Abstract
Ac cu mu la ti ng evi den ce shows that chro nic in fl am ma tion is as so cia ted to in crea sed ri sk of can cer. An in fl am ma to ry com po ne nt is pre se nt al so in the mic roen vi ron me nt of tu mou rs epi de mio lo gi cal ly un re la ted to in fl am ma tion. Exten si ve in ves ti ga tio ns over the pa st de ca de ha ve un co ve red ma ny of the im por ta nt mec ha nis tic pat hways un der lyi ng can ce r-re la ted in fl am ma tion. Pat hways lin ki ng in fl am ma tion and can cer ha ve been iden ti fi ed: an in trin sic one (dri ven by ge ne tic even ts that cau se neop la sia) and an extrin sic one (dri ven by in fl am ma to ry con di tio ns whi ch pre dis po se to can cer). Smoul de ri ng in fl am ma tion is a com po ne nt of the tu mour mic roen vi ron me nt and is a re cog ni zed hal lma rk of can cer. Key or ches tra to rs at the in ter-sec tion of the in trin sic and extrin sic pat hways in clu de tran scrip tion fac to rs (e.g. Nuc lear Fac tor kap pa-B, NFκB) that mo du la te the in fl am ma to ry res pon se throu gh so lub le me dia to rs (cyto ki nes, che mo ki nes) and cel lu lar com po nen ts (e.g. tu mo r-as so cia ted mac rop ha ges), pro mo ti ng tu mo ri ge-ne sis. NFκB aids in the pro li fe ra tion and sur vi val of ma lig na nt cel ls, pro mo tes an gio ge ge-ne sis and me tas ta sis, sub ver ts adap ti ve im mu ni ty, and al te rs res pon ses to hor mo nes and che mot he ra peu tic agen ts. Emer gi ng evi den ce al so sug ges ts that per sis te nt in fl am ma tion pro mo tes ge ne tic in sta bi li ty. Thus, can ce r-re la ted in fl am ma tion rep re sen ts a tar get for in no va ti ve diag nos tic and the ra peu tic stra te gies.
Key wor ds: can ce r-re la ted in fl am ma tion; cyto ki nes; che mo ki nes; mac rop ha ges
Re cei ved: July 29, 2011 Ac cep ted: Septem ber 19, 2011
Mo le cu lar pat hways in can ce r-re la ted in fl am ma tion
An na li sa Del Pre te1,2*, Pao la Al la ve na1, Giu sep pe San to ro3, Rug gie ro Fu ma ru lo3, Mas si mi lia no M. Cor si4, Al ber to Man to va ni1,5 1Is ti tu to Cli ni co Hu ma ni tas IRCCS, Via Man zo ni 56, 20089 Roz za no, Mi lan, Ita ly
2Depar tme nt of Ba sic Me di cal Scien ces, Uni ver si ty of Ba ri, Ba ri, Ita ly
3Depar tme nt of Bio me di cal Scien ces and Hu man On co lo gy, Uni ver si ty of Ba ri, Ba ri, Ita ly
4Depar tme nt of Hu man Mor pho lo gy and Bio me di cal Scie nces “Cit tà Stu di”, Uni ver si ty of Mi lan, and Soc. Cli ni cal Pat ho lo gy and IRCCS
Po lic li ni co San Do na to, Mi lan, Ita ly
5Depar tme nt of Tran sla tio nal Me di ci ne, Uni ver si ty of Mi lan, Mi lan, Ita ly
*Cor res pon di ng aut hor: an na li sa.del_prete@humanitasresearch.it; del pre tean na@ hot mail.com
