3.

5
Invasion and Metastasis

Summary
>>Metastasis results from the spread of
tumour cells from their original location
organ sites and form secondary tumours, called
metastases. Second, the tumour cells that are
capable of spreading have acquired special
properties that make them more resistant to
treatments and to destruction by the immune
system. Therefore, detection of distant spread
trate into healthy areas and cross vessel barri-
ers to enter the lymphatic or blood circulation.
Loco-regional invasion is in itself a factor of poor
prognosis, but not as poor as distant metastases.
A locally invasive (N1) tumour would normally
not be counted as metastatic disease. It may
cancer, several lines of cancer cell development
may exist. Most cells may develop in a certain
direction, which preserve traits of the general
architecture of the tissue where they arise. These
cells contribute to the growing local tumour
access to the liver. Invasion usually starts in the
first array of capillaries encountered within the
tumour or in the immediate tumour neighbour-
hood. Invasion also develops in the first lymph
nodes encountered as cancer cells leave their
(the seed) have an affinity for certain organs
(the soil) [5]. For example, breast cancer cells
that have a physiological need for calcium
selectively metastasise to bone because they
can use it as an abundant source of calcium.
to other organ sites; metastatic disease is and metastases is often an indicator of poor remain treatable using the same protocols as mass. Other cells may assume different shapes tissue of origin. Metastatic cells can hop from In general, cancer cells tend to metastasise to
the main cause of death from cancer prognosis for the patient. This is reflected in the non-metastatic, localised lesions, without the and roles and undergo morphological transi- node to node through lymphatic channels and organs where blood and energy supplies are
TNM classification system, which provides a need for extended whole-body treatments. tions that allow them to cross barriers and invade accumulate into draining nodes, from where abundant (such as liver or lung) or that are sep-
>>The organ distribution of metastases universal, simple system to describe the ana- other organs. These are the metastatic cells [2]. they can flow into efferent lymph nodes towards arated from the immune system by a physical
depends upon the type and location tomic extent of a cancer (Table 3.5.1). For a long time, metastatic disease has been It follows that metastatic cells can occur even in many organs. Lymphatic channels may present barrier (such as the brain).
of the primary tumour and the route of considered as the ultimate step in cancer pro- very small, apparently “early” cancer lesions. This less of a challenge to tumour cell entry than
dissemination of metastatic cells. The term “metastasis” comes from the combina- gression. It was thought that the most trans- may explain why over 10% of patients presenting capillaries because of their scanty basement Detecting these metastases is a major challenge,
tion of two Greek words, “meta”, meaning “next” formed cancer cells acquire the capacity to to oncology clinics may have metastases without membrane. The propensity of a tumour cell to as it is virtually impossible to explore all possible
>>The formation of metastasis involves a
or “beyond”, and “stasis”, meaning “location” or become independent from their organ of origin, an identified primary tumour. These patients are invade lymphatic vessels or through capillaries organ locations in sufficient detail. Advances in
series of steps during which cancer cells
“position”. A metastasis is therefore a misplaced to invade other organs, to travel in the body said to have Cancer of Unknown Primary origin depends upon its ability to adhere to specific medical imaging techniques are making it possi-
leave the original tumour, enter lymph or
lesion, a lesion that has changed position. The and to form colonies. This view is challenged by (CUP) or Unknown Primary Tumours (UPT) [3]. structures, such as reticular fibres in the subcap- ble to locate lesions of very small size, thus lower-
blood circulation, survive and migrate,
term “invasion” refers to the process by which recent discoveries on cancer stem cells, which In these patients, the primary tumour may be so sular sinus of draining nodes or endothelial cells ing the threshold for detection of metastases [6].
and colonize distant organs; this complex
a tumour can form metastases: it consists of a are capable of self-renewal and also of generat- small that it is not detectable even using sophisti- that line blood vessels. Interactions with these Current research is also focussing on detecting
process is driven by genetic and epige-
series of steps by which growing tumours disturb ing daughter cells that evolve into different cell cated methods. Yet these occult primary tumours structures are dependent upon the types of single, disseminating cancer cells in lymphatic
netic changes.
