski, J. E., Smith, A. C., Covey, J. M., Donohue,
S. J., Rhie, J. K. & Schweikart, K. M. in Anti-Cancer
Drug Design (ed. Baguley, B. C.) Chpt 17, 301–328
Abstract | New data indicate that primary dysfunction in the tumour
(San Diego, Academic Press, 2001). microenvironment, in addition to epithelial dysfunction, can be crucial for
6. Tomaszewski, J. E., Doroshow, J. H. in Molecular
Targets in Oncology (ed. Antman, K.) (Humana Press, carcinogenesis. These recent findings make a compelling case for targeting the
Totowa, USA, in the press).
7. Fox, E., Curt, G. A. & Balis, F. M. Clinical trial design for microenvironment for cancer chemoprevention. We review new insights into the
target-based therapy. Oncologist. 7, 401–409 (2002).
8. Millar, A. W., Lynch, K. P. Rethinking clinical trials for
pathophysiology of the microenvironment and new approaches to control it with
cytostatic drugs. Nature Rev. Cancer. 3, 540–545
(2003).
chemopreventive agents. The microenvironment of a cancer is an integral part
9. Rothenberg, M. L., Carbone, D. P. & Johnson, D. H. of its anatomy and physiology, and functionally, one cannot totally dissociate this
Improving the evaluation of new cancer treatments:
challenges and opportunities. Nature Rev. Cancer. 3, microenvironment from what have traditionally been called ‘cancer cells’. Finally,
303–309 (2003).
10. Kummar, S., Gutierrez, M. E., Doroshow, J. H. & Murgo, we make suggestions for more effective clinical implementation of this
A. J. Drug development in oncology: classical cytotoxics
and molecularly targeted agents. Br. J. Clin. Pharmacol.
knowledge in preventive strategies.
62, 15–26 (2006).
11. Workman, P. et al. Minimally invasive pharmacokinetic
and pharmacodynamic technologies in hypothesis- The continuing pandemic of cancer deaths or organ to both genetic and epigenetic
testing clinical trials of innovative therapies. J. Natl
Cancer Inst. 98, 580–598 (2006).
requires a reassessment of our basic assump- stress1–3, then knowledge and control of
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
agents: theory and practice. J. Natl. Cancer Inst. 96,
control it. Directly bearing on this, there has developing tumour become as important as
990–997 (2004). been an explosion of new information about the corresponding knowledge and control
13. Bartlett, J. M. Pharmacodiagnostic testing in breast
cancer: focus on HER2 and trastuzumab therapy. Am. J.
the tumour microenvironment, which is a of the dysfunctional epithelial cells within
Pharmacogenomics 5, 303–315 (2005). complex system of many cell types, includ- that tumour.
14. Lehmann, F., Lacombe, D., Therasse, P.,
Eggermont A. M. M. Integration of translational
ing endothelial cells and their precursors, New data from studies on the tumour
research in the european organization for research and pericytes, smooth-muscle cells, fibroblasts microenvironment suggest that we might
treatment of cancer research (EORTC) clinical trial
cooperative group mechanisms. J. Transl. Med. 1, 2
of various phenotypes, myofibroblasts, need to revise the very definition of the
(2003). neutrophils and other granulocytes (eosi- term ‘carcinoma’ (currently defined in class-
15. Hidalgo, M., and Eckhardt, S. G. Matrix nophils and basophils), mast cells, T, B and ical terms as a malignancy derived from
metalloproteinase inhibitors: how can we optimize their
development? Ann. Oncol. 12, 285–287 (2001). natural killer lymphocytes, and antigen- epithelial cells), and that to control cancer
16. Moore, M. J. et al. Comparison of gemcitabine presenting cells such as macrophages and in the future, we need to regard carcino-
versus the matrix metalloproteinase inhibitor BAY
12–9566 in patients with advanced or metastatic dendritic cells. All these cells can participate genesis and carcinomas as phenomena that
adenocarcinoma of the pancreas: a phase III trial of in tumour progression. If the process of occur in tissues, not in individual cancer
the National Cancer Institute of Canada Clinical
Trials Group. J. Clin. Oncol. 21, 3296–3302 (2003). carcinogenesis and its end result, invasive cells. From this perspective, the microenvi-
17. Van Den Bossche, B., Van de Wiele, C. Receptor imaging and metastatic cancer, are viewed as the ronment becomes an integral, essential part
in oncology by means of nuclear medicine: current
status. J. Clin. Oncol. 22, 3593–3607 (2004). maladaptive response of an entire tissue of the cancer.

NATURE REVIEWS | CANCER VOLUME 7 | FEBRUARY 2007 | 139


© 2007 Nature Publishing Group
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.

