Molecular mechanism of cancer metastasis.ppt

7/24/2019 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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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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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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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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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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+-ca"herin an" Rho $Pase signaling


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Rho $Pase at "ifferent stages oftumour progression


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& Motility promoting factors

epatocyte gro/th factorBscatteringfactor

4nsulin-like gro/th factor 44

:utota;in


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!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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! in"uce the formation ofranche" tuules


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2ignalling path/ays responsile forM+$-"epen"ent inasie gro/th


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!BMet regulate integrin ca"herinan" MMPs "uring inasion

Molecular mechanism of cancer metastasis.ppt

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