the architecture of the tissue where they arise, shapes and phenotypes depending upon inter- can be the site of formation of cells with a high adhesion molecules expressed by tumour cells, or blood vessels, and on identifying patterns
>>Metastasis may develop from a small take the space and place of normal cells, infil- actions with their environment [1]. Thus, in a given capacity to spread to other organs and form in particular the integrins. of gene expression in primary tumours that may
number of “cancer stem cells” which can aggressive colonies. predict their propensity to form metastases.
change shape and properties to dissemi- The distribution of metastases is not only a
nate into the organism and adapt to the T = primary tumour Organ preference of metastases matter of route of dissemination. The most Molecular biology of metastasis
conditions of different organs common places for the metastases to develop
TX Primary tumour cannot be assessed The organ distribution of metastases depends are the liver, the brain, the bones, the lung and The metastasic process consists of a series of
>>Treatment of metastasis often combines T0 No evidence of primary tumour upon the type and location of the primary the adrenal glands. There is a propensity for steps during which cancer cells leave the origi-
local therapy aimed at removing or Tis Carcinoma in situ tumour (Table 3.5.2) [4]. In many instances, it certain tumours to seed in particular organs. nal tumour site, enter lymph or blood circulation
neutralising the metastases, and systemic T1 Tumour invades submucosa is determined by the route of dissemination of This was first recognised by Stephen Paget in (a process called intravasasion), survive and
therapy aimed at destroying micrometas- T2 Tumour invades muscularis propria metastatic cells. For example, sarcomas tend 1889, based on his observation from autopsies migrate, and extravasate to colonise distant
tases as well as preventing the formation T3 Tumour invades through muscularis propria into subserosa or into non- to metastasise to lungs because of the venous of 700 women who died from metastatic breast organs. This complex process implies that can-
of additional ones peritonealized pericolic or perirectal tissues drainage of muscles; colon carcinoma cells cancer. He formulated the “seed and soil” didate metastatic cells acquire many properties
T4 Tumour directly invades other organs or structures and/or enter the portal circulation thereby gaining hypothesis, proposing that specific cancer cells through genetic or epigenetic changes [7, 8].
perforates visceral peritoneum
On the basis of their level of participation in the
metastatic process, Nguyen and Massagué
N = regional lymph have distinguished three general classes of
nodes
Primary tumour Site of metastasis
The ability of tumour cells to spread from their metastasis genes: metastasis initiation, metasta-
original location to invade and colonise distant NX Regional lymph nodes cannot be assessed Bronchial cancer Adrenal (often bilateral) sis progression, and metastasis virulence (Figure
organ sites is the main feature that distinguishes N0 No regional lymph node metastasis Breast ductal carcinoma Liver 3.5.1) [9]. Metastasis initiation genes are those
benign from malignant cancers. Metastatic N1 Metastasis in 1 to 3 regional lymph nodes Breast lobular carcinoma Diffuse peritoneal seeding that provide an advantage in primary tumours,
disease is also the major cause of death from N2 Metastasis in 4 or more regional lymph nodes paving the way for tumour cells to enter the
Breast Bone, ovary
cancer. As long as the tumour remains confined circulation. Metastasis progression genes are
M = distant
to one specific location, it remains curable pro- Lung Brain those that fulfil certain rate-limiting functions
metastasis
vided it can be removed surgically and that the Ocular melanoma Liver in primary tumour growth, and other specific
tumour does not irreversibly destroy the function MX Distant metastasis cannot be assessed functions in metastatic colonisation. Metastasis
M0 No distant metastasis Prostate Bone
of a vital organ. Once tumour cells start to spread virulence genes are those that provide a selec-
into the organism, however, they become more M1 Distant metastasis Melanoma Brain tive advantage in secondary sites but not in
difficult to control. First, they may reach distant Table 3.5.1 TNM classification of cancer of the colon and rectum Table 3.5.2 Site of metastasis of common cancers the primary tumour, thus participating in meta-

224 - Section 3 - Mechanisms of Carcinogenesis Chapter 3.5: Invasion and Metastasis - 225
 Adhesion. Epithelial cells are normally polarised being sheared and ripped away by movements and morphogenesis, and their activities are tightly the blood vessels that is typical of many cancers.