140 | FEBRUARY 2007 | VOLUME 7 www.nature.com/reviews/cancer


© 2007 Nature Publishing Group
PERSPECTIVES

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

NATURE REVIEWS | CANCER 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

142 | FEBRUARY 2007 | VOLUME 7 www.nature.com/reviews/cancer


© 2007 Nature Publishing Group
PERSPECTIVES

to finding monofunctional ‘magic bullets’, IGF1 HGF VEGF


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, IGF1R MET VEGFR
signal transducers and activators of tran- RAC1
Endothelial cell
scription (STATs), nuclear factor κB (NFκB) PI3K GRB2
and hypoxia-inducible factor 1α (HIF1α) NADPH SOS
Akt
are particularly attractive targets, as these oxidase ROS
three transcription factors are known to be Ras
mTOR
intimately involved in regulating inflam-
Raf
mation, wound healing and angiogenesis. NFκB IκB
p70S6K
STATs are constitutively overexpressed in
many cancers; their phosphorylation, which MEK
is required for transcriptional activity, is MMPs
HIF1α HIF1α ERK
regulated by a set of kinases (JAKs), phos- VEGF IL-8
HIF1β AP1 NFκB
phatases and binding proteins, all of which MET E-selectin
are targets for drug development50. Synthetic
triterpenoids, which have recently been
shown to be potent agents for the chemo- Figure 3 | Molecular targets for chemoprevention of angiogenesis (angioprevention). Growth
prevention of adenocarcinoma of the lung factors and their kinase receptors are frequent targets for cancer chemotherapy. These targets exist
in mice (K. Liby, unpublished observations), 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
have also been shown to be highly active in
chemoprevention targets shown in red. Several growth factors, such as insulin-like growth factor 1
regulating the phosphorylation of STAT3 (IGF1), hepatocyte growth factor (HGF) and vascular endothelial growth factor (VEGF), stimulate
and STAT5 (REF. 51). Gene-array studies have the proliferation of otherwise quiescent endothelial cells through the activation of their cognate
shown that STAT3 is a potent inducer of receptors. These cytokines activate paracrine or autocrine loops in the endothelial cells, resulting
many genes involved in wound healing and in neovascularization of the tumour. Several chemopreventive agents have also been shown to
repair52. Particularly striking is the ability of target signalling molecules or cascades that are downstream of the original receptors, such as
STAT3 to increase the expression of fibrino- phosphatidylinositol-3 kinase (PI3K), Akt–mammalian target of rapamycin (mTOR) and nuclear fac-
gen genes in lung cancer cells; fibrinogen can tor κB (NFκB), as well as the generation of reactive oxygen species (ROS) and hypoxia-inducible
increase tumour cell growth and metastasis factor 1α (HIF1α). The activation of NFκB or HIF1α, which are transcription factors, leads to the
by controlling cell adhesion, invasion, ang- 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
iogenesis and chemotaxis52,53. Similarly, the
downstream of the growth-factor receptors are Ras and extracellular signal-regulated kinase (ERK).
transcriptional activity of STAT3 is markedly See REFS 11,12,56,58–61,63,68,70,71,80,91,92 for details. AP1, activator protein 1; GRB2, growth
upregulated in vivo in the mouse lung dur- factor receptor-bound protein 2; IL8, interleukin 8; MMP, matrix metalloproteinase.
ing chronic inflammation, and the activation
of STAT3 is found at the leading edge of
human lung cancers, again suggesting a role clinical trials, such as curcumin55, N-acetyl and NFκB activation are associated with the
for STAT3 in stromal invasion52. Therefore, cysteine56, EGCG (epigallocatechin-3-gallate) downstream upregulation of survivin, an
STATs regulate processes that are crucial for from green tea56, silibinin57, xanthohumol58 apoptosis inhibitor, in tumour cells64; this
carcinogenesis in the microenvironment, and deguelin59 all regulate Akt and NFκB in has been correlated with angiogenic poten-
and are ideal targets for the development of endothelial cells. Many of these agents have tial. This observation also relates to the
new chemopreventive agents. also been found to be potent inhibitors of inhibition of the Akt–NFκB–survivin axis
The crucial role of NFκB and its associ- angiogenesis, and the repression of angiogen- in endothelial cells, as previously suggested
ated proteins in many aspects of inflamma- esis seems to be a key mechanism for the inhi- in chemoprevention studies57. Survivin is
tion47,54 indicates that it, too, is an important bition of tumour growth in animal models12. upregulated in endothelial cells in response
target for chemoprevention directed at the The anti-angiogenic effects of sulphoraphane60 to VEGF65,66, and vaccination against
microenvironment. The NFκB family of have been linked to the inhibition of NFκB61. survivin inhibits angiogenesis67. Therefore,
transcription factors and the various kinases Endothelial NFκB activity correlates with targeting a restricted signalling pathway can
that regulate NFκB (such as phosphati- angiogenesis62, whereas its inhibition is associ- repress inflammatory angiogenesis, a proc-
dylinositol 3-kinase (PI3K)–Akt), besides ated with the suppression of angiogenesis56,58,63. ess we have called ‘angioprevention’68 (FIG. 2).
participating in the regulation of many New drug discovery directed at regulating It remains to be determined if the NFκB
genes required for cell growth, survival NFκB function is a highly active field of inves- pathway can also target other host compo-
and invasion, are strongly pro-inflamma- tigation, and will undoubtedly generate newer nents: can it switch macrophage phenotypes
tory up-stream of COX2. Although these agents for chemoprevention. away from the carcinogenic M2 profile, or
effects have been extensively documented in Angiogenesis dependent on inflamma- can it suppress the aggressive CAF pheno-
tumour cells, it is now apparent that they are tion seems to be a central force in tumour type? Could chronic inhibition of the NFκB
also exerted on components of the micro- growth and expansion12, a concept that is pathway repress the colonization of distant
environment. Chemopreventive agents, reinforced by evidence that the inhibition sites by bone marrow precursor cell clusters
some of which are under investigation in of inflammation prevents angiogenesis. Akt and therefore prevent metastasis?

