REVIEW ARTICLE
Paget’s “Seed and Soil” Theory of Cancer Metastasis:
An Idea Whose Time has Come
Mohammed Akhtar, MD, FCAP, FRCPath, FRCPA,*
Abdulrazzaq Haider, MD,* Sameera Rashid, MD,†
and Ajayeb Dakhilalla M.H. Al-Nabet, PhD*
Abstract: The concept that the pattern of metastatic spread of
cancer is not random and that cancer cells exhibit preferences when
metastasizing to organs, dates back to 1889 when Steven Paget
published his “seed and soil” hypothesis. He proposed that the
spread of tumor cells is governed by interaction and cooperation
between the cancer cells (seed) and the host organ (soil). Extensive
studies during the last several decades have provided a better
understanding of the process of metastatic spread of cancer and
several stages such as intravasation, extravasation, tumor latency,
and development of micrometastasis and macrometastasis have
been defined. Furthermore, recent studies have shown that the
target organs may be prepared for metastatic deposits by
the development of premetastatic niches. This specialized micro-
environment is involved in promoting tumor cell homing,
colonization, and subsequent growth at the target organ. The
premetastatic niche consists of accumulation of aberrant immune
cells and extracellular matrix proteins in target organs. The primary
tumor plays a key role in the development of premetastatic niches
by producing tumor-derived soluble factors which mobilize bone
marrow-derived hematopoietic cells to the premetastatic niche.
Exosomes-derived from the primary tumor also contribute to can-
cer-favorable microenvironment in the premetastatic niches. These
changes prime the initially healthy organ microenvironment and
render it amenable for subsequent metastatic cell colonization.
Key Words: seed, soil, metastasis, exosomes, niche, premetastatic,
macrophage, intravasation, extravasation, bone marrow
(Adv Anat Pathol 2019;26:69–74)
C ancer metastasis is the spread of cancer cells beyond
where the tumor originated to other parts of the body
with the formation of new tumors. It is the single event that
results in the death of most patients with cancer. At the time
of cancer diagnosis, at least half of the patients already
present clinically detectable metastatic disease. Although the
primary tumor, in most cases may be eradicated by ther-
apeutic modalities such as surgical resection, radiotherapy,
and chemotherapy, its metastases, when distributed at dis-
tant sites in the body, are most difficult to eradicate by any
of the currently available therapeutic means, and finally,
From the *Department of Laboratory Medicine and Pathology, Divi-
sion of Anatomic Pathology; and †Department of Laboratory
Medicine and Pathology, Hamad Medical Corporation, Doha,
Qatar.
The authors have no funding or conflicts of interest to disclose.
Reprints: Mohammed Akhtar MD, FACP, FRCPath, FRCPA,
Department of Laboratory Medicine and Pathology, Hamad
Medical Corporation, P.O. Box 3050, Doha, Qatar (e-mail:
dr.mohammed.akhtar@gmail.com).
All figures can be viewed online in color at www.anatomicpathology.com.
Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
Adv Anat Pathol  Volume 26, Number 1, January 2019
Copyright r 2019 Wolters Kluwer Health, Inc. All rights reserved.
cause the patient’s death. Thus, metastasis is the most life-
threatening event in patients with cancer.1–3
It has long been observed that most cancers show an
organ-specific pattern of metastases. For example, colon
carcinomas metastasize usually to liver and lung but rarely
to bone, skin, brain, and kidneys. In contrast, breast carci-
nomas, frequently form metastases in most of these organs.
Similarly, prostate cancer metastasizes to the bone and only
rarely to lung and liver. Whether the distribution of meta-
static disease is a random process determined by the patterns
of blood supply and lymphatic flow or due to the active
interaction between the tumor cells and the host organ has
long been a matter of debate.2–4
The purpose of this review is to provide a brief per-
spective on our understanding of the mechanisms of meta-
stasis and to provide an update on recent findings with
regard to the interactions between the cancer cells and host
organ harboring the metastasis and to highlight changes in
the microenvironment of these organs before and after the
arrival of the metastatic cancer cells.
