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Microenvironmental regulation of metastasis
Citation for published version:
Joyce, JA & Pollard, JW 2009, 'Microenvironmental regulation of metastasis', Nature Reviews Cancer, vol.
9, no. 4, pp. 239-252. https://doi.org/10.1038/nrc2618
Digital Object Identifier (DOI):
10.1038/nrc2618
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Nature Reviews Cancer
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Published in final edited form as:
Nat Rev Cancer. 2009 April; 9(4): 239–252.
Published online 2008 March 12. doi: 10.1038/nrc2618
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Microenvironmental regulation of metastasis
Johanna A. Joyce
*
and Jeffrey W. Pollard
‡
Johanna A. Joyce: joycej@mskcc.org; Jeffrey W. Pollard: pollard@aecom.yu.edu
*
Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York,
USA
‡
Department of Developmental and Molecular Biology, Department of Obstetrics and Gynecology
and Women’s Health, Center for the Study of Reproductive Biology and Women’s Health, Albert
Einstein College of Medicine, Bronx, New York, USA
Abstract
Metastasis is a multistage process that requires cancer cells to escape from the primary tumour,
survive in the circulation, seed at distant sites and grow. Each of these processes involves rate-
limiting steps that are influenced by non-malignant cells of the tumour microenvironment. Many
of these cells are derived from the bone marrow, particularly the myeloid lineage, and are
recruited by cancer cells to enhance their survival, growth, invasion and dissemination. This
Review describes experimental data demonstrating the role of the microenvironment in metastasis,
identifies areas for future research and suggests possible new therapeutic avenues.
A variety of stromal cells in the surrounding environment are recruited to tumours, and these
not only enhance growth of the primary cancer but also facilitate its metastatic dissemination
to distant organs. Cancer cells in an aggressive primary mass are adept at exploiting that
particular tissue microenvironment; however, once they leave these favourable
surroundings, they must possess traits that will allow them to survive in new environments.
In order for a metastasis to occur, the intravasated cancer cell must survive in the circulation,
arrive at the target organ (seeding), extravasate into the parenchyma and show persistent
growth
1
. Each of these stages is inefficient and some are rate limiting
1,2
. For example,
senescence or apoptosis of cancer cells at the stage of entry into the metastatic site prevents
the spread of the majority of circulating cells
2–4
. Seeding can occur to multiple organs, but
metastatic tumours may grow in only one or a few
5
. There is also increasing evidence that in
some cases cancer cells can lie dormant for many years, and that seeding may occur several
years before diagnosis of the primary tumour
6–10
. In another phenomenon, termed
angiogenic dormancy, there is a balance of proliferation and apoptosis that results in
micrometastases that do not progress further
11,12
. The microenvironment clearly suppresses
© 2009 Macmillan Publishers Limited. All rights reserved
DATABASES
Entrez Gene: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene
Tgfbr2
UniProtKB: http://www.uniprot.org
CCL21 | CCL5 | CCL9 | CCR1 | CCR10 | CCR5 | CCR7 | CSF1 | CSF1R | CX3CR1 | CXCL5 | CXCR4 | EGF | EGFR | EMR1 |
ERBB2 | fibronectin | GROA | ID1 | IL8RB | integrin αM | KIT ligand | MMP2 | MMP9 | osteopontin | osteoprotegerin | plasminogen |
PROK2 | PTHRP | RANKL | S100A8 | S100A9 | SDF1 | tissue factor | TLR2 | TLR6 | TNFα | uPA | VCAM1 | VEGFA | VEGFR1 |
versican
FURTHER INFORMATION
Johanna Joyce’s webpage: http://www.mskcc.org/mskcc/html/52336.cfm
Jeffrey Pollard’s webpage: http://www.aecom.yu.edu/home/faculty/profile.asp?id=3865
ALL LINKS ARE ACTIVE IN THE ONLINE PDF
NIH Public Access
Author Manuscript
Nat Rev Cancer. Author manuscript; available in PMC 2012 January 4.
Published in final edited form as:
Nat Rev Cancer
. 2009 April ; 9(4): 239–252. doi:10.1038/nrc2618.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
the malignancy of these potentially metastatic cells
10
, and their re-activation to form a
clinically relevant metastasis probably occurs through perturbations in the
microenvironment. Nevertheless, despite this evidence for early seeding and dormancy,
tumour size and grade are the main predictors of metastasis, and this has been reinforced in
recent studies in mouse models
13
and by gene expression analysis that linked large tumour
size with metastasis-enhancing gene signatures
14
. It has been hypothesized that this may be
due to metastatic re- seeding to primary tumours
15
. If this is the case, nothing is currently
known about the underlying mechanisms. Successful metastatic outgrowth thus depends on
the cumulative ability of cancer cells to appropriate distinct microenvironments at each step
in the metastatic cascade: the primary tumour, systemic circulation and the final metastatic
site. In this Review we discuss instructive, and in some cases dominant, roles for the
microenvironment during the process of metastasis, with a particular focus on contributions
from bone marrow-derived cells (BMDCs).