NATURE REVIEWS | CANCER VOLUME 7 | FEBRUARY 2007 | 143


© 2007 Nature Publishing Group
PERSPECTIVES

Similarly, HIF1 — a master regulator in Table 2 | Two ‘scorecards’ for risk assessment for cardiovascular disease or cancer
the control of tissue homeostasis, crucial
Established scorecard for Proposed new scorecard for
in adaptive responses to tissue oxygenation cardiovascular risk (European cancer risk
including energy status, glucose and iron Society of Cardiology)
metabolism as well as growth factor signal-
Personal Age and sex Age and sex
ling69,70 — is a key target for the prevention and lifestyle
and treatment of cancer. Although HIF1 Smoking Smoking
components
contributes to an invasive, lethal phenotype Exercise
in the cancer cell71, in the microenviron- Dietary habits
ment, metabolic responses activated by
Obesity
HIF1 are required for the infiltration of
myeloid cells at early stages of inflamma- Reproductive history
tion72. The HIF1α subunit is currently the Use of drugs such as NSAIDs
target of significant drug development for Genetic Family history Family history
therapy. Recent studies with many agents analysis
indicate that HIF1α is an important target Oncogene and/or tumour-suppressor
mutations
for chemoprevention. For example, the
potent chemopreventive agent sulphora- Metabolic activity polymorphisms
phane controls HIF1 function in endothelial Laboratory Mean LDL cholesterol DNA adducts
cells by inhibiting expression of HIF1α and measurements
Mean HDL cholesterol/LDL:HDL ratio DNA oxidative damage score
HIF1-regulated genes60. Sulphoraphane is
Mean systolic blood pressure Proteomics score: tissue proteomics;
also a histone deacetylase inhibitor73. In serum proteomics
addition to being promising chemopreven-
Indications of diabetes Microbiopsy dysplasia score
tive agents74, histone deacetylase inhibitors
also inhibit HIF independent of the direct Hormone status
acetylation of HIF1α by promoting HIF1α Chronic infection (for example,
degradation75,76. Recent data indicate that Helicobacter pylori)
other chemopreventive agents, including Any new biochemical markers that
green-tea extracts and purified EGCG77, are developed
resveratrol78 and apigenin79, also target The scorecard of the European Society of Cardiology109 uses 5 principal factors: age, sex, smoking status, serum
HIF1α. HIF1α is therefore at the crossroads 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
of the main signalling pathways involved one form of cancer to another. Some of the risk factors related to personal lifestyle might be difficult to quantify at
in oncogenic tissue remodelling, as its the present time, although there are clearly good data at present regarding the risk attendant on most of the other
activation promotes both angiogenesis and 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
inflammation80. However, a word of caution for cancers at different organ sites. HDL, high-density lipoprotein; LDL, low-density lipoprotein; NSAIDs, non-
needs to be introduced here, as in some con- steroidal anti-inflammatory drugs.
texts the inhibition of either HIF1α or the
related factor HIF2α can promote tumour enzyme. Many chemopreventive agents that observation that angiogenesis is a key target
growth81,82. These bifunctional actions of promote NRF2 function and phase 2 activity of chemopreventive agents has led us to look
HIFs seem to depend on the context of the have been described85,86. for common molecular mechanisms. Some
microenvironment of tumour cells81,82. Ligands that bind to members of the clues come from the findings that non-
The transcription factor NRF2, together nuclear receptor superfamily are important steroidal anti-inflammatory drugs (NSAIDs),
with its associated inhibitor kelch-like chemopreventive agents in clinical medi- COX2 inhibitors in particular, are effective
ECH-associated protein 1 (KEAP1), are cine, and some of their actions might be chemopreventive agents, both in animals and
other factors that are targets for chemo- mediated by the tumour microenvironment. in people48,93,94. The suppression of COX2
preventive agents. This system is a primary Thus, the interaction of tamoxifen with the is now a crucial target for the control of
sensor of oxidative or electrophilic stress, oestrogen receptor is anti-angiogenic by tumours associated with chronic inflamma-
both of which have important roles in the virtue of its suppression of VEGF synthe- tion. Indeed, the first report to indicate that
microenvironment83. NRF2 upregulates the sis87,88. Similarly, bexarotene, a ligand for the COX2 can have a significant role in colon
transcription of an entire battery of ‘phase retinoid x receptors, has also recently been polyp formation presciently noted that COX2
2’ enzymes that protect both epithelium reported to have anti-angiogenic activity89. expression in polyps occurred in the stromal
and stroma from oxidative and electrophilic cells, rather than in the epithelium of the
stress, and serve to exert an inhibitory tone Angiogenesis as a key target for chemopre- polyp95. COX2 modulates angiogenesis96 and
on mutagenic activity and the inflammatory vention. Although we have reviewed many seems to be upstream of VEGF, but is down-
process. Some of these phase 2 enzymes cellular and molecular targets in the micro- stream of inflammatory signals activated by
include glutathione transferases, which environment for chemoprevention, angio- NFκB. There are many other molecular tar-
detoxify mutagenic electrophiles, as well as prevention seems to be particularly attractive gets in the angiogenic cascade. For example,
superoxide dismutases and catalase, which (FIG. 3). Controlling angiogenesis is clearly all of the transcription factors discussed above
deactivate reactive oxygen species. Heme an important strategy for the treatment of affect angiogenesis, and they will continue to
oxygenase-1, which is strongly anti-inflam- invasive cancers90–92. It is now essential to be important targets for chemoprevention.
matory84, is another important phase 2 apply this same strategy for prevention. The Interestingly, many anti-angiogenic agents

