ASIP Centennial Review

Matrix Metalloproteinases
Changing Roles in Tumor Progression and Metastasis
Laurie A. Shuman Moss, Sandra Jensen-Taubman,
and William G. Stetler-Stevenson
From the Radiation Oncology Branch, National Cancer Institute,
NIH, Bethesda, Maryland
Articles on tumor invasion, metastasis, and angiogen-
esis in normal and disease states have been well rep-
resented among the pages of The American Journal of
Pathology. Inadditionto exciting interest ina variety of
disease processes, these studies have been central in
defining the emerging field in cancer research known
as the tumor microenvironment. Early studies in this
field established the importance of the extracellular ma-
trix on tumor cell growth and differentiation. With
time, the role of the extracellular matrix and matrix
metalloproteinases in the regulation of tumor invasion,
metastasis, and angiogenesis was recognized, and AJP
has published seminal articles in this field. Moreover,
recent studies show evidence for a role of matrix met-
alloproteinases in the regulation of inflammation
within tumor lesions, making the targeting of matrix
metalloproteinases in cancer therapy even more com-
plex. This review attempts to summarize the contribution
of AJP to some of the key changes that have led to the
evolution of this field. (Am J Pathol 2012, 181:18951899;
http://dx.doi.org/10.1016/j.ajpath.2012.08.044)
It is now well established that the tumor microenviron-
ment has a major influence on the development, invasion,
and metastasis of cancer. Stephen Paget, who noted the
propensity for some types of cancer to metastasize to
specific organs, suggesting that the metastatic site is not
simply a matter of chance, was probably the first to rec-
ognize the importance of the microenvironment. This con-
cept of nonrandom metastasis is embodied in Pagets
1889 seed-soil hypothesis, which proposes that meta-
static cancer cells (seeds) interact with specific organ
microenvironments (soil) to result in metastasis forma-
tion.
1
We now know that the metastatic potential of a
tumor cell is dependent on genetic alterations within cells
of the primary tumor and also results from a dynamic
series of interactions between structural, soluble, and
changing cellular elements of the extracellular matrix and
stromal tissue compartment. This commentary will briefly
summarize The American Journal of Pathology contribu-
tions to the evolution of this field.
During the past 40 years, there has been increasing
recognition that metastatic disease is responsible for the
demise of most patients with cancer, resulting in a con-
current exponential increase in studies on the metastatic
process. The seminal observations by Paget
1
challenged
the prevailing viewpoint of his time that cancer metastasis
was a random process. However, James Ewing,
2
who
proposed that metastatic dissemination of cancer was
purely dependent on the anatomical distribution of the
vascular system, later challenged Pagets seed-soil hy-
pothesis in 1928. This controversy was finally resolved
with the work of Fidler and colleagues, who studied ex-
perimental metastasis in syngeneic mice to show that
subsequent metastatic growth at a distant organ site was
site specific, consistent with Pagets original hypothesis.
3
Critical to this work was the in vivo selection and charac-
terization of invasive and metastatic mouse tumor mod-
els.
3
For example, tumors s.c. implanted in mice showed
a different pattern of gene expression and metastasis
formation than tumors implanted in the tissue of origin
(orthotopic implantation), once again demonstrating the
influence of the local microenvironment on tumor growth,
selection, and metastasis.
46
During the past 30 years, the scope of metastasis
research has continued to expand, generating new roles
for proteases and an increased understanding of the
molecular mechanisms driving tumor angiogenesis.
Moreover, transcriptome profiling of metastatic versus
nonmetastatic tumors has revealed crucial information
Supported by a grant from the National Cancer Institute Center for Cancer
Research (ZIA SC009179-22), as part of the NIH intramural research
program.
Accepted for publication August 23, 2012.
Address reprint requests to William G. Stetler-Stevenson, M.D., Ph.D.,
National Cancer Institute, NIH, Bldg 10, Room 2A33, 10 Center Dr, MSC
1500, Bethesda, MD 20892-1500. E-mail: sstevenw@mail.nih.gov.