SEED AND THE SOIL THEORY
Steven Paget (son of the famous English surgeon and
pathologist Sir James Paget) proposed the “seed and soil”
theory of metastasis, which was based on analysis of 735
fatal cases of breast cancer, complete with the autopsy, as
well as many other cancer cases from the literature. His
findings were published in Lancet in 1889. He argued that
the distribution of metastases cannot be due to chance: the
“seed” refers to certain tumor cells with metastatic potential,
and the “soil” is any organ or tissue providing a proper
environment for the growth of the seeds. Paget suggested
that the spread of metastatic cells was organ specific and not
merely anatomic and involved interaction between the
cancer cells and the host organ. He concluded that meta-
stases developed only when the seed and soil were
compatible.5 This concept was in opposition to the pre-
vailing mechanistic hypothesis of Rudolf Virchow who
considered metastasis as the arrest of tumor cell emboli in
the vasculature.2,6
In 1928, James Ewing7 challenged Paget’s “seed and
soil” theory and hypothesized that metastatic dissemination
occurs by purely mechanical factors that are a result of the
anatomic structure of the vascular system. Thus, it would
be completely accounted for by the vascular connections of
the primary tumor so that tumor cell emboli are much more
likely to be mechanically trapped in the circulatory network
of the first connected organ, which will then sustain the
highest burden of metastatic colonization.
Other organs receive less tumor cells and develop fewer
metastatic tumors. That became the dominant view point
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Akhtar et al
and for the next several decades the concept of “seed and
soil” languished in the shadows. This proposal, however,
does not explain the observation that some organs, such as
brain, bone, and adrenals, are served by a small fraction of
the circulatory volume, yet they are frequently involved by
metastatic deposits of certain cancers. In contrast, organs,
such as heart, muscle, skin, kidney, and spleen, each of
which receives a considerable supply of blood, only occa-
sionally develop metastatic disease.3
In 1979, Sugarbaker8 postulated that while the regional
metastases could be due to anatomic or mechanical issues
such as lymphatic drainage as stated by Ewing, metastases
to distant organs are site specific and require a different
explanation. Seminal work by Hart and Fidler in the 1980s
supported Paget’s “seed and soil” theory by showing pref-
erential homing of tumor cells of B16 melanoma in specific
distant sites. Their work conclusively demonstrated that
while potentially metastatic tumor cells reached the vascu-
lature of all organs, the development of metastases occurred
selectively in certain organs but not others.9
THE START OF THE METASTATIC JOURNEY
The process of metastasis starts with the release of
malignant cells from its adhesive attachments to other cells
and the extracellular matrix including the basement mem-
branes. Further, the cancer cells acquire mesenchymal-like
properties via a process called epithelial mesenchymal
transition. This is mediated by cadherin molecule switching
involving downregulation of E-cadherin and upregulation of
mesenchymal cadherins such as N-cadherin, integrin-αvβ6,
vimentin, and matrix metalloproteinase.9 Such cells assume
motile phenotype and acquire migratory capabilities and
can interact with components of the extracellular matrix and
contribute to it by synthesizing and organizing new com-
ponents. They also remodel the extracellular matrix through
the production of matrix-degrading metalloproteinases.
Thus, the loss of cell-cell adhesions allows malignant tumor
cells to dissociate from the primary tumor and changes in
cell-matrix interaction enable the cells to invade the sur-
rounding stroma. As these motile cells pass through the
basement membrane and extracellular matrix, some tumor
cells will penetrate the blood vessels, thus entering the cir-
culation (intravasation) (Fig. 1). Tumor cells that have
successfully invaded the blood vessels adhere to blood pla-
telets that protect them from destructive physical forces such
FIGURE 1. Diagram showing the carcinoma cells invading the
stroma and undergoing EMT. The invading tumor cell may enter a
blood vessel and enter circulation (intravasation). EMT indicates
epithelial to mesenchymal transformation.
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Adv Anat Pathol  Volume 26, Number 1, January 2019
FIGURE 2. Following intravasation the tumor cell may be sur-
rounded by platelets and fibrin which protect the cancer cell from
the immune system. Please see this image in color online.
as hemodynamic shear and from sensitized killer mono-
nuclear cells. At the same time, there is an activation of
thrombosis with fibrin deposition. The aggregation of pla-
telets, fibrin, and tumor cells creates a tumor-platelet com-
plex that essentially acts as an embolus (Fig. 2). From this
point, these tumor cells move away from the primary site
and circulate in the blood circulation where they would
encounter resistance by the immune system and the mech-
anical stresses of blood flow. Some tumor cells will even-
tually survive and adopt a process to leave the blood
circulation, known as extravasation which is the reverse of
intravasation and in which cells adhere and penetrate the
blood vessel wall again. The tumor cells that escape from the
circulation, invade the host tissues.10–13 These cells undergo
mesenchymal-epithelial transformation and are now des-
ignated as disseminated tumor cells (DTCs) (Fig. 3).