144 | FEBRUARY 2007 | VOLUME 7 www.nature.com/reviews/cancer


© 2007 Nature Publishing Group
PERSPECTIVES

also have marked anti-inflammatory activity; the constant administration of drug) might significant effect on the risk of developing
good examples are EGCG97, angiostatin20 be associated with less cardiovascular risk. some cancers.
and fenretinide98,99, which has been clinically Close examination of the current use of An absence of symptoms is not a sign
effective for the prevention of breast cancer in these drugs will give more exact indications of health; everyone is at some finite risk.
premenopausal women100. of the risks associated with their use and of Ultimately, personal risk should not be
potential strategies to circumvent the nega- regarded in a ‘benefit versus risk’ evaluation,
Translation into effective prevention tive side effects encountered. but rather in a ‘risk versus risk’ paradigm,
In the United States, about one in three peo- It is essential to appreciate that everyone which compares the risk of using an inter-
ple will eventually develop cancer, and one in has some finite, measurable potential risk ventional agent with the risk of doing noth-
four will die from it. Every chronic disease has of developing cancer. As there are now new ing. The risk of doing nothing is the 25% risk
a latency period, during which pathogenesis methods to quantify that risk, we need to of eventually dying of cancer. Therefore, we
proceeds before symptoms and subjective do so, realizing that, for many people, total suggest that an index for selection for cancer
feelings of pain can be detected. The common risk factors might be miniscule. Sceptics chemoprevention is feasible — if an individ-
misconception that people are ‘healthy’ dur- maintain that in cancer we do not have ual has a score above a threshold value (to be
ing this latency period is the greatest single adequate simple markers of risk, such as defined) then that individual is a candidate
impediment to the effective implementation elevated cholesterol or high blood pressure as for chemoprevention (just as blood pressure
of chemoprevention42. However, clinical data indicators for cardiovascular disease. This is determines whether someone should receive
on chronic drug use for conditions other indeed true, but the problem might be able to anti-hypertensive medication, or low-density
than cancer, such as the use of statins for be overcome if we adopt a more sophisticated lipoprotein (LDL) cholesterol levels indicate
cardiovascular disease or NSAIDs for chronic approach and develop a new ‘integrated whether someone is a candidate for statins).
inflammatory diseases, suggest that preven- personal risk index’ for the development of These markers have been most useful in
tion has enormous potential to reduce cancer cancer (TABLE 2). Although none of the items the control of cardiovascular disease with
incidence. Statins reduce cancer incidence, shown in TABLE 2 are themselves guarantors chemo-preventive drugs. The control of can-
and it has been suggested that possible of future clinically manifest disease (in the cer with new chemopreventive agents should
mechanisms for this effect involve the sup- same way that neither high serum cholesterol be next. At the same time, we must be fully
pression of inflammation and angiogenesis in nor high blood pressure necessarily lead to aware of assuring the long-term safety of any
the microenvironment101. Recent studies have a cardiovascular incident), as an ensemble drug to be used for chemoprevention. Safety
now shown that the chronic use of NSAIDs, they might be empirically useful to indicate is always a paramount concern in chemo-
which is already known to reduce colon who might be the best candidates for prevention; clearly the risks associated with
cancer48, is also associated with a striking chemoprevention. Cancer risk tools for the the use of chemopreventive agents must be
reduction in the risk of breast cancer94. This evaluation of specific cancers at specific organ driven as close to zero as possible. Although
study found an approximately 50% reduction sites, such as the Gail model for breast cancer, transcription factors are attractive targets for
in breast cancer risk with aspirin use, and have been extremely useful in the design and chemoprevention (and have been clinically
relative risk dropped to 0.29 with specific interpretation of clinical chemoprevention useful targets), the multifunctional nature of
COX2 inhibitors. These data further confirm studies105–107. We now suggest that a risk index transcription factors also has attendant risks.
the importance of the microenvironment as a that translates across various cancer types However, if used judiciously, chemopreven-
target for chemoprevention. might also be useful, although such an index tion should ultimately facilitate the preserva-
NSAIDs are the most widely used would require a whole new set of parameters tion of health and improve the quality of life
medications in the world, and the broad and more effective ways of analysing many of many people.
use of these drugs has confirmed their markers that predispose to cancer risk.
effectiveness and relative safety. The well- Clearly, the risks are different for cancers at Conclusion
recognized gastrointestinal complications of different organ sites, but nevertheless, there Chemoprevention directed towards the
many NSAIDs led to the search for selective is a widespread public desire to have some control of carcinogenesis in its early stages
COX2 enzyme inhibitors. However, selective overall assessment of personal cancer risk. should ultimately provide a higher quality of
COX2 inhibitors have not found clinical What connection do any of the indicators life for people than waiting to treat end-stage
acceptance for chemoprevention because in TABLE 2 have with the microenvironment? disease. If we are to provide effective and safe
of increased cardiovascular risk associated As there are now intensive efforts to develop chemoprevention, we need to understand the
with chronic use, particularly at high doses. new biomarkers for assessing cancer risk, we primary role of the tumour microenviron-
For example, recent findings indicate that suggest that some of the cellular or biochemi- ment in determining the fate of putative
although celecoxib is an effective agent for cal measurements now be directed towards cancer cells and controlling their incipient
the prevention of colorectal adenomas, it evaluating abnormalities in the stromal malignant behaviour. In a holistic view of
cannot be routinely recommended for this microenvironment. In the past, almost all of carcinogenesis, one might now consider
indication at present because of potential the efforts in evaluating exfoliative cytology that the microenvironment is an essential,
cardiovascular events102–104. In colon cancer have been directed toward epithelial changes. intrinsic part of the tumour itself. The data
prevention studies, celecoxib at 200 mg or In the future, it should be possible, with we have summarized here clearly show a pri-
400 mg twice a day showed a 1.3 to nearly microbiopsy techniques, to assess cellular or mary role for the microenvironment during
2-fold increased cardiovascular risk. The molecular changes in the microenvironment carcinogenesis. These data further indicate
trend for a dose-related increase in cardio- of a developing carcinoma. Furthermore, as that the use of chemopreventive agents to
vascular events raises the possibility that we have discussed above, chemopreventive control the function and behaviour of cells in
lower doses or alternative dose scheduling agents such as the widely used NSAIDs affect the microenvironment will be an important
(such as the use of rest periods, rather than the microenvironment and clearly have a approach to the overall control of cancer.