The American Journal of Pathology, Vol. 181, No. 6, December 2012
Published by Elsevier Inc. on behalf of the
American Society for Investigative Pathology.
http://dx.doi.org/10.1016/j.ajpath.2012.08.044
1895
pertaining to the immunological characteristics of cancer
progression and metastasis and metabolic profiling of the
tumor microenvironment. The aim of this commentary is
to review the changing role of matrix metalloproteinases
(MMPs) in cancer progression and metastasis from past
years to current studies, with an emphasis on the protu-
morigenic and antitumorigenic activities of these en-
zymes.
Tumor Invasion and MMPs: Early Concepts
The invasive nature of malignant tumors has long been
associated with the ability to degrade collagens, just as
the resistance of cartilage to tumor invasion is associated
with the presence of collagenase inhibitors.
7
However, it
was not until Liotta
8
recognized the importance of base-
ment membrane (type IV collagen) degradation in delin-
eating the invasive and metastatic potential of carcinoma
that the enzymatic activities associated with cancer cells
became better defined. These investigators identified
and purified the type IV collagenase that became the
second member of the MMP family (MMP-2). During the
next 15 years, the MMP family expanded to include 23
zinc-dependent endopeptidases, many of which were
first identified by their overexpression in tumor cells. Their
structure and substrates have been reviewed else-
where.
9
Early immunohistochemical studies revealed an
association of MMPs with tumor invasion and progres-
sion, demonstrating enhanced expression in tumor
cells.
1012
Interestingly, MMPs were also observed in
stromal cells at the invasive front of lung and colorectal
tumors.
13,14
The physiological inhibitors of MMPs include the tissue
inhibitors of metalloproteinases (TIMPs), some of which
are ubiquitously expressed in normal and tumor tissue.
15
The expression of MMPs and TIMPs in the tumor microen-
vironment is diverse. Additional studies identified the ex-
pression of MMP-1, MMP-3, MMP-7, MMP-9, MMP-12,
and MMP-14 in a variety of tumor types,
14,1620
including
non-Hodgkins lymphomas.
21
Preliminary in vivo studies
suggested great promise using natural (TIMP) and syn-
thetic MMP inhibitors to inhibit tumor invasion and metas-
tasis in mouse tumor models. These and other such stud-
ies (many published in AJP) generated great interest in
the development and clinical testing of a variety of MMP
inhibitors for the treatment of patients with cancer. Unfor-
tunately, these studies showed significant adverse ef-
fects with no therapeutic benefit. The failure of these
drugs was attributed to several causes, including the
design of clinical trials in which primarily patients with
late-stage cancer were studied.
22
New Roles for MMPs in Tumor Progression
and Angiogenesis
During the past 15 years, the accumulation of evidence
supporting the role of MMPs and TIMPs in the tumor
microenvironment has become increasingly complex. For
example, overexpression of MMPs, such as MMP-3, in
normal breast epithelium has resulted in invasive tumor
formation via induction of an epithelial-to-mesenchymal
transition and increased genomic instability.
23
MMPs
have also altered cell-cell adhesion through cleavage of
E-cadherin, leading to enhanced cell motility, another
feature of the epithelial-to-mesenchymal transition. More-
over, MMPs can also activate growth factor signaling by
increasing the bioavailability of factors, such as trans-
forming growth factor-, fibroblast growth factor-2, and
vascular endothelial growth factor (VEGF)-A, leading to
tumor progression through stimulation of tumor fibro-
blasts and angiogenesis.
Tumor angiogenesis has long been a focus of studies
reported in AJP. During the past two decades, nearly
20% of the top 25 cited articles in AJP pertained to the
subject of physiological and/or pathological angiogene-
sis, with the most highly cited articles of both decades
dealing directly with this topic. The process of tumor
angiogenesis begins with blood vessel recruitment in
response to the release of angiogenic growth factors and
cytokines from tumor cells and the release of proteases,
such as MMP-9, into the surrounding extracellular ma-
trix.