In tro duc tion
The Ger man Pat ho lo gi st Vir chow is cre di ted wi th sug ges ti ng the ca sual li nk be tween in fl am ma tion and can cer in the 19th cen tu ry (1). This con clu sion
was ba sed on the ob ser va tion that tu mou rs of ten de ve lo ped in the set ti ng of chro nic in fl am ma tion and that in fl am ma to ry cel ls we re pre se nt in tu-mour biop sy spe ci me ns. Epi de mio lo gi cal stu dies ha ve re vea led that chro nic in fl am ma tion pre dis po-ses to diff e re nt types of can cer. It is es ti ma ted that un der lyi ng in fec tio ns and in fl am ma to ry res pon ses are lin ked to 15-20% of all dea th from can cer wor-ldwi de (2,3). The trig ge rs of chro nic in fl am ma tion whi ch in crea se can cer ri sk in clu de mic ro bial in
fec-tio ns (e.g. He li co bac ter pylo ri for gas tric can cer and mu co sal lympho ma), au toim mu ne di sea ses (e.g. in fl am ma to ry bowel di sea se for co lon can cer), and crypto ge nic in fl am ma to ry con di tio ns of un cer tain ori gin (e.g. pros ta ti tis for pros ta te can cer). The stron ge st evi den ce in hu ma ns of the ro le of in-fl am ma tion in can cer has been pro vi ded by stu-dies showi ng that lo ng-te rm the ra py wi th an ti-in-fl am ma to ry dru gs re sul ted in dec rea sed num be rs of re lap ses or fewer ap pea ran ces of new tu mou rs. Re cen tly, Rot hwe ll et al. (4) re-a na lyzed pa tie nt da-ta from eig ht ran do mi zed tria ls of dai ly as pi rin da- ta-ken for pre ven tion of car dio vas cu lar di sea se. As
pi-rin use rs we re fou nd to ha ve a sig ni fi can tly lower ri sk of dea th from can cer than tho se who di dn’t ta-ke the drug (4). Ear lier stu dies re por ted that dai ly uses of as pi rin and ot her no n-ste roi dal an ti-in fl am-ma to ry dru gs (NSAI Ds) over exten ded pe rio ds re-du ced the ri sk of co lo rec tal can cer or po lyp re cur-ren ce, but lit tle evi den ce was avai lab le that as pi rin mig ht al so re du ce ri sk of ot her can ce rs (5). In tria ls in whi ch the pa tien ts took as pi rin for at lea st 7.5 yea rs, the 20-years risk of can cer dea th, star ti ng from the ti me the tria ls be gan, was re du ced by 60% for gas troin tes ti nal can cer and by 30% on ave ra ge for ot her so lid can ce rs, su ch as oe sop ha-geal, pan crea tic, sto ma ch, lu ng, brain, and pros ta-te can ce rs (4). The se da ta in di ca ta-te that an ti-in fl am-ma to ry dru gs pre ve nt bo th gas troin tes ti nal and ot her so li d-or gan can ce rs, and sug ge st that an in-fl am ma to ry com po ne nt is pre se nt in the mic roen-vi ron me nt of mo st neop las tic tis sues, in clu di ng tho se not etio lo gi cal ly re la ted to an ob vious in-fl am ma to ry pro ce ss.
