Post on 10-Nov-2014
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Molecular mechanism of cancer metastasis
Dr. Yick-Pang Ching Department of PathologyRoom L7-05, Faculty Medicine BuildingTel: 28199656E.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 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
Cdc42GTP
Rac1GTP
Pak1
LIM kinase
Cofilin
Actin polymerisation
MLC Kinase
MLC Phosphorylation
Contraction
Stress fibers
Detachment
Filopodia 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