HOMING OF CIRCULATING TUMOR CELLS
Various explanations have been proposed for the site
selectivity and organ tropism of blood-borne distant meta-
stases, including tumor cell surface characteristics, adhesion
between tumor cells and the target organ components and
response to specific host tissue growth factors and chemo-
kines. An explanation for the different sites of tumor growth
involves interactions between the metastatic cells and the
organ environment, possibly in terms of specific binding to
endothelial cells. Endothelial cells in the vasculature of
different organs express different cell surface receptors
and growth factors that influence the phenotype of the
FIGURE 3. At the host organ the tumor cell penetrates the vas-
cular wall and enters the host organ tissue. This is usually followed
by MET. DTC indicates disseminated tumor cells; MET, mesen-
chymal to epithelial transformation. Please see this image in color
online.
Adv Anat Pathol  Volume 26, Number 1, January 2019
corresponding metastases. Greene and Harvey first sug-
gested that the organ distribution patterns of metastatic foci
were dependent on the formation of sufficient adhesive
bonds between arrested tumor cells and endothelial cells,
and they hypothesized that these interactions were similar
to those of lymphocyte/endothelial cells at sites of
inflammation.14–16
Circulating immune and stem cells are known to use
chemokine-mediated signaling to home on specific organs.
Chemokines are growth factor–like molecules that bind to
G-coupled receptors. They induce leukocytes to adhere
tightly to endothelial cells and to migrate towards a gra-
dient. Tumor cells also use similar mechanisms to direct
metastatic organ preference. The best-known example is the
expression of chemokine receptor 4 (CXCR4) in breast
cancer. Tumors with CXCR4 expression migrate to organs
that express high levels of its ligand CXCL12. CXCL12 is
expressed in the common sites of metastasis for breast
cancer: lung, liver, bone marrow, and brain. Similarly,
melanoma cells may be attracted to certain organs using
CCL27/CCR10 chemokine receptor combination.16,17
TUMOR LATENCY
The fact that tumor cells arrive and establish residence
at a new and potentially hostile environment does not mean
that they will necessarily survive and proliferate in the new
location. Survival and subsequent proliferation, however, is
a prerequisite for development of a secondary tumor at the
new location. Only a small fraction of these cells ultimately
survives in the new tissue location. It has been estimated that
<0.01% of circulating tumor cells eventually succeed in
forming secondary growths.18
After extravasation, a common theme of the metastatic
process is settlement of DTCs into latency, which can last
from several weeks to decades (Fig. 4). In cellular latency
isolated tumor cells enter a state of proliferative quiescence.
Indeed, in patient bone marrow samples most DTCs are
found as quiescent single cells. Another form of tumor
latency is the establishment of micrometastasis (Fig. 5). This
is metastatic lesion where tumor cells form small aggregates
in which rate of proliferation and tumor cell attrition are
exactly balanced. The loss of tumor cells may be due to
apoptosis, insufficient vascularization, or to constant culling
by immune defenses. Consequently, in a micrometastasis
FIGURE 4. The DTC enter a stage of tumor latency which may
last for a few weeks to decades. During latency tumor cells may be
disposed as isolated cells or in the form of micrometastasis. They
may also be destroyed by the immune system or undergo
apoptosis. DTC indicates disseminated tumor cells. Please see this
image in color online.
