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Bio2-Seminar

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REGULACIJA MIKROOKOLJA METASTAZ

MATEJA ZVER,

4. letnik kemije, smer biokemija in fizikalna kemija, študijsko leto 2010/2011

KAZALO
METASTAZE
INTERAKCIJE MED TUMORJEM IN STROMO NA PRIMARNEM MESTU ZDRAVO TKIVO V TELESU VLOGA STROMALNIH CELIC ZA RAZVOJ TUMORJEV KRONIČNO VNETJE IN VLOGA BMDC MAKROFAGI POVEZANI S TUMORJI MIKROOKOLJE METASTAZNIH MEST VLOGA PROTEAZ ZAKLJUČEK LITERATURA 3 3 3 3 4 4 5 6 6 8

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METASTAZE
Metastaze so večstopenjski proces, pri katerem rakave celice pobegnejo od primarnega tumorja, preživijo v obtoku ter se razširjajo na oddaljena mesta in rastejo. Vsaka od teh stopenj vsebuje korak, na katerega vplivajo zdrave celice mikrookolja tumorja. V članku opisujejo vlogo mikrookolja v metastazah, identificira območja za nadaljne raziskave ter predlaga nova možna področja zdravljenja. Različne stromalne celice v okolju so potrebne za pospeševanje rasti raka ter lažje razširjanje metastaz do drugih organov. Rakave celice spretno izkoriščajo predvsem mikrookolje tkiv. Vendar, ko le – te zapustijo ugodne pogoje za rast, morajo imeti lastnosti, ki jim bodo omogočale preživetje v novem okolju. Da se metastaze sploh pojavijo, morajo rakave celice preživeti v obtoku, prispeti morajo do tarčnega organa in pokazati stalno rast. Vsaka od stopenj je ali nepomembna ali pa odločilna. Staranje ali apoptoza rakavih celic, v stopnji vstopa v metastatično stanje, prepreči razširjenje večine celic v obtoku. Razširijo se lahko na več različnih organov, vendar metastazni tumorji lahko rastejo samo v nekaterih. Mikrookolje zavira malignost teh potencialno matestaznih celic. Če se te celice ponovno aktivirajo do klinično pomembne oblike, se to zgodi zaradi motenj v mikrookolju. Kljub temu sta velikost tumorja in razred glavna napovedovalca metastaz. To je bilo dodatno dokazano v študijah na mišjih modelih. Z analizo ekspresije genov so dokazali povezavo med velikostjo tumorja z metastazami, ki spodbujajo podpis genov. Uspešno razširjanje metastaz je odvisno od zmožnosti rakavih celic, da se ločijo od mikrookolja v vsakem koraku rasti metastaz. Kaskada metastaz je razdeljena v tri stopnje, in sicer primarni tumor, sistemski krvni obtok ter končno mesto metastaze.

INTERAKCIJE MED PRIMARNEM MESTU

TUMORJEM

IN

STROMO

NA

Tkiva vsebujejo številne celice, ki delujejo usklajeno. Te celice imajo opredeljen položaj in njihovo število je omejeno. Rakave celice izgubijo te lastnosti zaradi mutacij v onkogenih in tumorsko zaviralnih genih. Vendar te celice niso izgubile interakcije z okoljem ostalih celic. Te interakcije niso statične, se razvijajo skupaj s tumorjem, zlasti preko celic pridobljenih iz kostnega mozga (bone marrowderived cells – BMDCs). Mikrookolje ima lahko zaviralni učinek na najbolj agresivne maligne celice. Vendar, med napredovanjem tumorja, tumor obide te zaviralne signale in namesto tega izkoristi to okolje za nepravilno rast in na koncu pride do metastaz.

Zdravo tkivo v telesu
Homeostaza v zdravem tkivu je vzdržana s strogo nadzarovanim ravnovesjem med celično rastjo in smrtjo, ki je dosežena preko medcelične komunikacije. Pomembni regulator za normalno obnašanje celic in homeostaze tkiv je v okolici zunajceličnega matriksa. Zunajcelični matriks ima številne vloge. Deluje kot fizični oder, omogoča interakcije med različnimi celicami ter zagotavlja signale za preživetje in diferenciacijo. Za ohranjanje homeostaze v organih, lahko prepreči transformacijo normalnega tkiva z zagotavljanjem stabilne strukture tkiv. Nekatere študije kažejo, da je mikrookolje v embrijih močno pri reprogramiranju različnih rakavih celic, vključno z metastaznimi celicami.