Tumour–stroma interactions at the primary site
Tissues contain a plethora of cells that work in concert to effect normal physiology. These
cells have positional identity so that their location is defined and their number constrained.
Cancers have lost these constraints through mutations in oncogenes and tumour suppressor
genes. However, these tumour cells have not lost all their interactions with surrounding non-
malignant cells or with the extracellular architecture. Indeed, these interactions are not
static: they evolve along with the tumour, in particular through the recruitment of BMDCs.
In this section we discuss evidence that the microenvironment can exert inhibitory effects on
even aggressive malignant cells. However, during their progression, tumours circumvent
these inhibitory signals and instead exploit these surrounding cells to their own ends in
processes that result in inappropriate growth, invasion and ultimately metastasis.
Normal tissue homeostasis
Homeostasis in normal tissues requires a tightly controlled balance of cell proliferation and
death, which is achieved and maintained through intercellular communication. An important
regulator of normal cell behaviour and tissue homeostasis is the surrounding extracellular
matrix (ECM). The ECM has many functions, including acting as a physical scaffold,
facilitating interactions between different cell types, and providing survival and
differentiation signals. Maintaining organ homeostasis can prevent neoplastic transformation
in normal tissues by ensuring stable tissue structure, mediated by tight junction proteins and
cell adhesion molecules such as β1 integrins and epithelial (E)-cadherin
16,17
. Insight into the
dominance of the microenvironment over epithelial cell behaviour came from some of the
earliest pioneering studies in this field. Mintz and colleagues showed that the
microenvironment of a mouse blastocyst not only suppressed the tumorigenicity of
teratocarcinoma cells, but that those cells were stably reprogrammed, resulting in normal
chimeric mice
18
. Subsequent studies indicated that the embryonic microenvironment is
potent in its ability to reprogramme various cancer cells, including metastatic cells, to a less
aggressive phenotype
19–23
. Other groups have demonstrated a particularly important role for
stromal fibroblasts in modulating the malignant progression of transformed epithelial cells.
For example, co-culture experiments showed that normal fibroblasts prevented the growth of
initiated prostatic epithelial cells
24
, and could even reverse the malignant phenotype of
neoplastic epithelial cells
25
. During early tumour development, however, the protective
constraints of the microenvironment are overridden by conditions such as chronic
inflammation, and the local tissue microenvironment shifts to a growth-promoting state.
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Recruitment of stromal cells to developing tumours
It is now well established that primary tumours are composed of a multitude of stromal cell
types in addition to cancerous cells
26
. Among the stromal cell types that have been
implicated in tumour promotion are endothelial cells, which comprise the blood and
lymphatic circulatory systems, pericytes, fibroblasts and various BMDCs, including
macrophages, neutrophils, mast cells, myeloid cell-derived suppressor cells (MDSCs) and
mesenchymal stem cells (MSCs) (FIG. 1; TABLE 1). In recent years, the crucial
contribution of BMDCs to malignant progression has become increasingly evident, and will
be the central focus of this Review.
Chronic inflammation and BMDC recruitment
The presence of leukocytes in tumours in the past was generally thought to be a consequence
of a failed attempt at cancer cell destruction. However, tumours are not only effective in
escaping from immune-mediated rejection, they also modify certain inflammatory cell types
to render them tumour promoting rather than tumour suppressive. Furthermore, many of
these infiltrating immune cells may not be associated with the detection of cancer cell
antigens, but may alternatively be associated with the tissue disruption that is caused by
inflammatory agents or be a response to the growth of the tumour as it is established. This is
particularly evident in cancers associated with chronic inflammation, where the initial
inflammatory response is not resolved, and systemic conditions that promote continued
recruitment of bone marrow-derived inflammatory cells to the tumour mass are established
instead
27
. Thus a chronic inflammatory state can quickly set up a cascade of events in which
the tumour-promoting effects of immune cells are progressively amplified, often as a by-
product of their normal wound-repairing or developmental roles
28
. However, a complication
is that there is no clear association between the presence of any individual adaptive or innate
immune cell type and a defined outcome in terms of malignancy or prognosis across a range
of different tumour microenvironments. Even within individual cell types, there are
opposing functions; for example, CD4
+
T cells, macrophages, and natural killer (NK) T cells
have either tumour-suppressive or tumour-promoting properties depending on the tissue
context and cellular stimuli
29,30
.
