journal reading brain metastasis

8/16/2019 Journal Reading Brain Metastasis

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Review Article*

THE MOLECULAR BIOLOGY OFBRAIN METASTASIS

Oleh : dr. Heldrian D. Suyuthie

*Hindawi Publishing Corporation

Journal of Oncology

Volume 2012 !rticle "# $2%&'1 1( pages

doi)1011&&+2012+$2%&'1

Gazanfar Rahmathulla,1, 2 Steven A. Toms, and Ro!ert ".#eil1, 2

,ecei-ed 20 October 2011. !ccepted 2& /o-ember 2011


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1. Introduction

Brain metastases are the most frequentlydiagnosed intracranial neoplasms in adults

Annual incidence estimated at 200,000

cases in the USA alone 10 times greater than primary brain

tumors

Up to 20–40 of patients !ith systemicmalignancies !ill de"elop Brain

about 10–20 !ill be symptomatic


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#n"asi"e screeningparado$ically escalating

incidence and pre"alence% A "ariety of systemic

malignancies can metastasi&e

to the central ner"oussystem'()S*

+aority of the lesions come

from- lung cancer '40–.0

breast cancer '20–/0*,

melanoma '.–10*,


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+ost Br+s occur corresponding to"ascular distribution and tissue

"olumes (erebral hemispheres '0*

(erebellum '1.* and

Brainstem '.*,

Br+s are a maor cause ofmorbidity and mortality

(linical features of the metastasis

corresponding to the location resenting !ith nonspeci3c central

ner"ous system features headache, cogniti"e impairment,

and sei&ures


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5he central ner"ous system'()S* acts as a 6safe ha"en7

Beyond the reach of nearly allchemotherapeutic agents%

5he blood brain barrier 'BBB*

pre"ents the entry of mostchemotherapeutic agents,

the brain can act as a refuge

for metastatic tumors 5he microen"ironment of the

()S is e$ceptional


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Formation of mta!tatic tumor


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". T# Mta!tatic $roc!!

+etastatic rocess

+igration (oloni&ation


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T# Mta!tatic $roc!!


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2.1. Migration

Cellular Heterogeneity andProliferation

Epithelial-Mesenchymal Transition(EMT)

Interactions with Tumor Stroma

ocal In!asion

E-Cadherin-Catenin Comple" (ECCC)#Integrins# and $ther Molecules

%enetic &lterations


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Cellular Heterogeneity and Proliferation

5he primary tumor are geneticallyheterogeneous and ha"e "aryingpotentials to metastasi&e%

cell8s ability to in"ade adacent tissues,initiate 'neo9* angiogenesis, disseminate,and adhere to ne! tissue substrates, !hilee$pressing an a:nity for the ()S

circum"ent inhibitors of cell proliferationsuch as cell cycle chec;point and


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Epithelial-Meenchy!al"ranition #EM"$

re"ersible phenomenon !herein cells candedi=erentiate, migrate to a distant focus,and then redi=erentiate bac; to their

original cell, forming a ne! structure Signals acti"ating the >+5 can be intrinsic

and e$trinsic

5ransdi=erentiation appears to be initiatedby release of certain >+59inducingtranscription factors '>+595?s* thattransform epithelial cells into

mesenchymal deri"ati"es, gi"ing thesecells the ca acit to in"ade resist


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%nteraction with "u!or&tro!a.

rogression in cancer also in"ol"esacti"ating a number of cells in theadacent stroma "ia paracrine signaling

5hese stromal cells, including endothelialcells, pericytes, 3broblasts, andleu;ocytes, pro"ide a number ofprotumorigenic factors !hich sustain

tumor gro!th


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'ocal %nvaion.

