Cell 127, November 17, 2006 ©2006 Elsevier Inc. 679
How tumors spread and kill their host organism remains
an enigma, but not for lack of attention. For more than a
century, cancer biologists have postulated that metas-
tasis results from the interplay of wandering tumor cells
with permissive target tissues. Yet, decades of scrutiny
into the molecular bases of cancer have largely focused
on what causes oncogenic transformation and the incip-
ient emergence of tumors. By comparison, the study of
how tumor cells take steps toward metastasis (that is, by
altering their microenvironment, entering the circulation,
and colonizing a distant organ) has received less atten-
tion. Progressively, however, the idea has emerged that
tumors are more than just a mass of transformed cells.
A renewed focus on the problem of metastasis is now
apparent, and for good reason—metastasis remains the
cause of 90% of deaths from solid tumors.
Several developments point toward progress. Recent
work suggests that certain oncogenic events, such as
evasion of growth suppression or of DNA-damage check-
points, may also contribute to the evolution of tumors
to the metastatic state because they create genomic
instability. With increasing resolution, the genetic and
epigenetic aberrations in tumors and their surrounding
stroma are being profiled genomewide in both animal
models and clinical samples. New evidence points at the
engagement of cellular accomplices from the stroma to
aid in tumor-cell survival and parasitic dominance at dis-
tant organ sites. Molecular mediators of tumor-cell hom-
ing to and colonization of specific organ sites are also
beginning to emerge. Recent technological advances
allow validation of these new findings through the analy-
sis of clinical samples. Taking stock of these develop-
ments may help in the creation of a roadmap to guide
A Problem of Evolution
An underlying concept in our analysis is that metastasis
emerges from the somatic evolution of a genetically diver-
sified cancer-cell population under the selective pressures
of an environment that imposes tight rules on cell behav-
ior. In essence, this explains why millions of cells might be
released by a tumor into the circulation every day, but only
a tiny minority of these cells will colonize a distant organ.
The utter inefficiency of the metastatic process implies
that healthy tissues display a marked hostility toward
invading tumor cells. This is not surprising. In a highly
evolved organism, homeostatic mechanisms ensure that
order is maintained in its tissues. To achieve metastasis,
cancer cells must therefore evade or co-opt multiple rules
and barriers that were refined over hundreds of millions of
years of organismal evolution. Thus, metastasis is akin to
an evolutionary process that involves selection of geneti-
cally heterogeneous lineages of cancer cells within the
ecosystem of an organism.
Several discrete steps are discernable in the biologi-
cal cascade of metastasis: loss of cellular adhesion,
increased motility and invasiveness, entry and survival
in the circulation, exit into new tissue, and eventual
colonization of a distant site (Chambers et al., 2002;
Fidler, 2003). Seminal work using experimental assays
for metastasis demonstrated that rare clones within
malignant cell populations were endowed with several
of these metastasis-promoting functions (Fidler, 2003).
The implication was that cells that comprise a metastatic
lesion were descendants of an exceedingly rare cell from
the primary tumor that stochastically expressed many, if
not all, of the genes necessary for successful execution
of the metastatic cascade (Fidler, 2003).
Recent advances in the molecular profiling of cancer
using genomic-level approaches have revealed genes
whose expression in primary tumors correlates strongly
with the likelihood of metastatic recurrence (Weigelt et al.,
2005). These observations have also prompted a recon-
sideration of how, where, and when cancer cells acquire
genes of relevance to metastasis and have raised the pos-
sibility that cells with metastatic potential may not be as
rare in primary tumors as was originally believed (Bernards
and Weinberg, 2002). Furthermore, recent evidence under-
scores the profound impact that the transformed cell of ori-
gin has on the metastatic course of a tumor—an important
concept that conventional models for the selective evolu-
tion of cancers did not fully appreciate.
Cancer Metastasis: Building a Framework
Gaorav P. Gupta1 and Joan Massagué1,2,*
1Cancer Biology and Genetics Program, and Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center, New
York, NY 10021, USA
2Box 116, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA
Metastasis occurs when genetically unstable cancer cells adapt to a tissue microenviron-
ment that is distant from the primary tumor. This process involves both the selection of traits
that are advantageous to cancer cells and the concomitant recruitment of traits in the tumor
stroma that accommodate invasion by metastatic cells. Recent conceptual and technological
advances promote our understanding of the origins and nature of cancer metastasis.