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Atypical Thymoma
FIGURE 5. Photomicrograph featuring a micrometastasis of
breast cancer in a lymph node. Please see this image in color
online.
despite active tumor cell proliferation, the tumor size
remains too small for clinical detection by conventional
methods.19–21
The duration of metastatic latency varies between cancer
types, and for the most aggressive ones it is very short, resulting
in high relapse and mortality rates following diagnosis. In lung
cancer, the metastatic latency interval usually lasts only a few
weeks. In this type of cancer, malignant cells acquire metastatic
traits for rapid and massive cell dissemination, followed by
colonization of multiple secondary organs. The short latency in
lung cancer implies that malignant cells in the primary tumor
acquire most of the metastatic traits, thus enabling them to
overtake organs immediately after arrival. In contrast, a well-
known example of a tumor type with very long latency is
prostate cancer. Similarly, some of the breast cancer metastasis
may also remain dormant only to present with widespread
metastasis years and even decades later.22
THE METASTATIC NICHE AND FORMATION
OF MACROMETASTASIS
DTCs need time to alter or unleash the required
functions for tumor initiation and expansion in the secon-
dary site. For the successful establishment of a metastasis
several crucial events must take place, the most important
among which are cell cycle activity and angiogenesis. It is
obvious then that there are intrinsic differences in genomic
makeup of tumor cells that must be evaluated to understand
the factors intrinsic to the cell (seed). However, it is equally
important to acknowledge the microenvironmental con-
dition of the host tissue, the soil that plays a key role in the
acquisition of proliferative phenotype by the tumor cells.
Studies using, radioactive labeling of the injected can-
cer cells showed that they were equally likely to be trapped
in a variety of tissue.18 So, just landing in a tissue is not
enough for cancer cells to develop a secondary tumor;
rather, some role of the tissue itself may be crucial in sus-
taining the new growth. The findings of Tarin et al23 that the
development of secondary cancer was rare even upon direct
deposition of millions of tumor cells into the vena cava
(to reduce ascites from ovarian cancer) is a good indication
of the importance of other factors involved.
In stem cell biology the specialized microenvironment
that supports stem cell maintenance and actively regulates
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Akhtar et al
cell function and proliferation is termed as niche.24 A similar
model has been suggested to delineate the interactions of
malignant cells with their microenvironment at metastatic
sites. This microenvironment comprises supportive non-
neoplastic stromal cells, soluble factors, vascular networks,
nutrients and metabolic components, and the structural
extracellular matrix architecture. Although the precise
genetic makeup of a cell is undoubtedly pivotal in deter-
mining its malignant phenotype, the metastatic niche model
stipulates that microenvironmental factors are also impor-
tant in permitting malignant cells to realize their metastatic
potential. Thus, with the right genetic makeup of the tumor
cells accompanied by a permissive and supportive environ-
ment in the host organ, the tumor cells may proliferate and
ultimately develop into a clinically detectable macrometa-
stasis. The metastatic niche model suggests that a suitably
conducive microenvironment must evolve for tumor cells
to be able to engraft and proliferate at secondary sites with
the transition from micrometastatic to macrometastatic
status.25 The idea that cancer cells require some nourish-
ment and support from their environment to develop is an
important focus of research today, with the aim of unrav-
eling the molecular mechanisms that bring seed and soil
together to promote metastasis.
THE CONCEPT OF PREMETASTATIC NICHE
The premetastatic niche can be defined as a supportive and
receptive tissue microenvironment undergoing a series of
molecular and cellular changes to form the metastatic-des-
ignated sites, prior to the arrival of the metastatic tumor.
Dr Lyden and colleagues pioneered the research on the pre-
metastatic niche and the role and significance of the premeta-
static niche in metastasis has attracted more and more attention
in recent years.26 Their landmark study was the first demon-
stration of a microenvironment designed to attract tumor cells
to a target organ and set the stage for future work to discover
additional factors that contribute to premetastatic niche
formation.
The process of premetastatic niche formation in distant
organs is initiated by the primary tumor that produces tumor-
derived secreted factors prior to tumor dissemination.27 These
factors include vascular endothelial growth factor (VEGF-A)
and placental growth factor among others. These factors
increase the proliferation of fibroblast-like stromal cells, which
contribute to local deposition of fibronectin. Tumor-derived
secreted factors promote premetastatic niche formation by
mobilizing and recruiting VEGFR1+ bonemarrow-derived
hematopoietic progenitor cells directly from the bone marrow
to the premetastatic niche (Fig. 6). These cells express VLA−4
that binds to fibronectin and allows them to assemble at the
site. Most notably, the VEGFR1+ niche cells act as harbingers
of organ-specific carcinoma spread. Others, such as tumor
necrosis factor alpha (TNF-a) and transforming growth factor
b (TGF-b), along with VEGF-A, induce the expression of
S100A8 and S100A9 in the lung to develop premetastatic
niches.25–30
Premetastatic niche formation is facilitated in large part by
the presence of a suppressed immune system. Primary tumors
recruit myeloid cells, which are the precursors to immune cells.