Key fea tu res of can ce r-re la ted in fl am ma tion (CRI) in clu de leu ko cyte in fi l tra tion, mos tly tu mour as so-cia ted mac rop ha ges (TA M); the pre sen ce of cyto ki-nes su ch as TNF-α, IL-1, IL-6 or che mo ki ki-nes su ch as CCL2 and CXCL8; and the oc cur ren ce of an gio ge-ne sis and tis sue re mo del li ng. Mo le cu lar and cel lu-lar pat hways lin ki ng in fl am ma tion and can cer ha-ve been iden ti fi ed (2). Two ge ne ral pat hways can be sche ma ti cal ly des cri bed. In the in trin sic pat-hway, ge ne tic even ts (e.g. on co ge nes, ge ne tic aber ra tio ns) cau si ng neop las tic tran sfor ma tion, ini tia te the expres sion of in fl am ma tio n-re la ted prog ram mes whi ch gui de the con struc tion of an in fl am ma to ry mic roen vi ron me nt. The extrin sic pat hway is dri ven by in fl am ma to ry leu ko cytes and so lub le me dia to rs that es tab li sh in fl am ma to ry con di tio ns that in crea se can cer ri sk. The chro nic in fl am ma tion as so cia ted wi th the in fec tio ns cau-sed by mo st or all pat ho ge ns (e.g. He pa ti tis B and C vi ru ses, and He li co bac ter pylo ri) fa vou rs ini tia tion and prog res sion of tu mou rs (6). In ad di tion to fec tio ns, mec ha ni cal, ra dia tion, and che mi cal in-sul ts may be res pon sib le for in duc tion of in fl am-ma tion as so cia ted wi th hu am-man am-ma lig nan cy. Key or ches tra to rs at the in ter sec tion of the in trin sic and extrin sic pat hway in clu de tran scrip tion fac to rs
[e.g. Nuc lear Fac tor kap pa-B (NFκB), Sig nal Tran-sdu ce rs Ac ti va tor of Tran scrip tio n3 (STAT3)] (7,8), cyto ki nes (e.g. TNF), and che mo ki nes (9). Thus, can ce r-re la ted in fl am ma tion is a key com po ne nt of the tu mour mic roen vi ron me nt and a re cog ni-zed hal lma rk of can cer (10,11). He re we wi ll re view bo th in trin sic and extrin sic pat hways and their mu-tual con nec tion and in fl uen ce. Knowled ge of the-se mec ha nis ms may not on ly en han ce our un der-stan di ng of the pro ce ss of car ci no ge ne sis and of the mul ti fa ce ted ro le played by in fl am ma tion, but cou ld al so he lp to iden ti fy new tar ge ts for the ra-peu tic in ter ven tion.
The in trin sic pat hway lin ks in fl am ma tion
and on co ge nes
The pre sen ce of in fl am ma to ry com po nen ts in tu-mou rs not epi de mio lo gi cal ly re la ted to in fl am ma-tion rai sed the ques ma-tion of whet her ge ne tic even ts that cau se neop la sia can be res pon sib le for the ge-ne ra tion of an in fl am ma to ry en vi ron me nt. This ques tion has been ad dres sed by usi ng prec li ni cal and cli ni cal set tin gs in whi ch va rious on co ge ne tic mec ha nis ms can be as ses sed. A use ful cli ni cal exam ple of con nec tion be tween on co ge nes and in fl am ma to ry mi lieu is rep re sen ted by hu man pa-pil la ry thyroid car ci no ma (PTC), a tu mour cha rac-te ri zed by the pre sen ce of che mo ki ne-gui ded mac rop ha ge and den dri tic ce ll in fi l tra tion (12-14). Rear ran ge men ts of the chro mo so me whe re is lo-ca ted the ge ne en co di ng the pro tein tyro si ne ki-na se RET rep re se nt a freque nt, ear ly, cau sa ti ve, and suffi cie nt ge ne tic eve nt in the pat ho ge ne sis of PTC. In an ap prop ria te cellu lar con text pro vi ded by pri ma ry hu man thyro cytes, the ac ti va tion of RET in du ces a tran scrip tio nal prog ram me con nec ted to in fl am ma tion (12). In par ti cu lar, the RET/PTC-ac-tivated tran scrip to me pro fi le in clu des: co lo ny-sti-mu la ti ng fac to rs (CSFS), whi ch pro mo te leu ko cyte rec ruit me nt and sur vi val; in ter leu kin 1β (IL-1β), one of the main in fl am ma to ry cyto ki nes; cyclo-oxyge-na se 2 (COX2), frequen tly expres sed in can cer and in vol ved in the synthe sis of pros tag lan di ns; che-mo ki nes at trac ti ng che-mo no cytes and den dri tic cel ls (CCL2, CCL20); an gio ge nic che mo ki nes (CXCL8); co-or di na te in duc tion and in hi bi tion of mat
rix-deg ra di ng en zymes and in hi bi to rs; up-re gu la tion of L-se lec tin and expres sion of the che mo ki ne re-cep tor CXCR4 on the ini tia ted cel ls (15). Key ele-men ts of the RET/PTC-activated in fl am ma to ry prog ram me we re fou nd in biop sy spe ci me ns, and pa tien ts wi th lymph no de me tas ta sis showed hig-her le ve ls of the in fl am ma to ry mo le cu les in their pri ma ry tu mou rs (12,15,16). The se re sul ts show that an ear ly, cau sa ti ve, and suffi cie nt ge ne tic eve nt (RET/PTC) in vol ved in the pat ho ge ne sis of a hu-man tu mour di rec tly pro mo tes the bui ld-up of an in fl am ma to ry mic roen vi ron me nt to its di re ct ad-van ta ge (12).