680 Cell 127, November 17, 2006 ©2006 Elsevier Inc.
Although developments such as these reflect the
complexity of cancer progression, they do not detract
from the idea that metastatic cells must overcome
numerous physical obstacles barring metastasis. The
common biological challenges posed by these barri-
ers suggest that there might be recurrent themes for
metastatic progression, just as there are for primary
tumor formation (Figure 1). In this way, cancer may
progress as a disease of genetically heterogeneous
cell populations driven to evolve by sequential envi-
The Early Origin of Cellular Heterogeneity
Evolutionary processes require a source of heterogene-
ity within the population, from which advantageous traits
can be selected. In the context of a tumor, this hetero-
geneity is amply supplied by the intrinsic instability of
cancer genomes in the form of DNA mutations, chro-
mosomal rearrangements, and epigenetic alterations.
Evidence that highly metastatic clones from tumor-cell
populations had a higher rate of genetic mutability than
nonmetastatic clones from the same tumor provided
an early link between metastasis and genetic instability
Major alterations in genomic DNA were once viewed
as an exclusive trait of advanced cancers. However, it is
now recognized that DNA damage and genomic instabil-
ity are underlying features of human cancer from the ear-
liest stages of tumorigenesis. Damage to genomic DNA
is evident even in apparently normal cells and becomes
amplified as tumors emerge (Bartkova et al., 2005;
Feinberg et al., 2006; Gorgoulis et al., 2005). Genomic
instability may be directly driven by mutations leading to
tumor initiation that were once thought to cause abnor-
mal cell proliferation but not much else. For example,
inactivation of the cell cycle suppressor Retinoblastoma
(Rb) alters the expression of the mitotic checkpoint
regulator Mad2, which fosters aneuploidy (Hernando et
al., 2004). Hyperactive mediators of oncogenic signal-
ing such as Akt can attenuate the DNA-damage check-
point response by disabling damage sensors such as
the kinase Chk1 (Puc et al., 2005). Telomeric crisis may
wreak havoc on the genomes of cancer cells, produc-
ing a myriad of traits associated with tumor progression
(Maser and DePinho, 2002). Moreover, epigenetic plas-
ticity must be recognized as an important source of can-
cer-cell heterogeneity (Baylin and Ohm, 2006; Feinberg
et al., 2006). As a recent example, ectopic overexpres-
sion of the polycomb group protein EZH2, which results
in alterations in chromatin remodeling, correlates with
metastasis and poor overall survival in prostate cancer
patients (Varambally et al., 2002).
Pressures that Select for an Aggressive Phenotype
The inappropriate proliferation of cells harboring onco-
genic lesions is challenged by multiple layers of mecha-
nisms that suppress tumor formation (Figure 2). Several
of these barriers are cell intrinsic (such as the genotoxic
stress induced by oncogenes, the expression of growth
inhibitory, apoptotic and senescence pathways, and
telomere attrition). Evasion of these tumor suppressive
pathways is a hallmark of primary tumors (Hanahan and
Weinberg, 2000). However, an entirely distinct class of
pressures comes from sources that are extrinsic to the
cancerous cells. Factors in the tumor microenvironment
that limit tumor progression include extracellular matrix
components, basement membranes, reactive oxygen
species, the limited availability of nutrients and oxy-
gen, and attack by the immune system (Figure 2). How
tumors cells respond to these external cues influences,
Figure 1. Stages of Metastatic Progression
Metastasis proceeds through the progressive acquisition of traits that
allow malignant cells originating in one organ to disseminate and colo-
nize a secondary site. Although these traits are depicted as part of
a contiguous biological sequence, their acquisition during metastatic
progression need not follow this particular order. Although in some
cases several factors may be necessary to implement a single step in
this cascade, other mediators of metastasis may facilitate execution
of multiple stages simultaneously. Similarly, the specific steps of this
sequence that are rate limiting for metastatic progression may also
vary from one tumor to the next.
Cell 127, November 17, 2006 ©2006 Elsevier Inc. 681
sometimes in dramatic fashion,
their metastatic potential. An
example is provided by the cel-
lular response to hypoxia, which
is emerging as a major player
that shapes the aggressiveness
of primary tumors.