24,25
Indeed, we know that tumor blood vessels are
formed by several processes, including the sprouting of
endothelial cells from local capillaries and small blood
vessels in response to angiogenic growth factors (angio-
genesis) and the recruitment of endothelial progenitors
from bone marrow (vasculogenesis). Tumors may also
co-opt existing blood vessels, illustrated by the formation
of localized tumor cell growth around pre-existing tissue
blood vessels. Furthermore, tumor cells have also formed
vascular channels and expressed endothelial markers, a
process known as vasculogenic mimicry, first described
by Hendrix and colleagues
26
in AJP. Notably, all of these
mechanisms of tumor vascularization have some require-
ment for MMP activity, primarily MMP-1, MMP-2, MMP-9,
and MMP-14. In addition to their pro-angiogenic function,
it is appreciated that MMPs can also promote anti-angio-
genic activity. Indeed, a variety of endogenous angio-
genesis inhibitors are derived from MMP-mediated deg-
radation of extracellular matrix macromolecules. These
inhibitors include angiostatin, a 38-kDa fragment of plas-
minogen; endostatin, a fragment of type XVIII collagen;
and tumstatin, which is derived from type IV collagen.
Therefore, the timing of MMP-directed cancer therapy is
critical in regulating the balance of endogenous angio-
genesis inhibitors with pro-angiogenic agents, which in
turn is a critical determinant controlling the angiogenic
switch and initiation of tumor angiogenesis.
Normal blood vasculature consists of two interacting
cell types, endothelial cells and surrounding pericytes,
that share a common basement membrane and commu-
nicate via physical contact and paracrine signaling. In
fact, these pericyteendothelial cell interactions are re-
quired for vessel survival, maturation, and stabilization.
27
Conversely, tumor-associated blood vessels demon-
strate functional and anatomical heterogeneity, and often
become leaky in the sense that they allow the escape of
circulating plasma macromolecules.
28
This occurs in re-
sponse to the production of vascular permeability factor
(alias VEGF) by tumor cells. This hyperpermeability of
tumor blood vessels is recognized as an initial step of
1896 Shuman Moss et al
AJP December 2012, Vol. 181, No. 6
both pathological and physiological angiogenesis, simi-
lar to that observed in wound healing and inflammation.
29
This results in an investment of the tumor vessels with a
provisional matrix composed principally of fibrin that
stimulates endothelial cell growth and migration. The
structural basis for blood vessel leakiness in tumors is
associated with defective endothelial cells that form gaps
between cells and transcellular holes.
30
In addition to the
defective endothelial lining composed of branched, dis-
organized, and loosely connected endothelial cells, the
pericyte covering of tumor vessels is also abnormal. Al-
though ubiquitously present, tumor vesselassociated
pericytes show morphological abnormalities, including
an abnormally loose association with endothelia and long
cytoplasmic projections that extend deep into the tu-
mor.
31
It is well documented that tumor progression and me-
tastasis depend on the formation and recruitment of new
blood vessels in response to the release of pro-angio-
genic factors, such as basic fibroblast growth factor-2,
VEGF, and/or IL-8. The concept that a dominance of
anti-angiogenic factors, including endogenous angio-
genesis inhibitors (eg, thrombospondin and TIMPs), is
superseded by an overabundance of pro-angiogenic
factors before the initiation of tumor vascularization is
referred to as the angiogenic switch. This idea resulted in
attempts to target new cancer therapies aimed at inhib-
iting tumor angiogenesis and Food and Drug Administra-
tion approval of the first angiogenesis-targeted therapeu-
tic agent, bevacizumab, in 2004. In addition to the
potential therapeutic value in understanding tumor vas-
cularization, investigators also realized the prognostic
value in studying tumor angiogenesis. Although first dem-
onstrated for melanoma,
32
Weidner and colleagues
33
used sections from 49 patients with primary invasive
breast cancer to demonstrate a statistically significant
correlation between the density of microvessels and the
incidence of metastasis. Highly cited studies from AJP
reported this strong correlation in prostate and ovarian
cancers.
34,35
Similar studies confirmed this correlation in
non-small-cell lung cancer, and later studies in early-
stage breast cancer showed that microvessel density
predicted relapse-free and overall survival.
34,36
Cancer Immunity and MMPs
Research into MMP regulation of immune responses is
accelerating. Given the close association between can-
cer progression and inflammation, the role of MMPs in
regulating the immune response has become an area of
increasing importance. One mechanism of interest sug-
gests that the cleavage of pro-tumor necrosis factor-
from the cell surface promotes NF- signaling in tumor
cells. The activation of NF- signaling, and Stat-3 sig-
naling, leads to the activation of a feed-forward loop,
resulting in production of chemokines and recruitment of
tumor-infiltrating immune cells.
