Molecular mechanism of
cancer metastasis
Dr. Yick-Pang Ching
Department of Pathology
Room L7-05, Faculty Medicine Building
Tel: 28199656
E.Mail: ypching@hkucc.hku.h
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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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Forms of cancer metastasis
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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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II) Molecular mechanisms of metastasis
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5 major steps in metastasis
1. Invasion and infiltration of surrounding normal
host tissue with penetration of small lymphatic
or vascular channels;
2. Release of neoplastic cells, either or single cells
or small clumps, into the circulation;
3. Survival in the circulation;
4. Arrest in the capillary beds of distant organs;
5. 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-, cysteine-,
aspartyl-, and metalloproteinase.
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MMP family
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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
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
Stimuli
Cdc42
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
MET-dependent invasive growth
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HGF/Met regulate integrin,
cadherin and MMPs during invasion
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