NATURE REVIEWS | CANCER VOLUME 7 | FEBRUARY 2007 | 145


© 2007 Nature Publishing Group
PERSPECTIVES

Adriana Albini is at the IRCCS Multimedica Science 25. Shao, J., Sheng, G. G., Mifflin, R. C., Powell, D. W. & 53. Palumbo, J. S. et al. Spontaneous hematogenous and
and Technology Park, Viale Fantoli 15/16, Sheng, H. Roles of myofibroblasts in prostaglandin lymphatic metastasis, but not primary tumor growth or
E2-stimulated intestinal epithelial proliferation and angiogenesis, is diminished in fibrinogen-deficient mice.
Milan, 20138, Italy.
angiogenesis. Cancer Res. 66, 846–855 (2006). Cancer Res. 62, 6966–6972 (2002).
Michael B. Sporn is at the Dartmouth Medical School, 26. Calle, E. E., Rodriguez, C., Walker-Thurmond, K. & 54. Karin, M. NFκB and cancer: mechanisms and targets.
Department of Pharmacology, Hanover, Thun, M. J. Overweight, obesity, and mortality from Mol. Carcinog. 45, 355–361 (2006).
cancer in a prospectively studied cohort of U. S. 55. Aggarwal, S. et al. Curcumin (diferuloylmethane) down-
New Hampshire 03755, USA.
adults. N. Engl. J. Med. 348, 1625–1638 (2003). regulates expression of cell proliferation and
Correspondence to M.B.S. and A.A. 27. Calle, E. E. & Thun, M. J. Obesity and cancer. antiapoptotic and metastatic gene products through
Oncogene 23, 6365–6378 (2004). suppression of IκBα kinase and Akt activation. Mol.
e-mails: michael.sporn@dartmouth.edu;
28. Wellen, K. E. & Hotamisligil, G. S. Inflammation, Pharmacol. 69, 195–206 (2006).
adriana.albini@multimedica.it stress, and diabetes. J. Clin. Invest. 115, 1111–1119 56. Pfeffer, U. et al. Molecular mechanisms of action of
doi:10.1038/nrc2067 (2005). angiopreventive anti-oxidants on endothelial cells:
Published online 12 January 2007 29. Comoglio, P. M. & Trusolino, L. Cancer: the matrix is microarray gene expression analyses. Mutat. Res. 591,
now in control. Nature Med. 11, 1156–1159 (2005). 198–211 (2005).
1. Farber, E. & Rubin, H. Cellular adaptation in the 30. Grobstein, C. Inductive tissue interaction in 57. Singh, R. P., Dhanalakshmi, S., Agarwal, C. &
origin and development of cancer. Cancer Res. 51, development. Adv. Cancer Res. 4, 187–236 (1956). Agarwal, R. Silibinin strongly inhibits growth and
2751–2761 (1991). 31. Wiseman, B. S. & Werb, Z. Stromal effects on survival of human endothelial cells via cell cycle arrest
2. Clark, W. H. Jr. The nature of cancer: morphogenesis mammary gland development and breast cancer. and downregulation of survivin, Akt and NFκB:
and progressive (self)-disorganization in neoplastic Science 296, 1046–1049 (2002). implications for angioprevention and antiangiogenic
development and progression. Acta Oncol. 34, 3–21 32. Allinen, M. et al. Molecular characterization of the therapy. Oncogene 24, 1188–1202 (2005).
(1995). tumor microenvironment in breast cancer. Cancer Cell 58. Albini, A. et al. Mechanisms of the antiangiogenic
3. Sporn, M. B. The war on cancer. Lancet 347, 6, 17–32 (2004). activity by the hop flavonoid xanthohumol: NFκB and
1377–1381 (1996). 33. Ishiguro, K., Yoshida, T., Yagishita, H., Numata, Y. & Akt as targets. FASEB J. 20, 527–529 (2006).
4. Mueller, M. M. & Fusenig, N. E. Friends or foes- Okayasu, T. Epithelial and stromal genetic instability 59. Dell’eva, R. et al. The Akt inhibitor deguelin, is an
bipolar effects of the tumour stroma in cancer. Nature contributes to genesis of colorectal adenomas. Gut angiopreventive agent also acting on the NFκB
Rev. Cancer 4, 839–849 (2004). 55, 695–702 (2006). pathway. Carcinogenesis 4 September 2006 [epub
5. Joyce, J. A. Therapeutic targeting of the tumor 34. Weber, F. et al. Total-genome analysis of BRCA1/2- ahead of print].
microenvironment. Cancer Cell 7, 513–520 (2005). related invasive carcinomas of the breast identifies 60. Bertl, E., Bartsch, H. & Gerhauser, C. Inhibition of
6. Bissell, M. J. & Labarge, M. A. Context, tissue plasticity, tumor stroma as potential landscaper for neoplastic angiogenesis and endothelial cell functions are novel
and cancer: are tumor stem cells also regulated by the initiation. Am. J. Hum. Genet. 78, 961–972 (2006). sulforaphane-mediated mechanisms in chemoprevention.
microenvironment? Cancer Cell 7, 17–23 (2005). 35. Streubel, B. et al. Lymphoma-specific genetic Mol. Cancer Ther. 5, 575–585 (2006).
7. Bhowmick, N. A., Neilson, E. G. & Moses, H. L. Stromal aberrations in microvascular endothelial cells in B-cell 61. Xu, C., Shen, G., Chen, C., Gelinas, C. & Kong, A. N.
fibroblasts in cancer initiation and progression. Nature lymphomas. N. Engl. J. Med. 351, 250–259 (2004). Suppression of NF-κB and NF-κB-regulated gene
432, 332–337 (2004). 36. Hida, K. & Klagsbrun, M. A new perspective on tumor expression by sulforaphane and PEITC through IκBα,
8. Bissell, M. J., Kenny, P. A. & Radisky, D. C. endothelial cells: unexpected chromosome and IKK pathway in human prostate cancer PC-3 cells.
Microenvironmental regulators of tissue structure and centrosome abnormalities. Cancer Res. 65, Oncogene 24, 4486–4495 (2005).
function also regulate tumor induction and 2507–2510 (2005). 62. Huang, S., DeGuzman, A., Bucana, C. D. & Fidler, I. J.
progression: the role of extracellular matrix and its 37. Kim, B. G. et al. Smad4 signalling in T cells is required Nuclear factor-κB activity correlates with growth,
degrading enzymes. Cold Spring Harb. Symp. Quant. for suppression of gastrointestinal cancer. Nature angiogenesis, and metastasis of human melanoma cells
Biol. 70, 1–14 (2005). 441, 1015–1019 (2006). in nude mice. Clin. Cancer Res. 6, 2573–2581 (2000).
9. Huang, S. & Ingber, D. E. A non-genetic basis for 38. Bindra, R. S. & Glazer, P. M. Genetic instability and the 63. Huang, S., Pettaway, C. A., Uehara, H., Bucana, C. D. &
tumorigenesis and metastatic progression: self- tumor microenvironment: towards the concept of Fidler, I. J. Blockade of NF-κB activity in human
organizing attractors in cell regulatory networks. microenvironment-induced mutagenesis. Mutat. Res. prostate cancer cells is associated with suppression of
Breast Dis. (in the press). 569, 75–85 (2005). angiogenesis, invasion, and metastasis. Oncogene 20,
10. Kumar, V., Abbas, A. K. & Fausto, N. Robbins and 39. Kelloff, G. J., Hawk, E. T. & Sigman, C. C., eds. Cancer 4188–4197 (2001).