These cells enable the tumor cells to avoid detection by the
immune system as they metastasize, and thus allow the meta-
stasis to flourish. Once the primary tumors have entered the
bloodstream, myeloid cells that have been recruited by the tumor
protect the cancer cells from detection by the immune system,
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Adv Anat Pathol  Volume 26, Number 1, January 2019
FIGURE 6. Cartoon depicting the formation of a premetastatic
niche. The primary tumor produces TDSFs that start the formation of
the premetastatic niche by transfer of BDHCs to the target organ.
The primary tumor also causes accumulation of TAMs in the pre-
metastatic niche. These cells protect disseminated tumor cells from
the immune system. TDSFs also cause inflammation in the devel-
oping premetastatic niche with accumulation of inflammatory cells
and formation of the intercellular matrix. Increased vascularity also
contributes to the niche formation. Tumor-derived exosome play a
crucial role in maintaining a cancer friendly microenvironment in the
niche. BDHC indicates bone marrow-derived hematopoietic cells;
TAM, tumor-associated macrophages; TDSF, tumor-derived soluble
factors. Please see this image in color online.
which would otherwise be more likely to be effective in halting
metastasis. Myeloid progenitor cells, recruited at various stages
in their cell cycle, are believed to constitute much of the
premetastatic niche, as they can protect the tumor cells from the
standard immune response as the cancer cells attempt to colonize
the premetastatic niche. Given their important role in protecting
the growing metastasis from immune system attacks, myeloid
cells are a key factor in the development of the premetastatic
niche, and thus eventually in promoting metastases.29,31
Chemokines, also play a significant role in the creation of
premetastatic niches and metastases. The primary tumor,
to evade detection by the immune system, uses chemokines
to increase recruitment of bone marrow-derived myeloid cells
to secondary organs. In addition, cancer cells from the
primary tumor can be used to induce inflammation in the
future site of the premetastatic niche in the secondary organ,
which is like the immune response created by an infection.
Thus, the large presence of immune cells allows the pre-
metastatic niche to ward off attacks by the immune system
and therefore allow the tumor to metastasize without
inhibition.29,32
The formation of a premetastatic niche not only involves
the recruitment of foreign cells, such as immune cells, but also
the reprogramming of the resident stromal cells to facilitate
metastatic growth. Normal lung fibroblasts express miR-30
family members to restrain MMPs, such as MMP9, to stabilize
the lung vasculature. Cancer cells reprogram fibroblasts to
decrease their expression of miR-30 family members, resulting
in enhanced MMP activity, vascular permeability, and meta-
stasis. Factors secreted from the primary tumor induce the
expression of α-smooth muscle actin—in premetastatic fibro-
blasts, activating them to induce remodeling extracellular matrix
through secretion of fibronectin, Lysyl Oxidases LOX and
LOXL2, thereby generating a more permissive microenviron-
ment for survival and outgrowth of DTC.28,29,33–35
Thus, immune suppression, combined with hypoxia
and changes in extracellular matrix, among other processes,
Adv Anat Pathol  Volume 26, Number 1, January 2019
are essential steps in creating premetastatic niches that allow
tumor cells to grow in a foreign and hostile environment
without being destroyed by the typical response of the
immune system.