Classification of these immune cells into different cellular states or subtypes has helped
provide some insight into their disparate functions (TABLE 1). For example, type 1 CD4
+
T
cells (T
H
1) aid CD8
+
T cells in tumour rejection, whereas type 2 CD4
+
T cells (T
H
2) and
CD4
+
T regulatory cells block the activation of CD8
+
T cells
30
. Like CD4
+
T cells,
macrophages can either impede or promote tumour progression, depending on their
functional state (TABLE 1). Several recent studies have found correlations between
particular immune cell infiltrates in primary tumours and patient prognosis. For example,
infiltration of CD8
+
T cells and mature dendritic cells is associated with a favourable
prognosis in colorectal cancer and head and neck cancer (reviewed in REF. 31). An
extensive macrophage infiltration, however, correlates with poor patient prognosis in >80%
of cancers analysed, including breast, thyroid and bladder cancer in which there is a positive
association with metastasis (reviewed in REFS 31,32).
The induction of angiogenesis is a crucial early stage in the development and growth of most
solid tumours, and is also necessary for haematogenous dissemination of cancer cells. Bone
marrow-derived myeloid cells, including macrophages
33
, TIE2-expressing monocytes
(TEMs)
34
, neutrophils
35
and mast cells
36,37
have all been shown to contribute to tumour
angiogenesis through their production of growth factors, cytokines and pro-teases such as
vascular endothelial growth factor A (VEGFA), PROK2 (also known as BV8) and matrix
metalloproteinases (MMPs), respectively (reviewed in REF. 38) (BOX 1). Several of these
cell types have also been implicated in the later stages of tumour progression, namely
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invasion and metastasis, and the ability of these BMDCs to enhance tumour malignancy
directly and indirectly is discussed below.
Box 1
Proteases in invasion and metastasis
The importance of chemoattractant signalling in cancer cell intravasation has been
revealed by the studies that are discussed throughout this Review. However, to physically
invade into blood vessels, proteolytic degradation is required. Proteases are often
produced by invasive cancer cells, but in many cases bone marrow-derived cells,
including macrophages, have been shown to be the major cell type that supplies crucial
proteases to the tumour microenvironment. These stromal cell-derived proteases include
specific matrix metalloproteinases
142,143
, cysteine cathepsins
144,145
and serine
proteases
146
. There are several possible mechanisms by which these proteases can
promote cancer cell invasion and intravasation, as indicated in the figure. Individual
proteases cleave cell-adhesion molecules, such as epithelial (E)-cadherin, leading to the
disruption of cell–cell junctions
145,147
. The loosening of cell contacts facilitates cancer
cell migration, either as individual cells or in groups, and protease degradation or
turnover of proteins in the extracellular matrix (ECM) and basement membrane enables
invasive cells to migrate into the surrounding tissue and vasculature. Not only are
proteases essential for the degradation of extracellular proteins, they also have more
specialized processing roles that are important for cell signalling, such as in the restricted
cleavage of pro-domains and subsequent activation of growth factors and cytokines
148
,
which may significantly increase chemoattraction, cell migration and metastasis. These
different modes of protease-enhanced invasion are not mutually exclusive; rather, it is
likely that they act in concert to promote cancer cell spread. All of these functions are
tightly regulated in a cascade of protease interactions, allowing for control and
amplification of proteolysis in invasion and metastasis
149
. Accordingly, when members
of some of these protease families are pharmacologically inhibited or genetically ablated,
there is a marked reduction in cancer cell invasion
142,150,151
.
Tumour-associated macrophages
Macrophages can be considered the prototypical BMDC type capable of modifying cancer
cell behaviour and have been shown to promote tumour angiogenesis, invasion,
intravasation and metastasis in animal models
39,40
. Macrophages are inherently plastic cells,
and this adaptability may be exploited by the tumour to elicit distinct functions at different
stages of tumour progression. Although macrophage classification schemes (TABLE 1) have
been useful in terms of assigning potential functions to tumour-associated macrophages
(TAMs), little is known about the complexity of individual macrophage activities and their
associated molecular profiles in cancer. In particular, the factors controlling the balance
between tumour-suppressing and tumour-promoting activities of macrophages, and how that
equilibrium changes over the course of tumour progression, are not known. We propose that
multiple subpopulations of TAMs exist within a tumour, which probably change temporally
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