and attached to each other via different types of the ECM. Many differences in integrin expres- regulated. Activation depends upon cleavage of Intravasation is also enhanced by an epithelial-
of cell-to-cell junctions, such as tight junctions, sion between benign and malignant cells have the leader domain and is regulated by endog- to-mesenchymal transition that confers to carci-
adherens junctions and desmosomes, as well as been documented. They allow cells to develop enous MMP inhibitors, which include a-2 macro- noma cells plasticity and added motility similar
through intercellular adhesion molecules such as different binding and adhesion properties, ena- globulin and tissue inhibitors of metalloprotein- to embryonic cells [19,20]. Although the rate
E-Cadherin. Initiation of metastasis requires releas- bling them to detach from their original support ases (TIMPs). An imbalance between MMPs and of malignant cell shedding in the bloodstream
ing cells from cell-to-cell contacts that keep them and to seek novel adhesion points on ECM naturally occurring MMP inhibitors may cause an generally increases with tumour size and grade,
into their proper place in the epithelium. Thus, components as well as on cells lining blood or excess of extracellular matrix destruction, allow- dissemination can occur from the early stages of
cancer cells usually demonstrate multiple changes lymphatic vessels. ing cancer cells to invade surrounding tissues and the primary tumour. Only a minute proportion of
in the expression of cell adhesion components metastasise. Two of the most studies MMPs are cells that enter blood vessels or lymphatics will
[13]. E-Cadherin, in particular, is a frequent target Other cell adhesion molecules implicated in MMP-2 and -9 (gelatinase A and B, respectvely). ultimately generate metastases. Indeed, dissemi-
for genetic or epigenetic alterations that down- cancer progression and metastasis include There is clear evidence for increased levels of nating cells are faced with multiple challenges.
regulate its function, which may be considered members of the immunoglobulin supergene active forms of MMP-2 and/or 9 in bladder, Among those, the most significant ones are the
as a tumour suppressor gene. First, its constitutive family such as ICAM-1, ICAM-22, VECAM and breast, colon, protaste, lung, oesophageal and capacity to escape cell death due to the detach-
mutation predisposes to some forms of cancer PECAM. The latter are upregulated on activated gastric cancer tissues. This increased expression ment of their support (a process called “anoikis”,
(such as gastric cancer) and its re-introduction endothelial cells, and can interact with integrins can take place in cancer cells and/or in surround- from the Greek word “oikos”, meaning “home”,
in metastatic cancer cells quench their invasive on leucocytes or circulating tumour cells to facili- ing normal stromal cells, indicating that cancer preceded by the negative Greek prefix alpha),
potential. Secondly, it interacts with beta-Catenin, tate their extravasation. CD44 is an adhesion cells can somehow induce stromal cells to secrete to escape recognition and destruction by the
an important oncogene, and provides a signal- molecule normally present both at the surface of factors that facilitate migration, invasion and, immune system and to recruit partners that facili-
ling connection between structural cell adhesion epithelial cells and of lymphocytes. On normal ultimately, metastasis. Urokinase plasminogen tate their circulation and extravasation, including
and cell proliferation. Loss of E-Cadherin frees cells, however, CD44 is expressed as different activator (uPA) is also frequently upregulated in in particular the formation of partner aggregates
beta-Catenin from its anchor at the cell membrane splicing variants in both cell types. A change in cancer. It controls the synthesis of plasmin, which [21]. Adhesion molecules that mediate attach-
and makes it available for translocation into the splicing patterns from “epithelial-type” to “hae- degrades laminin and also activates gelatinases. ment to capillary walls play a critical role in the
nucleus, where it can activate transcription factors matopoietic-type” may assist in carcinoma cell Thus, upregulation of these enzymes in cancer dissemination process.