Vloga stromalnih celic za razvoj tumorjev
Ugotovljeno je bilo, da so primarni tumorji sestavljeni iz različnih tipov stromalnih celic in rakavih celic. K spodbujanu rasti tumorjev pripomorejo celice, ki

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sestavljajo krvni in limfni obtok, različne celice pridobljene iz kostnega mozga (BMDCs), vključno z makrofagi, mastociti, meiloidne celice, ki so pridobljene iz zaviralnih celic (MDSCs) in mezenhimske matične celice (MSCs).

Slika 1: mikrookolje primarnega tumorja

Rakave celice primarnega tumorja so obkrožene s kompleksnim mikrookoljem, ki vsebuje številne celice.

Kronično vnetje in vloga BMDC
V preteklosti so prisotnost levkocitov v tumorjih povezovali s posledico neuspešnega uničenja rakavih celic. Vendar tumorji lahko pobegnejo pred imunsko zavrnitvijo in tudi spremenijo določene tipe vnetnih celic tako, da lažje rastejo. Mnoge celice imunskega sistema niso povezane z detekcijo antigena rakavih celic, vendar so povezane z motnjami v tkivu, ki jih povzročajo protivnetna zdravila, ali pa so kot odgovor na rast tumorja. To je zlasti očitno pri raku, ki je povezan s kroničnim vnetjem, kjer začetni vnetni odziv še ni dokazan. Stanje kroničnega vnetja hitro vzpostavi kaskado dogodkov, v katerih se učinki rasti tumorjev imunskih celic postopno razširjajo. Vendar še vedno ni jasne povezave med prisotnostjo katergakoli samostojnega tipa prilagodljivih ali prirojenih imunskih celic. Prav tako ni definiran izid v smislu malignosti ali prognoze v različnih mikrookoljih tumorjev.

Makrofagi povezani s tumorji
Makrofage lahko štejemo med prototipe BMDC - jev, ki so zmožni spreminjanja obnašanja rakavih celic in spodbujajo angiogenezo (fiziološki process rasti novih krvnih žil iz že obstoječih žil), invazijo ter metastazo na živalskih modelih. Makrofagi so sami po sebi plastične celice in to prilagodljivost izkorišča tumor pri različnih stopnjah rasti tumorja. Razvrstitev makrofagov je zelo uporabna pri pripisovanju potencialnih funkcij makrofagov povezanih s tumorji, vendar je zelo malo znano o kompleksnosti aktivnosti posameznega makrofaga in njihova povezava z rakom. Zlasti dejavniki nadzorovanja ravnovesja med spodbujanjem in

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odpravljanjem tumorja ter kako se ravnotežje spremeni med samim napredovanjem tumorja, še vedno niso znani. Najverjetneje večino makrofagov, povezanih s tumorji, obstajajo v samem tumorju in se najverjetneje začasno spremenijo med razvojem tumorja in spremenijo tudi lego glede na mikrookolje tumorja. Mnoge študije so dokazale pomembno vlogo makrofagov pri regulaciji napredovanja tumorja. Uporabili so gensko manipulacijo ali farmakološko izčrpavanje. Ti pristopi so povzročili znatno zmanjšanje prenosa makrofagov v sam tumor, kar je pripeljalo do inhibicije angiogeneze tumorja, rasti tumorja ter metastaz v različnih živalskih modelih.

MIKROOKOLJE METASTAZNIH MEST
Metastazno mesto je nov izziv za kroženje tumornih celic. V gostiteljskem tkivu se morajo prilagoditi, preživeti in rasti preden postanejo klinično pomembni. Vsaka stopnja je pomemba in pogosto tudi odločilna. Po prilagoditvi in pobegu v parenhim (skupina celic), mnoge metastazne celice mirujejo. Le nekatere se nato ponovno aktivirajo in se razvijejo do tumorja. Lokalno mikrookolje ima pomebno vlogo v vsaki stopnji metastaze in vloga BMDC – jev je ključna za metastazne celice.