Cotran Pathologic Basis of Disease, 7th Edition chemoprevention: strategies for cancer 64. Reed, J. C. The Survivin saga goes in vivo. J. Clin.
47–118 (Elsevier Saunders, Philadelphia, 2005). chemoprevention (Humana Press, Totowa, NJ, 2005). Invest. 108, 965–969 (2001).
11. Dvorak, H. F. Angiogenesis: update 2005. J. Thromb. 40. Lippman, S. M. & Lee, J. J. Reducing the ‘risk’ of 65. Tran, J. et al. A role for survivin in chemoresistance of
Haemost. 3, 1835–1842 (2005). chemoprevention: defining and targeting high risk — endothelial cells mediated by VEGF. Proc. Natl Acad.
12. Albini, A., Tosetti, F., Benelli, R. & Noonan, D. M. Tumor 2005 AACR Cancer Research and Prevention Sci. USA 99, 4349–4354 (2002).
inflammatory angiogenesis and its chemoprevention. Foundation Award Lecture. Cancer Res. 66, 66. O’Connor, D. S. et al. Control of apoptosis during
Cancer Res. 65, 10637–10641 (2005). 2893–2903 (2006). angiogenesis by survivin expression in endothelial cells.
13. Maruotti, N., Cantatore, F. P., Crivellato, E., Vacca, A. 41. De Flora, S. & Ferguson, L. R. Overview of mechanisms Am. J. Pathol. 156, 393–398 (2000).
& Ribatti, D. Angiogenesis in rheumatoid arthritis. of cancer chemopreventive agents. Mutat. Res. 591, 67. Xiang, R. et al. A DNA vaccine targeting survivin
Histol. Histopathol. 21, 557–566 (2006). 8–15 (2005). combines apoptosis with suppression of angiogenesis in
14. Karin, M. Inflammation and cancer: the long reach of 42. Sporn, M. B. & Liby, K. T. Cancer chemoprevention: lung tumor eradication. Cancer Res. 65, 553–561
Ras. Nature Med. 11, 20–21 (2005). scientific promise, clinical uncertainty. Nature Clin. (2005).
15. Sparmann, A. & Bar-Sagi, D. Ras-induced interleukin- Pract. Oncol. 2, 518–525 (2005). 68. Tosetti, F., Ferrari, N., De Flora, S. & Albini, A.
8 expression plays a critical role in tumor growth and 43. Kelloff, G. J. et al. Progress in chemoprevention drug Angioprevention: angiogenesis is a common and key
angiogenesis. Cancer Cell 6, 447–458 (2004). development: the promise of molecular biomarkers for target for cancer chemopreventive agents. FASEB J. 16,
16. Balkwill, F., Charles, K. A. & Mantovani, A. Smoldering prevention of intraepithelial neoplasia and cancer — 2–14 (2002).
and polarized inflammation in the initiation and a plan to move forward. Clin. Cancer Res. 12, 69. Brahimi-Horn, M. C. & Pouyssegur, J. The hypoxia-
promotion of malignant disease. Cancer Cell 7, 3661–3697 (2006). inducible factor and tumor progression along the
211–217 (2005). 44. Coussens, L. M. & Werb, Z. Inflammation and cancer. angiogenic pathway. Int. Rev. Cytol. 242, 157–213
17. Lewis, C. E. & Pollard, J. W. Distinct role of Nature 420, 860–867 (2002). (2005).
macrophages in different tumor microenvironments. 45. Balkwill, F. Cancer and the chemokine network. Nature 70. Esteban, M. A. & Maxwell, P. H. HIF, a missing link
Cancer Res. 66, 605–612 (2006). Rev. Cancer 4, 540–550 (2004). between metabolism and cancer. Nature Med. 11,
18. Zhu, P. et al. Macrophage/cancer cell interactions 46. Condeelis, J. & Pollard, J. W. Macrophages: obligate 1047–1048 (2005).
mediate hormone resistance by a nuclear receptor partners for tumor cell migration, invasion, and 71. Semenza, G. L. Hypoxia, clonal selection, and the role
derepression pathway. Cell 124, 615–629 (2006). metastasis. Cell 124, 263–266 (2006). of HIF-1 in tumor progression. Crit. Rev. Biochem. Mol.
19. Benelli, R., Albini, A. & Noonan, D. in The neutrophil: 47. Karin, M. & Greten, F. R. NFκB: linking inflammation Biol. 35, 71–103 (2000).
An emerging regulator of inflammatory and immune and immunity to cancer development and progression. 72. Cramer, T. et al. HIF-1α is essential for myeloid cell-
response (ed. M. A. Cassatella) 167–181 (Karger, Nature Rev. Immunol. 5, 749–759 (2005). mediated inflammation. Cell 112, 645–657 (2003).
Basel, 2003). 48. Mann, J. R., Backlund, M. G. & DuBois, R. N. 73. Myzak, M. C., Dashwood, W. M., Orner, G. A., Ho, E. &
20. Benelli, R. et al. Neutrophils as a key cellular target for Mechanisms of disease: inflammatory mediators and Dashwood, R. H. Sulforaphane inhibits histone
angiostatin: implications for regulation of angiogenesis cancer prevention. Nature Clin. Pract. Oncol. 2, deacetylase in vivo and suppresses tumorigenesis in
and inflammation. FASEB J. 16, 267–269 (2002). 202–210 (2005). Apc-minus mice. FASEB J. 20, 506–508 (2006).
21. Scapini, P. et al. CXCL1/macrophage inflammatory 49. Suh, N. et al. Synthetic triterpenoids enhance 74. Kopelovich, L., Crowell, J. A. & Fay, J. R. The epigenome
protein-2-induced angiogenesis in vivo is mediated by transforming growth factor β/Smad signaling. Cancer as a target for cancer chemoprevention.
neutrophil-derived vascular endothelial growth factor- Res. 63, 1371–1376 (2003). J. Natl Cancer Inst. 95, 1747–1757 (2003).
A1. J. Immunol. 172, 5034–5040 (2004). 50. Yu, H. & Jove, R. The STATs of cancer--new molecular 75. Kong, X. et al. Histone deacetylase inhibitors induce
22. Kalluri, R. & Zeisberg, M. Fibroblasts in cancer. Nature targets come of age. Nature Rev. Cancer 4, 97–105 VHL and ubiquitin-independent proteasomal
Rev. Cancer 6, 392–401 (2006). (2004). degradation of hypoxia-inducible factor 1alpha. Mol.
23. Orimo, A. et al. Stromal fibroblasts present in invasive 51. Liby, K. et al. The synthetic triterpenoid CDDO- Cell Biol. 26, 2019–2028 (2006).
human breast carcinomas promote tumor growth and Imidazolide suppresses STAT phosphorylation and 76. Fath, D. M. et al. Histone deacetylase inhibitors repress
angiogenesis through elevated SDF-1/CXCL12 induces apoptosis in myeloma and lung cancer cells. the transactivation potential of hypoxia-inducible
secretion. Cell 121, 335–348 (2005). Clin. Cancer Res. 12, 4288–4293 (2006). factors independently of direct acetylation of HIF-α. J.
24. Powell, D. W. et al Myofibroblasts. I. Paracrine cells 52. Dauer, D. J. et al. Stat3 regulates genes common to Biol. Chem. 281, 13612–13619 (2006).
important in health and disease. Am. J. Physiol. 277, both wound healing and cancer. Oncogene 24, 77. Zhang, Q. et al. Green tea extract and (-)-
C1–C9 (1999). 3397–3408 (2005). epigallocatechin-3-gallate inhibit hypoxia- and