involved in stimulating cell proliferation. dissemination by providing recognition signals can lead to proteolytic cascades that degrade
Fig. 3.5.1 A general view of the sequence of biological events involved in the formation of metastases [9] that lymphocytes normally use during their homing the basement membranes and components of the Numerous innate and adaptive immune effector
Epithelial cells entertain contacts with the basal to specific tissues [15,16]. Thrombospondin medi- stroma [18]. cells and molecules participate in the recogni-
membranes and with the ECM through many ates adhesion between circulating tumour cells, tion and destruction of cancer cells, a process
static colonization but not in primary tumour Metastasis initiation. Acquisition of metas- other classes of molecules. Among them, platelet and endothelial cells, promoting emboli- Besides their direct role in degrading ECM com- that is known as cancer immunosurveillance.
development. However, before becoming tastatic potential requires that candidate cells integrins deserve special mention as changes in sation (vessel obstruction). This induces endothe- ponents, MMPs are also indirectly involved in Disseminating cancer cells avoid immunosurveil-
candidates to metastasis, malignant cells must break away from the primary tumour and their expression patterns may have a profound lial cells to retract, exposing the vessel’s basement promoting metastasis through their roles in ang- lance through many mechanims that can classi-
fulfil a number of tumorigenic conditions (see attach to and degrade the protein structures influence on enabling cancer cells to adapt to membrane and providing tumour cells an access iogenesis. The formation of capillary sprouts is fied into two broad categories: the outgrowth of
Molecular hallmarks of cancer, Chapter 3.1): that make up the surrounding extracellular changes in their micro-environment, a pre-req- for adhering to exposed proteins [17]. a physiological process that requires localised poorly immunogenic tumour-cell variants (immu-
they must be capable of unlimited proliferation, matrix (ECM). Most solid tumours arise from uisite for successful migration. Integrins are cell proteolysis of the stroma (mediated in part by noselection) and the subversion of the immune
of evasion from the environmental constraints of epithelial cells that are normally bounded by surface receptors that mediate a dual, signalling Matrix dissolution. Invasive cancer cells show MMP-2 and MMP-9 in addition to uPA). MMP-9 system (immunosubversion). The former category
their tissue of origin, and of attracting a blood basement membranes which separate them and adhesion function [14]. Among the ligands increased expression of many enzymes, as well plays a role in the “angiogenic switch” that occurs include a series of mechanisms by which dissemi-
supply through the formation of new capillaries from the underlying stroma and mesenchymal of integrins are fibronectin, vitronectin, collagen, as decreased expression of their regulators, during cancer progression by releasing VEGF by nating cancer cells conceal or down-regulate
and blood vessels, a process called angiogen- compartments. Breaching the basement mem- and laminin. Integrins are heterodimeric proteins involved in the degradation of components of sequestration in the ECM. Furthermore, these antigens and recognition molecule complexes at
esis [10]. As tumours grow, they must adapt and brane is the first step in the transition from in containing two distinct chains, α (alpha) and β the ECM, thus physically opening up breaches proteases also contribute to sustained tumour their surface. The latter category include the pro-
respond to environmental pressures such as situ carcinoma to invasive, potentially meta- (beta). In mammals, 19 γ and 8 β subunits have that facilitate cancer cell dissemination [8]. One growth by the ectodomain cleavage of mem- duction of sets of cytokines that down-regulate
those exerted by the immune response, the low- static cancer [12]. The basement membrane is been characterised. Through different combina- important group of such enzymes is the matrix brane-bound pro-forms of growth factors, and immune responses and the stimulation of regula-
ering oxygen tension and the increased acidic composed of a complex of structural proteins tions of alpha and beta subunits, about 24 unique metalloproteinases (MMP). The MMP family con- the release of peptides which are mitogenic and tory T-cells that induce a form of immune toler-
environment [11]. Such capacities are acquired including Collagen IV (the major component), integrins can be generated. The molecular mass tains a diverse group of enzymes with different chemotactic for cancer cells. ance towards cancer cells. Metastasis appears
during tumour initiation and local development, laminin, entactin, and heparan sulfate pro- of the integrin subunits can vary from 90 to 160 substrate preference (collagenase, gelatinase, to correlate with changes in the immunogenic
but must remain active throughout the develop- teoglycans. Interactions of tumour cells with kDa, with the intracellular domain representing stromelysin, proenzyme). All family members com- Metastatic dissemination. Dissemination starts properties of tumour cells.