Mo re in ge ne ral, diff e re nt types of al te ra tio ns con-cur ri ng to tu mour prog res sion, su ch as ac ti va tion of on co ge nes, or inac ti va tion of tu mour sup pres-so rs, may trig ger the in fl am ma to ry cas ca de. Mem-be rs of the epi der mal growth fac tor re cep tor (EGFR) fa mi ly ha ve tyro si ne ki na se ac ti vi ty and are frequen tly in vol ved in hu man can cer. EGFR ac ti va-tion in glio ma in du ces COX2 expres sion via p38-mi to ge n-ac ti va ted pro tein ki na se (MAPK) ac ti va-tion of Sp1/Sp3 (17); COX2 is an in de pen de nt prog-nos tic fac tor in glio ma. Ras fa mi ly on co ge nes, the mo st frequen tly mu ta ted do mi na nt on co ge nes in hu man can cer, when ac ti va ted, are ab le to in du ce expres sion and pro duc tion of in fl am ma to ry me-dia to rs. Tran sfer of ras on co ge ne in to a cer vi cal car ci no ma li ne (He La) in du ces the pro duc tion of CXCL8 (18,19), a che mo ki ne whi ch pro mo tes an-gio ge ne sis and tu mour prog res sion. Mo reo ver, mi-ld chro nic pan crea ti tis, pos sib ly mir ro ri ng cli ni cal epi de mio lo gy, ac ts in con ce rt wi th K-ras mu ta tion to in du ce pan crea tic in tra-e pit he lial neop la sia and in va si ve duc tal car ci no ma (20). Alo ng the sa me li-nes Braf, frequen tly ac ti va ted in ma lig na nt me la-no ma, in du ces cyto ki nes whi ch con tri bu te to a pro-tu mour mi lieu (21). Anot her on co ge ne, myc, en co des a tran scrip tion fac tor that is ove r-expres-sed in ma ny hu man tu mou rs: de re gu la tion of this ge ne ini tia tes and main tai ns key as pec ts of the tu-mour phe no type. In ad di tion to pro mo ti ng ce ll au-to no mous pro li fe ra tion, myc in struc ts re mo del li ng of the extra cel lu lar mic roen vi ron me nt wi th in fl am-ma to ry cel ls and me dia to rs playi ng key ro les. The
myc-ac ti va ted ge ne tic prog ram me al so in clu des
se ve ral CC che mo ki nes whi ch rec ruit ma st cel ls.
Ma st cel ls, that ha ve lo ng been known to dri ve an-gio ge ne sis, he re sus tain new ves sel for ma tion and tu mour growth (22).
