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

Overview
What is metastasis?
Molecular mechanisms of metastasis
Signalling pathways involved in
metastasis

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

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

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

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

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 or 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.

2.

3.

Translocation of cells across

extracellular matrix barriers
Lysis of matrix protein by specific
proteinases
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.

2.

Integrin: cell-matrix adhesion

E-cadherin/catenin adhesion
complex: cell-cell adhesion

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1) Integrin

Heterodimeric transmembrane
receptors consists of and 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 and 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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