ment of metastatic disease, since they are criti- basement membranes and ECM components only a minor part (40 to 70 amino-acids). Integrins prise a leader domain, a propeptide domain and when aggressive tumour cells enter the blood-
cal for cancer cells to survive during their spread comprise two critical phase phases: adhesion couple the ECM outside the cell to the intracellu- a highly conserved catalytic domain containing stream through the newly formed vasculature that Metastatic colonisation. The process by which
into the organism and during the development and matrix dissolution. lar cytoskeleton. This bond ensures that the cell a zinc atom involved in substrate binding. They they have attracted. This process is facilitated by disseminating cancer cells leave the bloodstream
distant colonies. can tightly adhere to ECM components without play important roles during normal development the particular, incomplete and leaky structure of to enter the parenchyma of another organ is

226 - Section 3 - Mechanisms of Carcinogenesis Chapter 3.5: Invasion and Metastasis - 227
termed extravasation. Metastatic cells extrava- mesoderm. In this process, epithelial cells acquire follows from this model that two critical character-
sate by breaching the capillaries in which they are fibroblast-like properties, show reduced adhe- istics of mobile cancer stem cells are the cyclical WEBSITES
embedded, either by vascular-remodelling events sion to ECM and increased mobility, exactly like activation and inhibition of expression of genes
that allow migration across the capillary wall or metastatic cancer cells. involved in EMT, as well as the capacity to recruit How cancer grows and spreads: An interactive,
as a result of mechanical disruption of capillar- normal, non-cancer cells to become essential animated presentation that shows how cancer
ies by expanding tumour emboli. On entry into EMT is essential for many morphogenetic events partners in the metastatic process. progresses through the 14 stages of a typical
another organ, tumour cells are confronted with such as organogenesis, wound healing, tissue cancer. http://www.childrenshospital.org/
a different microenvironment in which they must remodelling and heart development. A landmark Treatment of metastatic cancer research/_cancer/index.html
survive, develop, and eventually expand in the of EMT is the loss of E-Cadherin expression, a
same way as they did in their organ of origin. To phenomenon that is common in many epithe- The presence, number and organ location of Metacancer: resources and support for meta-
help them in the process of establishing a new lial tumours. However, E-Cadherin expression metastases are critical parameters in select- static cancer survivors and their caregivers.
“home” in their adoptive tissue, cancer cells recruit remains detectable in many invasive tumours, ing appropriate therapeutic methods. In most http://www.metacancer.org/index.php
bone-marrow-derived progenitor cells and other raising questions about the whether EMT is a instances treatment will consist of a combination
local cells that provide a permissive “niche” for general phenomenon in advanced cancer, or of local therapy aimed at removing or neutralising
metastasis [22]. Once metastatic cells are estab- a property assumed only by a limited number of the metastases, and systemic therapy aimed at
lished, active colonisation proceeds through the cells. This paradox has been largely resolved by destroying micrometastases as well as preventing
recruitment of organ-specific components of the the observation that, in cancer, EMT could gener- the formation of additional ones [25] [26]. The
tumour microenvironment, such as the activa- ate cells with properties of stem cells, including main local treatments are surgery and radiosur-
tion of bone-resorbing osteoclasts by breast in particular self-renewal through asymetric divi- gery (that is, the use of 3-dimensional radiation
cancer cells during osteolytic metastasis [23]. Full sion. In normal tissues, stem cells are present only treatment to deliver high radiation doses in a very
metastatic colonisation can occur by immediate in proliferative areas such as the basal layer of delimited area of the body). Systemic treatments
growth of cancer cells upon their extravasation, squamous mucosa or crypts of glandular mucosa. include chemotherapy and radiation therapy
or after a prolonged period of micrometastatic Such stem cells become embedded within small, (which are active against both primary and met-
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(SCSC) [2]. These SCS are, to a large extent, when appropriate, hormone therapy. Biological
Epidermal-mesenchyme transition responsible for sustained production of daughter therapies may use monoclonal antibodies that
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