ROLE OF EXOSOMES IN TUMOR METASTASIS
Exosomes are spherical to cup shaped, lipid bilayer
membrane nanovesicles 40 to 100 nm in diameter. These
vesicles are secreted by many cells and can be found in most
body fluids such as urine and blood as well as in super-
natants of cultured cells. Exosomes must be differentiated
from other secreted cellular entities such as microvesicles
(50 to 1000 nm in diameter) and ectosomes, which are
microvesicles derived from neutrophils or monocytes and
apoptotic bodies (500 to 2000 nm in diameter).36,37
Exosome formation is a fine-tuned process which
includes 4 stages: initiation, endocytosis, multivesicular
bodies formation, and exosome secretion. Multivesicular
bodies are endocytic structures formed by the budding of an
endosomal membrane into the lumen of the compartment
(Fig. 7). After vesicular accumulation, the multivesicular
bodies are either sorted for cargo degradation in the lyso-
some or released into the extracellular space as exosomes by
fusing with the plasma membrane.38
In addition to lipids, nucleic acids, and proteins have
also been detected in exosomes. The protein composition of
tumor cell-derived exosomes has been well characterized for
several cancers by using different proteomic methods. To
date, 4563 proteins, 1639 mRNAs, and 764 miRNAs have
been identified in exosomes from different species and tis-
sues by independent examinations.39
The exosomes can transfer their constituentsand cargo
to neighboring or distant cells with preservation of their
function. Several mechanisms for the uptake of exosomes by
recipient cells, such as exosome fusion with the membrane of
the recipient cell, endocytosis by phagocytosis, and receptor-
ligand interaction.40 Initially discovered as the garbage bags
for removal of unwanted material from cells, the role of
exosomes in immune response and cancer is gradually rec-
ognized. Exosomes are now considered important mediators
FIGURE 7. Early endosome is formed from the plasma
membrane via endocytic pathway. MVB can be formed by the
invagination of the endosomal membrane. During the biogenesis
of exosomes and before their secretion, proteins (cytosolic pro-
teins, receptors), nucleic acids (eg, mRNA, miRNA, DNA), and
lipids are uploaded to exosomes. Dependent on the function and
content, MVB then can be directed to fuse with the plasma
membrane and release to the extracellular space as exosomes.
Alternatively, contents of MVB may be degraded by fusion with
lysosomes. MVB indicates multivesicular body. Please see this
image in color online.
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Atypical Thymoma
in intercellular communication. The capability of exosomes
to transfer proteins, DNA, mRNA, as well as non-coding
RNAs has made them an attractive focus of research into
the pathogenesis of different diseases, including cancer.40,41
It has been noted that cancer cells secrete much higher
amounts of exosomes in comparison with nontransformed
cells. These exosomes not only influence proximal tumor cells
and stromal cells in local microenvironment, but also can
exert systemic effects when participating in blood circulation.
Exosomes have been shown to be implicated in the induction
of apoptosis of cytotoxic T cells, expansion and function of
regulatory T cells (Treg cells), induction of M2 polarization of
macrophages, inhibition of cytotoxicity of natural killer cells,
inhibition of differentiation of dendritic cells, expansion and
activation of myeloid-derived suppressor cells and mobi-
lization of neutrophils. Exosomes released under hypoxic
conditions can stimulate angiogenesis through interactions
with endothelial cells.
Exosomal transforming growth factor β (TGFβ) can
induce differentiation of fibroblasts into tumor-supporting
myofibroblasts and exosomes from ovarian cancer are
able to convert adipose-derived mesenchymal stem cells
into myofibroblast-like cells, supporting tumor growth and
angiogenesis.36,41
As exosomes can transfer specific proteins and nucleic
acids to recipient cells in the tumor microenvironment or at
specific distant sites, cancers have used exosomes as a tool
by which cancer cells can transfer malignant phenotype to
normal cells and establish a fertile local and distant micro-
environment to help cancer cell growth. Exosomes con-
tribute to tumor metastasis by enhancing tumor cell
migration and invasion, remodeling the extracellular matrix
and establishing premetastatic niche.36,41–43
CONCLUSIONS
A better understanding of the mechanisms of meta-
static disease in recent years seems to support the seed and
soil theory proposed by Steven Pagets almost 130 years ago.
Preventing metastasis in high-risk patients would be far
better than having to treat it later. Recent recognition of the
concept of the premetastatic niche allows researchers to
consider several new possibilities for treating cancer.44
Research on the mechanisms that control and support
the viability of latent metastatic cells should yield clues for
targeting cancer with the goal of preventing metastasis.
Factors from the primary tumor that structurally alter the
secondary organ to facilitate its colonization by tumor cells
could also potentially be targeted to stop metastasis. Rec-
ognition of the role of exosomes in tumor progression is also
an important potential target for early detection of cancer
and prevention of premetastatic niche formation.
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