In tumors, hypoxia is a strong
selective pressure that promotes
the outgrowth of malignant cells
with a diminished susceptibility
to undergo apoptosis. The cellu-
lar response to low oxygen ten-
sion involves the stabilization of a
hypoxia inducible factor-1 (HIF-1)
transcriptional complex that acti-
vates genes that promote angio-
genesis, anaerobic metabolism,
cell survival, and invasion (Harris,
2002). Tumors that exhibit abun-
dant HIF-1 stabilization have a
greater likelihood of developing
metastatic relapse and corre-
late with a shorter survival time
(Semenza, 2003). Accordingly,
by analyzing global transcript
levels an “epithelial cell hypoxia
signature” has been established
that is an independent predictor
of metastatic risk for both breast
and ovarian carcinomas (Chi et
al., 2006). A subset of HIF-1 tar-
get genes may act as mediators
of metastatic progression. HIF-
1 induces the expression of the
chemokine receptor CXCR4 in
renal cell carcinoma cells, which
metastatic dissemination (Staller
et al., 2003). A recent study
implicates lysyl oxidase (LOX)
as a HIF-1 target that mediates
metastasis of human breast can-
cer cells in a mouse model and
correlates with poor overall sur-
vival among estrogen receptor-
negative breast cancer patients
(Erler et al., 2006). LOX is required for the maturation
of newly synthesized collagen fibrils and may promote
metastasis through changes in focal adhesion kinase
activity. Hypoxia can also induce expression of Met,
thereby facilitating tumor cell invasion mediated by HGF
(the ligand for Met) (Pennacchietti et al., 2003).
Other aspects of the microenvironment may also drive
the selective evolution of primary tumors. For instance,
reactive species of nitrogen and oxygen, which are gen-
erated by both infiltrating inflammatory cells and rapidly
proliferating tumor cells, can contribute to the genomic
instability of cancer cells and
promote the expression of genes
that facilitate metastasis (Hus-
sain et al., 2003). Tumors also
exert different physical pressures
than well-organized tissues. For
example, tensional forces on
mammary epithelial cells dur-
ing tumorigenesis may result in
clustering of mechanotransduc-
ing integrins and subsequent
downstream activation of ERK
and Rho-GTPase (Paszek et al.,
2005). These signaling events
promote tumor-cell proliferation
and disrupt tissue polarity.
Prerequisites for Metastasis
Normal cells constitute lineages
that extend from stem cells to
terminally differentiated progeny.
Stem cells have the capacity to
divide with at least one daugh-
ter retaining the phenotype of
the mother. Similarly, the long-
term tumorigenic potential of
some tumors may rely on a small
proportion of malignant cells
endowed with a similar capacity
to indefinitely self renew. These
tumor-initiating cells are some-
times referred to as cancer stem
cells (Pardal et al., 2003). As was
originally demonstrated for hema-
tological malignancies (Bonnet
and Dick, 1997), solid malignan-
cies of the breast and brain have
recently been shown to contain
cells with such tumor-initiating
capacity (Al-Hajj et al., 2003;
Singh et al., 2004). When isolated,
these cells were capable of giving
rise to all other transformed cel-
lular phenotypes (as defined by
cell surface markers) observed
in the original tumor. Additionally,
they were capable of initiating secondary tumors from
very low numbers of transplanted cells (a surrogate for
self-renewal activity). However, the idea that self renewal
in solid tumors is a property of only a tiny cell subpopu-
lation in a tumor mass is currently supported by limited
evidence. Moreover, if self-renewing tumor cells are the
only cells capable of generating secondary growths, then
one might expect that the prevalence of tumor-initiating
cells in a tumor would reflect the overall proclivity for met-
astatic recurrence. This, however, has yet to be shown.
Regardless of the relative abundance of self-renewing
Figure 2. Pressures that Drive Selection for
Cell-intrinsic mechanisms limit the aberrant hyper-
proliferation of normal cells. Bypass of these cellular
restraints, in part fueled by genomic and epigenomic
instabilities, is a hallmark of cancer. The local micro-
environment provides extrinsic barriers that are evolu-
tionarily conserved to preserve normal tissue structure
and function. These barriers can be broadly classified
as chemical, physical, or biological in nature. Exam-
ples for each category are provided. These extrinsic
barriers limit the outgrowth of tumors at the primary
site, but a related set of barriers also challenges the
intrusion of disseminated cancer cells into a second-
ary organ. As tumors evolve, these pressures drive the
selection for traits that enable cancerous cells to by-
pass them. Tumors with limited cellular heterogeneity
may be unable to overcome these pressures and may
spontaneously regress or subsist in balance with these
tumor suppressive forces. Alternatively, in tumors con-
taining a high degree of cellular heterogeneity, aggres-
sive cellular subpopulations that can resist, co-opt, or
overcome these barriers may dominate the cancer,
rendering it primed for metastatic progression.
694 Cell 127, November 17, 2006 ©2006 Elsevier Inc.
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