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Overview
What is metastasis?
Molecular mechanisms of metastasis
Signalling pathways involved in metastasis
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I) What is cancer metastasis?
 Cancer defines as a population of cells that have
lost their normal controls of growth and
differentiation and are proliferating without check.
 Metastasis is the process by which a tumor cell
leaves the primary tumor, travels to a distant site
via the circulatory system, and establishes a
secondary tumor.
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Preferential metastatic sites
Primary tumour
Common distant site (s)
Breast’ adenocarcinoma
Bone, brain, adrenal
Prostate adenocarcinoma
Bone
Lung small cell carcinoma
Bone, brain, liver
Skin cutaneous melanoma
Brain, liver, Bowel
Thyroid adenocarcinoma
Bone
Kidney clear cell carcinoma
Bone, liver, thyroid
Testis carcinoma
Liver
Bladder carcinoma
Brain
Neuroblastoma
Liver, adrenal
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Reason for organ selectivity
Mechanistic theory: determined by the pattern of blood
flow.
“Seed and soil” theory: the provision of a fertile
environment in which compatible tumor cells could
grow.
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Determining factors
 Appropriate growth factors or extracellular matrix
environment.
 Compatible adhesion sites on the endothelial
lumenal surface.
 Selective chemotaxis at which the organ producing
some soluble attraction factors to the tumor cells.
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5 major steps in metastasis
1.
2.
3.
4.
5.
Invasion and infiltration of surrounding normal host
tissue with penetration of small lymphatic or vascular
channels;
Release of neoplastic cells, either single cells or small
clumps, into the circulation;
Survival in the circulation;
Arrest in the capillary beds of distant organs;
Penetration of the lymphatic or blood vessel walls
followed by growth of the disseminated tumor cells.
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Stages of metastasis
 Invasion : primary tumour cells enter circulation.
 Circulation to the secondary site of tumour growth.
 Colonisation : formation of secondary tumour.
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Tumor invasion
1.
Translocation of cells across extracellular matrix
barriers.
2.
Lysis of matrix protein by specific proteinases.
3.
Cell migration.
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Components of invasion
a) Matrix degrading enzymes
b) Cell adhesion
c) Cell motility
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a) Matrix degrading enzymes
 Required for a controlled degradation of components
of the extracellular matrix (ECM).
 The proteases involved in this process are classified
into
serine-,
metalloproteinase.
cysteine-,
aspartyl-,
and
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Matrix metalloproteinases (MMP)
 16 members, subdivided into 4 groups, based
on their structural characteristics and substrate
specificities.
 Soluble and secreted groups; collagenase,
gelatinase and stromelysins.
 Membrane type (MT-MMP) group are anchored
in the plasma membrane.
 A zinc ion in the active centre of the protease is
required for their catalytic activities.
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Regulation of MMP
 MMP is controlled by an increased expression on a
transcriptional level.
 MMPs are calcium-dependent proteases, which are
synthesized as a inactive proenzymes and are activated
by the cleavage of a propeptide.
 MMP activity is regulated by specific inhibitors, the tissue
inhibitors of MMP (TIMPs). Binding TIMP to MMP is in a
1:1 stoichiometry.
 MMP2 and MMP9, which cleave type IV collagen the major
constituent of basement membrane, are believed to be of
special importance.
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Serine proteases
 Serine protease involved in ECM degradation are
plasmin, plasminogen activators and cathepsin G.
 Plasmin is believed to be the most important serine
protease, firstly because its ability to degrade several
matrix components like gelatin, fibronectin or laminin,
and secondly by the possible activation of numerous
proforms of MMPs by propeptide cleavage.
 Plasmin is synthesized in its inactive proform,
plasminogen, which can be converted to plasmin by
plasminogen activator.
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Plasminogen activator
 Two main types : urokinase (uPA) and tissue (tPA).
 uPA is bound to the surface of tumor cells by means of
a specific receptor (uPAR).
 There are specific inhibitors (PAI-1 and PAI-2) for the
PA.
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Interaction between tumour cells and the
surrounding connective tissue
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Cell adhesion and metastasis
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b) Cell attachment (Adhesion)
1.
Integrin: cell-matrix adhesion.
2.
E-cadherin/catenin adhesion complex: cell-cell
adhesion.
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1) Integrin
 Heterodimeric transmembrane receptors consists of a
and b subunits.
 Function to provide interactions between cells and
macromolecules in the ECM.
 Integrin can affect the transcription of MMP genes.
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Integrin signaling
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2) E-cadherin and catenin complex
 Most important cell-cell adhesion molecules.
 Reduce expression of E-cadherin and catenin
increase the invasiveness of tumor cells
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Cadherin-mediated cell-cell adhesion
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p120 catenin
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c) Cell migration
1.
Small Rho GTPase family
2.
Motility promoting factors
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Small Rho GTPase
Cdc42
Stimuli
Rac1
GTP
GTP
Pak1
MLC Kinase
LIM kinase
Stress fibers
MLC Phosphorylation Cofilin
Contraction
Filopodia
Actin polymerisation
Detachment
Lamellipodia
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Model of Rho GTPase regulation
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Regulation of Rho GTPase
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Cell movement
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Rho GTPase is required for the transition
of invasive phenotype
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Signaling pathways related to integrin and
small GTPase
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E-cadherin and Rho GTPase signaling
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Rho GTPase at different stages of tumour
progression
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2) Motility promoting factors
 Hepatocyte growth factor/scattering factor
 Insulin-like growth factor II
 Autotaxin
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HGF/scatting factor
 Heterodimer of a and b chains
 HGF normally acts as a paracrine growth factor, but in
tumor cells it can act as an autocrine
 HGF binds to the c-Met receptor and activated the
downstream effectors
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HGF induce cell scattering and invasion
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HGF induce the formation of branched tubules
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Signalling pathways responsible for METdependent invasive growth
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HGF/Met regulate integrin, cadherin and
MMPs during invasion
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