146 | FEBRUARY 2007 | VOLUME 7 www.nature.com/reviews/cancer


© 2007 Nature Publishing Group
PERSPECTIVES

serum-induced HIF-1α protein accumulation and VEGF 103. Bertagnolli, M. M. et al. Celecoxib for the prevention of invited experts). Eur. J. Cardiovasc. Prev. Rehabil. 10,
expression in human cervical carcinoma and hepatoma sporadic colorectal adenomas. N. Engl. J. Med. 355, S1–S10 (2003).
cells. Mol. Cancer Ther. 5, 1227–1238 (2006). 873–884 (2006).
78. Zhang, Q. et al. Resveratrol inhibits hypoxia-induced 104. Solomon, S. D. et al. Effect of celecoxib on Acknowledgements
accumulation of hypoxia-inducible factor-1α and VEGF cardiovascular events and blood pressure in two trials We thank M. Padgett for expert editorial and stylistic assist-
expression in human tongue squamous cell carcinoma for the prevention of colorectal adenomas. Circulation ance in the preparation of this manuscript. K. Liby, F. Tosetti,
and hepatoma cells. Mol. Cancer Ther. 4, 1465–1474 114, 1028–1035 (2006). R. Benelli and D. Noonan have given valuable suggestions
(2005). 105. Gail, M. H. & Costantino, J. P. Validating and and comments. We are especially indebted to C. Leaf for com-
79. Fang, J. et al. Apigenin inhibits VEGF and HIF-1 improving models for projecting the absolute risk of ments about ‘risk versus risk’. A.A. is supported by grants
expression via PI3K/AKT/p70S6K1 and HDM2/p53 breast cancer. J. Natl Cancer Inst. 93, 334–335 from the Associazione Italiana per la Ricerca sul Cancro
pathways. FASEB J. 19, 342–353 (2005). (2001). (AIRC) and Ministero della Salute. M.B.S. is supported by
80. Semenza, G. L. Targeting HIF-1 for cancer therapy. 106. Freedman, A. N. et al. Estimates of the number of US grants from the US National Cancer Institute and the National
Nature Rev. Cancer 3, 721–732 (2003). women who could benefit from tamoxifen for breast Foundation for Cancer Research.
81. Blouw, B. et al. The hypoxic response of tumors is cancer chemoprevention. J. Natl Cancer Inst. 95,
dependent on their microenvironment. Cancer Cell 4, 526–532 (2003). Competing interests statement
133–146 (2003). 107. Szabo, E. Selecting targets for cancer prevention: where The authors declare no competing financial interests.
82. Acker, T. et al. Genetic evidence for a tumor suppressor do we go from here? Nature Rev. Cancer 6, 867–874
role of HIF-2α. Cancer Cell 8, 131–141 (2005). (2006). DATABASES
83. Talalay, P., Dinkova-Kostova, A. T. & Holtzclaw, W. D. 108. Hanahan, D. & Folkman, J. Patterns and emerging The following terms in this article are linked online to:
Importance of phase 2 gene regulation in protection mechanisms of the angiogenic switch during
Entrez Gene: http://www.ncbi.nlm.nih.gov/entrez/query.
against electrophile and reactive oxygen toxicity and tumorigenesis. Cell 86, 353–364 (1996).
fcgi?db=gene
carcinogenesis. Adv. Enzyme Regul. 43, 121–134 109. De Backer, G. et al. European guidelines on
COX2 | CXCR2 | CXCR4 | CXCL12 | HIF1α | iNOS | KEAP1 |
(2003). cardiovascular disease prevention in clinical practice:
MMP9 | NFκB | NRF2 | PAI1 | PI3K | SMAD4 | STAT3 | STAT5 |
84. Ryter, S. W., Alam, J. & Choi, A. M. Heme oxygenase-1/ third joint task force of European and other societies on
TGFβ | VEGFA
carbon monoxide: from basic science to therapeutic cardiovascular disease prevention in clinical practice
Access to this interactive links box is free online.
applications. Physiol. Rev. 86, 583–650 (2006). (constituted by representatives of eight societies and by
85. Zhang, Y. & Gordon, G. B. A strategy for cancer
prevention: stimulation of the Nrf2-ARE signaling
pathway. Mol. Cancer Ther. 3, 885–893 (2004).
86. Lee, J. S. & Surh, Y. J. Nrf2 as a novel molecular target
for chemoprevention. Cancer Lett. 224, 171–184
(2005).
87. Buteau-Lozano, H., Ancelin, M., Lardeux, B., Milanini,
SCIENCE AND SOCIETY
J. & Perrot-Applanat, M. Transcriptional regulation of
vascular endothelial growth factor by estradiol and
tamoxifen in breast cancer cells: a complex interplay
between estrogen receptors α and β. Cancer Res. 62,
A mesothelioma epidemic in
4977–4984 (2002).
88. Loureiro, R. M. & D’Amore, P. A. Transcriptional
regulation of vascular endothelial growth factor in
cancer. Cytokine Growth Factor Rev. 16, 77–89 (2005).
Cappadocia: scientific developments
89. Yen, W. C., Prudente, R. Y., Corpuz, M. R., Negro-Vilar,
A. & Lamph, W. W. A selective retinoid X receptor
