molecular mechanism of cancer metastasis.ppt
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Molecular mechanism ofcancer metastasis
Dr. Yick-Pang ChingDepartment of Pathology
Room L7-05 !aculty Me"icine #uil"ing
$el% &'())*5*
+.Mail% ypching,hkucc.hku.h
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erie/
hat is metastasis1
Molecular mechanisms of metastasis
2ignalling path/ays inole" in
metastasis
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4 hat is cancer metastasis1
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 adistant site via the circulatory system, and
establishes a secondary tumor.
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!orms of cancer metastasis
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Preferential metastatic sites
Primary tumour Common distant site (s)Breast adenocarcinoma Bone, brain, adrenal
Prostate adenocarcinoma Bone
!ung small cell carcinoma Bone, brain, liver
"kin cutaneous melanoma Brain, liver, Bowel
#hyroid adenocarcinoma Bone
$idney clear cell carcinoma Bone, liver, thyroid
#estis carcinoma !iver
Bladder carcinoma Brain
%euroblastoma !iver, adrenal
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Reason for organ selectiity
Mechanistic theory%"etermine" y thepattern of loo" flo/.
82ee" an" soil9 theory%the proision ofa fertile enironment in /hichcompatile tumor cells coul" gro/
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Determining factors
:ppropriate gro/th factorsore;tracellular matri; enironment
Compatile a"hesion siteson theen"othelial lumenal surface
2electie chemota;isat /hich the
organ pro"ucing some soluleattraction factors to the tumor cells
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44 Molecular mechanisms of metastasis
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5 ma
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(0
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((
2tages of metastasis
4nasion % primary tumour cells entercirculation
Circulation to the secon"ary site oftumour gro/th
Colonisation% formation of secon"arytumour
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(&
$umor inasion
(. $ranslocation of cells acrosse;tracellular matri; arriers
&. Lysis of matri; protein y specificproteinases
3. Cell migration
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Components of inasion
a Matri; "egra"ing en>ymes
Cell a"hesion
c Cell motility
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a Matri; "egra"ing en>ymes
Re?uire" for a controlle" "egra"ationof components of the e;tracellularmatri; @+CM
$he proteases inole" in this processare classifie" into serine- cysteine-
aspartyl- an" metalloproteinase.
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MMP family
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Matri; metalloproteinases @MMP
&' members, subdivided into groups, based
on their structural characteristics and
substrate specificities
"oluble and secreted groups collagenase,
gelatinase and stromelysins
Membrane type (M#*MMP) group are
anchored in the plasma membrane + inc ion in the active centre of the protease
is re-uired for their catalytic activities.
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Regulation of MMP
MMP is controlled by an increased epression on atranscriptional level.
MMPs are calcium*dependent proteases, which aresynthesied as a inactive proenymes and areactivated by the cleavage of a propeptide.
MMP activity is regulated by specific inhibitors, thetissue inhibitors of MMP (#/MPs). Binding #/MP to MMPis in a &0& stoichiometry.
MMP& an" MMP) /hich cleae type 4A collagenthe ma
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2erine proteases
"erine protease involved in 1CM degradation areplasmin, plasminogen activators and cathepsin 2.
Plasmin is believed to be the most important serineprotease, firstly because its ability to degrade severalmatri components like gelatin, fibronectin or laminin,and secondly by the possible activation of numerousproforms of MMPs by propeptide cleavage.
Plasmin is synthesied in its inactive proform,plasminogen, which can be converted to plasmin byplasminogen activator.
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()
Plasminogen actiator
$/o main types % urokinase @uP: an"tissue @tP:.
uP: is oun" to the surface of tumorcells y means of a specific receptor@uP:R
$here are specific inhiitors @P:4-(
an" P:4-& for the P:.
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&0
4nteraction et/een tumour cells an"the surroun"ing connectie tissue
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Cell a"hesion an" metastasis
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Cell attachment
(. 4ntegrin% cell-matri; a"hesion
&. +-ca"herinBcatenin a"hesioncomple;% cell-cell a"hesion
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( 4ntegrin
etero"imeric transmemranereceptors consists of an" suunits
!unction to proi"e interactionset/een cells an" macromolecules inthe +CM
4ntegrin can affect the transcription of
MMP genes
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4ntegrin signaling
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& +-ca"herin an" catenin comple;
Most important cell-cell a"hesionmolecules
Re"uce e;pression of +-ca"herin an"catenin increase the inasieness oftumor cells
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&*
Ca"herin-me"iate" cell-cell a"hesion
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p(&0 catenin
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&'
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c Cell migration
(. 2mall Rho $Pase family
&. Motility promoting factors
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2mall Rho $PaseStimuli
Cdc42GTP
Rac1GTP
Pak1
!/M kinase
Cofilin
+ctin polymerisation
M!C $inase
M!C Phosphorylation
Contraction
"tress fibers
3etachment
Filopodia Lamellipodia
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3(
Mo"el of Rho $Pase regulation
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Regulation of Rho $Pase
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Cell moement
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4ho 2#Pase is re-uired for the transition
of invasive phenotype
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2ignaling path/ays relate" tointegrin an" small $Pase
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3*
+-ca"herin an" Rho $Pase signaling
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Rho $Pase at "ifferent stages oftumour progression
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3'
& Motility promoting factors
epatocyte gro/th factorBscatteringfactor
4nsulin-like gro/th factor 44
:utota;in
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3)
!Bscatting factor
etero"imer of an" chains
! normally acts as a paracrinegro/th factor ut in tumor cells itcan act as an autocrine
! in"s to the c-Met receptor an"actiate" the "o/nstream effectors
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! in"uce cell scattering an"inasion
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6(
! in"uce the formation ofranche" tuules
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6&
2ignalling path/ays responsile forM+$-"epen"ent inasie gro/th
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!BMet regulate integrin ca"herinan" MMPs "uring inasion
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