37
The activation of NF-
signaling can also stimulate MMP production in tumor
and surrounding stromal cells. In addition, tumor-infiltrat-
ing immune cells (eg, neutrophils, macrophages, and T
cells) can release cytokines that further stimulate tumor
growth. Interestingly, MMPs may also exert tumor-sup-
pressor activity through proteolytic modification of
chemokines, such as CXC stromal-derived factors and
members of the monocyte chemoattractant protein
family, resulting in loss of activity and suppression of
the tumor immune response.
38
The MMPs most closely
associated with modulating the immune response in-
clude MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, and
MMP-12. Thus, such as tumor angiogenesis, modula-
tion of tumor-associated inflammation using MMP-di-
rected therapies will depend on identification of the
specific MMP target and an understanding of the cor-
rect therapeutic window.
New Roles for MMPs: The Premetastatic
Niche
MMPs also play a role in establishing the premetastatic
niche, or environment conducive to tumor cell growth
at a secondary site in the body. The premetastatic
niche is generated before the arrival of disseminated
primary tumor cells and initiated by soluble factors,
including VEGF-A, transforming growth factor-, and
tumor necrosis factor-, secreted by tumor cells at the
primary site. Premetastatic niche formation is associ-
ated with increased fibronectin production that can
facilitate attachment of VEGF receptor 1positive bone
marrowderived progenitor cells to perpetuate a mi-
croenvironment favorable to metastasis.
39
Progenitor
cells in the premetastatic niche have contributed to the
release of soluble kit-ligand and VEGF into the mi-
croenvironment, aiding in stem and progenitor cell re-
cruitment from the bone marrow and angiogenesis,
respectively.
24,40
In addition, Hiratsuka and col-
leagues
41
reported that the S100 chemokines, S100A8
and S100A9, are up-regulated in premetastatic lung
endothelium, resulting in increased expression of se-
rum amyloid A3. Serum amyloid A3 has bound toll-like
receptor 4 on lung endothelial cells and macrophages,
activating NF-B and enhancing primary tumor cell
migration to the lungs.
41
NF-B activation also in-
creases the production of MMPs, further promoting
extracellular matrix degradation and release of growth
factors.
42
Furthermore, MMP-3 and MMP-10, along
with angiopoietin 2, are up-regulated in the lung by
primary tumor cells and function synergistically to dis-
rupt vascular integrity to facilitate lung metastasis. In
support of these findings, spontaneous lung metasta-
sis of MDA-MB-231-Luc-D3H1 cells was significantly
inhibited when expression of all three factors was
knocked down.
43
Although the activation of MMPs in
distant sites has aided premetastatic niche formation
and metastasis, further studies are needed to identify
specific mechanisms in MMP-mediated metastatic
niche formation and therapeutic development and de-
livery to prevent the formation of a premetastatic niche.
ASIP Centennial Review 1897
AJP December 2012, Vol. 181, No. 6
Concluding Remarks
This survey of the past 25 plus years summarizes some
of the major developments regarding the association
between MMPs and immunoregulatory factors within the
tumor microenvironment. In doing so, it is evident that
AJP has played a major role in furthering our understand-
ing of tumor progression, metastasis, and angiogenesis,
as well as the role of MMPs in these processes. The
original concept of MMPs directing tumor and endothelial
cell invasion has expanded to an investigation of their
role in the generation of endogenous angiogenesis inhib-
itors, regulation of tumor immune responses, and gener-
ation of the premetastatic niche. However, MMPs are not
confined to the pathological characteristics of tumor in-
vasion, metastasis, and angiogenesis. AJP contains nu-
merous reports on the role of MMPs in a variety of other
pathological conditions, such as arthritis, idiopathic pul-
monary fibrosis, biliary fibrosis, dissecting aortic aneu-
rysms, myocardial infarction, preeclampsia, and macular
degeneration. With its broad focus, AJP continues to
foster the integration between various disciplines that
rapidly advances our understanding of basic and trans-
lational knowledge of the pathogenesis, classification,
diagnosis, and mechanisms of disease.
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AJP December 2012, Vol. 181, No. 6