agonist bexarotene (LGD1069, targretin) inhibits
and unexpected social outcomes
angiogenesis and metastasis in solid tumours. Br. J.
Cancer 94, 654–660 (2006).
90. Folkman, J. Tumor angiogenesis: therapeutic Michele Carbone, Salih Emri, A. Umran Dogan, Ian Steele, Murat Tuncer,
implications. N. Engl. J. Med. 285, 1182–1186
(1971).
Harvey I. Pass and Y. Izzettin Baris
91. Carmeliet, P. Angiogenesis in life, disease and medicine.
Nature 438, 932–936 (2005). Abstract | In Cappadocia, Turkey, an unprecedented mesothelioma epidemic
92. Kerbel, R. S. Antiangiogenic therapy: a universal
chemosensitization strategy for cancer? Science 312, causes 50% of all deaths in three small villages. Initially linked solely to the exposure
1171–1175 (2006).
93. Brown, J. R. & DuBois, R. N. COX-2: a molecular target to a fibrous mineral, erionite, recent studies by scientists from Turkey and the
for colorectal cancer prevention. J. Clin. Oncol. 23,
2840–2855 (2005).
United States have shown that erionite causes mesothelioma mostly in families
94. Harris, R. E., Beebe-Donk, J. & Alshafie, G. A. that are genetically predisposed to mineral fibre carcinogenesis. This manuscript
Reduction in the risk of human breast cancer by
selective cyclooxygenase-2 (COX-2) inhibitors. BMC reports, through the eyes of one of the researchers, the resulting scientific advances
Cancer 6, 27 (2006).
95. Oshima, M. et al. Suppression of intestinal polyposis in that have come from these studies and the social improvements that were brought
Apc delta716 knockout mice by inhibition of
cyclooxygenase 2 (COX-2). Cell 87, 803–809 (1996).
about by both the scientists and members of the Turkish Government.
96. Masferrer, J. L. et al. Antiangiogenic and antitumor
activities of cyclooxygenase-2 inhibitors. Cancer Res.
60, 1306–1311 (2000). Mesothelioma is a cancer arising from link between asbestos exposure and
97. Donà, M. et al. Neutrophil restraint by green tea:
inhibition of inflammation, associated angiogenesis,
the mesothelial cells that line the pleural, mesothelioma was established in 1960, it
and pulmonary fibrosis. J. Immunol. 170, 4335–4341 pericardial and peritoneal surfaces1,2. is still unclear whether all types of asbestos
(2003).
98. Ferrari, N. et al. The transforming growth factor-beta
Although there are rare benign variants cause mesothelioma3–6 (BOX 2).
family members bone morphogenetic protein-2 and of mesothelioma, such as multicystic
macrophage inhibitory cytokine-1 as mediators of the
antiangiogenic activity of N-(4-hydroxyphenyl)retinamid
mesothelioma or mesothelioma of the Mechanisms of mineral fibre carcinogenesis
e. Clin. Cancer Res. 11, 4610–4619 (2005). atrioventricular node, which are not related The mechanisms of mineral fibre carcino-
99. Shishodia, S., Gutierrez, A. M., Lotan, R. & Aggarwal,
B. B. N-(4-hydroxyphenyl)retinamide inhibits invasion,
to asbestos exposure1,2, this article focuses genesis have been studied prevalently using
suppresses osteoclastogenesis, and potentiates on the relatively more common malignant crocidolite asbestos, and are summarized
apoptosis through down-regulation of IκBα kinase and
nuclear factor-κB-regulated gene products. Cancer Res.
mesothelioma. In the United States there below. Carcinogenesis as a result of expo-
65, 9555–9565 (2005). are approximately 2,500 cases and deaths sure to crocidolite has been linked to its
100. Veronesi, U. et al. Fifteen-year results of a randomized
phase III trial of fenretinide to prevent second breast
per year of malignant mesothelioma, which ability to induce the expression of both
cancer. Ann. Oncol. 17, 1065–1071 (2006). is often related to asbestos exposure (BOX 1). tumour-necrosis factor-α (TNFα) and its
101. Demierre, M. F., Higgins, P. D., Gruber, S. B., Hawk, E.
& Lippman, S. M. Statins and cancer prevention.
Median survival is approximately 1 year receptor (TNFR1) in mesothelial cells and
Nature Rev. Cancer 5, 930–942 (2005). from diagnosis because current therapies in macrophages that phagocytose asbestos7.
102. Arber, N. et al. Celecoxib for the prevention of
colorectal adenomatous polyps. N. Engl. J. Med. 355,
have only marginal effects in altering the Indeed, Tnfr1 knockout mice do not develop
885–895 (2006). natural course of the disease1. Although the fibroproliferative lesions after asbestos

NATURE REVIEWS | CANCER VOLUME 7 | FEBRUARY 2007 | 147


© 2007 Nature Publishing Group