Tu mour sup pres sor pro tei ns can al so re gu la te the pro duc tion of in fl am ma to ry me dia to rs. Exam ples of su ch pro tei ns are the von Hip pel Lin dau/hypox-ia-inducible fac tor (VHL/HIF), tran sfor mi ng growth fac to r-β (TGF-β) and phos pha ta se and ten sin ho-mo lo gue (PTEN). The che ho-mo ki ne re cep tor CXCR4, frequen tly expres sed on ma lig na nt cel ls and im pli-ca ted in ce ll sur vi val and me tas ta sis, as we ll as TNF-α lies downstream of the VHL/HIF axis in hu-man re na l-ce ll car ci no ma cel ls (23). In no n-sma ll ce ll lu ng can cer (NSCLC) mu ta tion of PTEN re sul ts in up-re gu la tion of HI F-1 ac ti vi ty and in HI F-1-de-pen de nt tran scrip tion of the CXCR4 ge ne, whi ch pro mo tes me tas ta sis for ma tion. In an ani mal mo-del of brea st car ci no ma, inac ti va tion of the ge ne en co di ng the type II TGF-β re cep tor in du ces the pro duc tion of CXCL5 and CXCL12, at trac ti ng mye-loi d-de ri ved sup pres sor cel ls (MDSC) whi ch fa ci li-ta te me li-tas li-ta sis (24,25). Al pha ca te nin is mo re than a tu mour sup pres sor seques te ri ng be ta-ca te nin: its ab la tion re sul ts in NFκB ac ti va tion, in duc tion of ge nes in vol ved in in fl am ma tion, ce ll pro li fe ra tion, wou nd-hea li ng, and ul ti ma te ly squa mous ce ll car-ci no ma (26). The pu ta ti ve tu mour sup pres sor se-map ho rin 3B is al so ab le to trig ger an IL-8-me dia-ted pro-me tas ta tic prog ram me, sug ges ti ng a mul-ti fa ced ro le for this mo le cu le (27). P53 has been con nec ted to CXCR4 li ga nd expres sion. In deed, wit hin bo th hu man and mou se fi b rob las ts, p53 can sup pre ss the pro duc tion of CXCL12 and at te-nua te tu mour de ve lop me nt and me tas ta sis (28). Thus, on co ge nes rep re sen ta ti ve of diff e re nt mo le-cu lar clas ses and mo des of ac tion (tyro si ne ki na-ses, ra s-raf, nuc lear on co ge nes) as we ll as tu mour sup pres sor ge nes, sha re the ca pa ci ty to or ches tra-te pro-in fl am ma to ry prog ram mes (Figure 1). Al-thou gh the se res ponses may sha re com mon ele-men ts in se ve ral tis sues (e.g. a li nk to an gio ge ne sis, rec ruit me nt of cel ls of mye lo-mo no cytic ori gin) so-me is sues, su ch as the na tu re of in fl am ma to ry com po nen ts, if they are es sen tial or re dunda nt, their ro le in diff e re nt tis sues and in diff e re nt types of can cer, need to be elu ci da ted.
me dia to rs. The im pli ca ted in fl am ma to ry con di tio-ns are qui te di ver se, in clu di ng a wi de ar ray of chro-nic in fec tio ns, expo su re to noxious agen ts that trig ger in fl am ma tion (e.g. gas tric acid refl ux, to-bac co, as bes tos) and au to-im mu ne con di tio ns (22,29). The be st es tab lis hed li nk be tween chro nic in fl am ma tion and can cer is co lo rec tal can cer that de ve lo ps in pa tien ts wi th in fl am ma to ry bowel di-sea ses (IBD, ul ce ra ti ve co li tis and Cro hn di di-sea se). The se pa tien ts ha ve fi ve- to se ve n-fo ld in crea sed ri sk of de ve lo pi ng co lo rec tal can cer (43% of pa-tien ts wi th ul ce ra ti ve co li tis de ve lop co lo rec tal can cer af ter 25 to 35 yea rs) (30). In a mu ri ne mo del of IBD, the de ve lop me nt of co li ti s-as so cia ted co lo-rec tal can cer can be in hi bi ted by bloc ki ng TNF-α expres sion (31). Lu ng can cer is a lea di ng cau se of can cer deat hs (32). Al thou gh to bac co expo su re is evi de nt in near ly 90% of all pa tien ts wi th lu ng can-cer, ot her chro nic ai rway in fl am ma to ry con di tio ns (e.g. as bes to sis, si li co sis, expo su re to air bor ne par-ti cu la te mat ter, idio pat hic pul mo na ry fi b ro sis, tu-ber cu lo sis, e tc) are all in de pen de nt ri sk fac to rs for lu ng can cer and may ac cou nt for a pro por tion of the no n-smo ki ng re la ted ca ses (33).