5umor e$pansion causes adacent >(+compression and modi3es lymphatic andblood "essel @o!, e"entually leading to

basement membrane 'B+* thinning% (ombined !ith the "arious molecular and

cellular e"ents, this leads to e"entualtumor metastasis

5o reach the circulation, tumor cells mustpenetrate the B+, tra"erse thee$tracellular connecti"e tissue matri$

'>(+* tissue, and then breach the "ascularbasement membrane B+ to enter the


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E-Cadherin-Catenin Co!ple( #ECCC$)%ntegrin) and ther Molecule

#n the process of tumor metastasis, tumorclones become discohesi"e, fail to adhereto one another, and de"elop a more

disordered cytoarchitecture, !hich allo!sthese cells to separate from the tumormass%

5he ability of tumor cells to escape the

primary site is dependent on their abilityto remodel the >(+


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+enetic Alteration

Se"eral ;no!n tumor suppressor genes'5Ss* that function at the le"el of escapeand migrationCintra"asation

enetic acti"ation or inacti"ation ofpromoterCsuppressor genes in humancancer can be the result of mutations,deletions, loss of hetero&ygosity,

multiplication, and translocation


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,ie!ination

tumor cell must sur"i"e its e$posure to high shear forcesand "aried stress patterns

5umor cells respond by reenforcing their cytos;eleton andincreasing the ability to adhere to the "ascular !all

Dn adhering to endothelium of target tissue, the tumor cellsbeha"e li;e macrophages, creating pseudopodia, andpenetrating the cell9cell unctions, dri"en by dynamicremodeling of the cellular cytos;eleton


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Coloniation

$rgan-Specic Inltration

The # *unction of the rainMicroen!ironment#and rain Metastasis

+eoangiogenesis and Proliferation Cascade-+onspecic Contri,utors to

Metastasis

$!er!iew of micro+&s (mi+&s) andTheir Emerging ole in $ncogenesis.


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Cancr C%%! In&ad


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rgan-&pecic %nltration

5he metastatic deposits occur in certainorgan tissues because of the in@uence ofhematogenous dynamics

5he o"ere$pression of the cell adhesionmolecule, metadherin, in breast cancerma;es it easier for tumor cells to targetand adhere to endothelial lining in the lung

parenchyma >$act causes of preferential metastatic

sites ha"e not been clearly elucidated


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"he ///) 0unction of the /rainMicroenviron!ent) and /rainMetatai

assage of tumor cells across the BBBoccurs "ia mechanisms !hich ha"e not yetbeen delineated fully

three proteins that mediate breastmetastasis to the brain and lungs ha"ebeen described

(ycloo$ygenase 2 or (DE2 'also ;no!nas 5S2*,

>?F,

Gigand and heparin binding epidermal

gro!th factor 'HB>?*


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eoangiogenei andProliferation

A ;ey component of both primary andsecondary 'metastatic* tumor gro!th atany site is angiogenesis

arious angiogenic factors ha"e beenscrutini&ed as "iable targets for treatment%

ascular endothelia gro!th factor '>?*is the most commonly recogni&edangiogenic factor%


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Cacade-onpecicContriutor to Metatai

5here are certain molecular contributionsthat cannot be attributed to a speci3c stepin the cascade, either because they are

acti"e at e"ery le"el or, as in most cases,their true function is yet to be disco"ered

Se"eral other genetic mar;ers ha"e beenlocated that pertain to metastasis in

particular these genes may be used to predict a high

ris; of metastasis early in the diagnosis


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verview of !icroRA #!iRA$ and"heir E!ergingRole in ncogenei

5he dysregulated e$pression of a singlemiF)A can cause a cascade of silencinge"ents capable of eliciting disease

de"elopment in humans, !hich includescancer


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Conc%u!ion

5he metastatic cascade, from its initiationto its completion in the brain, is ane$tremely comple$, multistep process%

As more e"idence regarding the molecularand genetic factors that contribute to thecascade appears, targeting this ominousdisease !ith multiple therapeutic

strategies comes closer% Ino!ledge of the metastatic process may

lead to better detection and treatment of

brain metastases%


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TERIMA'AS

IH

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