Slika 2: usoda tumorskih celic v metastaznem mikrookolju

Po vstopu rakavih celic različni koraki vplivajo na sposobnost teh celic za vzpostavitev sekundarnih tumorjev na metastaznem mestu. Pri vsakem koraku se lahko tumorna celica sreča z različnimi usodami (smrt, mirovanje ali preživetje), kar je lahko spodbujeno s faktorji mikrookolja, vključno z zaščito agregatov trombocitov v obtoku, z aktivacijo stromalnih celic.

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VLOGA PROTEAZ
Proteaze so pogosto produkt invazivnih rakavih celicah, pogosto pa tudi produkt BMDC - jev, vključno z makrofagi. Dokazano je bilo, da so to glavni tipi celic, ki oskrbujejo mikrookolje s proteazami. Proteaze, ki so pomembne so specifične metaloproteinaze, cisteinski katepsini in serinske proteaze. Obstajajo različni možni mehanizmi, po katerih lahko te proteaze spodbujajo invazijo rakavih celic, kot je prikazano na spodnji sliki. Posamezne protease cepijo molekule celične adhezije (skupek celic na površini),

Slika 3: proteaze v invaziji ter metastazi

kot je epitelni (E) – kadherin (transmembranski protein), kar vodi do motenj v križiščih med celicami. Zrahljanost kontaktov med celicami olajša potovanje rakavih celic, ali kot posamezne celice, ali v skupinah, in zaviralci proteaz v zunajceličnem matriksu (ECM) omogočajo, da invazivne celice potujejo v okoliško tkivo in ožilje. Ne samo, da so proteaze bistvenega pomena za razgradnjo zunajceličnih proteinov, imajo tudi bolj specifično vlogo, ki je pomembna pri signalizaciji celic, kot je omejena cepitev pro – domen in kasnejša aktivacija rasnih faktorjev ter citokinov (majhne molekule), kar lahko močno poveča potovanje celic in metastazo. Ta različna načina povečanja invazije se med seboj ne izključujeta, temveč je verjetno, da delujeta usklajeno pri spodbujanju razširjanja rakavih celic. Vse te funkcije so urejene v kaskado interakcij proteaz, ki omogoča nadzor in ojačanje proteolize v invaziji ter metastazi. Skladno s tem je to, da če je kateri član družine proteaz farmakološko inhibiran ali gensko spremenjen, pride do znatnega zmanjšanja invazije rakavih celic.

ZAKLJUČEK
Iz pregleda je razvidno, da primarni tumorji in metastatični “poganjki” vsebujejo številne tipe celic. Večino teh celic izhaja iz kostnega mozga. Analize tumorjev so osredotočene na en tip celice oziroma posamezni produkt gena v celici. Rak je sistemska bolezen, pri kateri lahko tumor vpliva na več sistemov v organizmu. Kot rezultat tega se rakave celice razširjajo in metastaze se večajo. To ponavadi vključuje premik BMDC – jev, ki se nahajajo na mestih tumorja. Spremenijo ekologijo mest tumorja, največkrat, vendar ne vedno, v korist samega tumorja. Te spremembe spremenijo imunski odziv v živali, ki ima tumor, pogosto z globoko imunosupresijo proti novim antigenom, ki so izraženi v samih tumornih celicah. Še vedno obstaja nejasen premik BMDC – jev, kako se prenesejo iz

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kostnega mozga v kri in nazaj ter v različna tkiva. Nejasno je tudi, kaj ureja končno spremembo in funkcijo BMDC – jev na teh mestih. Cilj vseh raziskav je, da se ustvari biološki pogled preprečitve efektov mikrookolja za večanje tumorjev, z vzpostavitvijo takšnega mikrookolja, ki lahko popolnoma povrne maligni fenotip v normalnega. Čeprav je optimisitčno misliti, da so lahko vse spremembe reverzibilne, so bile različne tehnike uporabljene, ki so izbrale za tarčo stromalne celice v primarnem tumorju. Nekatere te tehnike so imele terapevtski učinek. Koncept, ki nastaja pri zdravljenju raka, vključje potovanje različnih tipov BMDC – jev, čemur sledi zdravljenje s tradicionalnimi kemoterapevtiki oziroma s ciljnjimi terapijami, ki lahko prispevajo ali k pomankanju odziva ali k pridobljeni rezistenci na zdravilo.

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LITERATURA
Joyce, J.A., Pollard, J.W.: Microenvironmental regulation of metastasis. Nature Rev. Cancer 9, 239 – 252 [2009]

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