Reac ti ve oxygen spe cies (ROS) and nit ro gen in ter-me dia tes are ob vious in fl am ma tio n-ge ne ra ted can di da te me dia to rs for DNA da ma ge, and evi-den ce ob tai ned in vit ro and in vi vo is con sis te nt wi-th wi-this view (2). Re cen tly, mi toc hon drial ROS pro-duc tion has been de mon stra ted to be requi red for me dia ti ng K-ra s-in du ced lu ng can cer in mi ce (34). In ad di tion, mi toc hon drial pro duc ts re lea sed by da ma ged ce ll can ac ti va te in fl am ma tion and act as sig nal li ng mo le cu les that trig ger pro duc tion of pro-in fl am ma to ry cyto ki nes (35). Mi toc hon drial ROS ha ve been re cen tly shown to be in du ced by in fl am ma so me ac ti va to rs, and the se mi toc hon-drial ROS are in tu rn requi red for the ac ti va tion of the in fl am ma so me (36). Ove ra ll, im por ta nt new mo le cu lar pat hways in vol vi ng mi toc hon drial da-ma ge and ROS pro duc tion are bei ng elu ci da ted that pro foun dly aff e ct not on ly DNA da ma ge and ac ti va tion of on co ge nes, but al so diff e re nt as pec ts of in fl am ma tion, sug ges ti ng an im por ta nt ro le as up stream re gu la to rs of can ce r-re la ted sig nal li ng pat hways that pro mo te in fl am ma tion and tu mo ri-ge ne sis (37).
FIGURE 1. Mo le cu lar pat hways lin ki ng in fl am ma tion and can cer.
Two pat hways can be iden ti fi ed as the ma jor affl ue nt to the in-fl am ma to ry mi lieu: the in trin sic one, whe re ge ne tic even ts (e.g. on co ge nes) in du ci ng neop las tic tran sfor ma tion trig ger the in-fl am ma to ry cas ca de, and the extrin sic pat hway whe re chro nic in fl am ma tion (e.g. in fec tio ns, ir ri tan ts) sig ni fi can tly in crea ses the ri sk for diff e re nt types of can cer. The two pat hways con ver-ge, re sul ti ng in the ac ti va tion of tran scrip tion fac to rs (e.g. NFκB) that coor di na te the pro duc tion of in fl am ma to ry me dia to rs and the ac ti va tion of va rious leu ko cytes ge ne ra ti ng a can ce r-re la-ted in fl am ma to ry mic roen vi ron me nt. CRI rep re sen ts a re cog ni-zed hal lma rk of can cer.
IBD - in fl am ma to ry bowel di sea se; COPD - chro nic obstruc ti ve pul mo na ry disea se; ROS - reac ti ve oxygen spe cies; NFκB - nuc-lear fac tor kap pa B; STAT - signal tran sdu ce rs acti va tor of tran-scrip tion; HIF - hypoxia indu cib le fac tor; TAM - tumour asso cia-ted mac rop ha ges; MDSC - myeloi d-deri ved sup pres sor cel ls; PMN - polymor phic nuc lear cel ls; COX2 - cyclo-oxyge na se 2; VEGF - vascu lar endot he lial growth fac tor.
The extrin sic pat hway
In the extrin sic pat hway, in fl am ma tion is main ly trig ge red by leu ko cytes pro du ci ng in fl am ma to ry
EXTRINSIC PATHWAY
Infections
Inflammatory Conditions (IBD) Irritants (COPD) ROS INTRINSIC PATHWAY Oncogenetic events Tyrosine Kinase Nuclear Oncosuppressors TRANSCRIPTION FACTORS NFkB, STAT3, HIF CANCER-RELATED INFLAMMATION INFLAMMATORY CELLS
TAM, MDSC, Mast Cells, PMN, Eosinophils
SOLUBLE MEDIATORS
Cytokines (TNF, IL-1, IL-6) Chemokines (CCL2, CXCL8) COX2, VEGF Evasion of Apoptosis Sustained Angiogenesis Tissue Invasion Metastasis Insensivity to Growth Inhibitors Self-Sufficiency in Growth Signals Limitless Replicative Potential
Anot her exam ple is rep re sen ted by the aber ra nt expres sion of ac ti va tio n-in du ced cyti di ne dea mi-na se (AID) that is in du ced in gas tric epit he lium by
He li co bac ter pylo ri (38). AID is a mem ber of the
cyti-di ne-dea mi na se fa mi ly that ac ts as a DNA- and RNA-e di ti ng en zyme. The H. pylo ri-me dia ted up re-gu la tion of AID re sul ted in the ac cu mu la tion of nuc leo ti de al te ra tio ns in gas tric cel ls, lea di ng to the de ve lop me nt of gas tric can cer (38). In ad di tion, the ec to pic AID pro duc tion, in du ced by TNF sti-mu la tion in hu man bi le-du ct cel ls, is as so cia ted wi-th chro nic bi lia ry in fl am ma tion and wi-the de ve lop-me nt of cho lan gio car ci no ma (39). The re fo re, AID may li nk chro nic in fl am ma tion to DNA da ma ge in the se tu mou rs.
Key or ches tra to rs at the in ter sec tion
pat hway of can ce r-re la ted in fl am ma tion
Amo ng the mo le cu lar playe rs in vol ved in CRI, key en do ge nous pro mo te rs in clu de tran scrip tion fac to-rs su ch as NFκB, sig nal tran sdu cer ac ti va tor of tran-scrip tio n-3 (STAT3), and pri ma ry in fl am ma to ry cyto-ki nes su ch as IL-1β, IL-6, IL-23, and TNF-α (8,40-42). NFκB is a key or ches tra tor of in na te im mu ni ty and in fl am ma tion and it has re cen tly emer ged as po-ten tial mo le cu lar brid ge be tween tu mour cel ls and in fl am ma to ry cel ls (40). In bo th cel lu lar con texts, NFκB ope ra tes downstream of the sen si ng of mic-ro bes or tis sue da ma ge by the to ll-li ke re cep tor (TLR)-MyD88 pat hway, the in fl am ma to ry cyto ki nes TNF-α and IL-1β, and downstream of tis sue da ma-ge that re sul ts in re lea se of ala rm sig na ls. In ad di-tion, NFκB ac ti va tion can be the re su lt of ce ll-au to-no mous ge ne tic al te ra tio ns (am pli fi ca tion, mu ta-tio ns, or de le ta-tio ns) in can cer cel ls.
NFκB in du ces the expres sion of in fl am ma to ry cyto-ki nes, ad he sion mo le cu les, key en zymes in the pros tag lan din syntha se pat hway (COX2), nit ric oxi-de (NO) syntha se, and an gio ge nic fac to rs. In can-cer and epit he lial cel ls expo sed to car ci no ge ns, NFκB pro mo tes ce ll sur vi val and pro li fe ra tion by the ac ti va tion of ge nes en co di ng for pro tei ns re-gu la ti ng ce ll cycle prog res sion (e.g. cyclin D, c-myc) and apop to sis (e.g. cIA Ps, A1/BFL1, Bcl2, c-Flip). He-pa to car ci no ge ne sis sig ni fi can tly de pen ds on NFκB ac ti va tion in bo th pa ren chymal (he pa to cytes) and
non pa ren chymal cel ls of the li ver (43). Stro ng ge-ne tic evi den ce, in clu di ng tis sue-spe ci fi c ge ge-ne tar-ge ti ng of com po nen ts of the Ikk com plex, su ch as Ikap pa B-ki na se be ta (IKKβ), has de mon stra ted a cru cial ro le of NFκB in tu mour pro mo tion in pro to-typic tis sues of CRI (e.g. gas troin tes ti nal tra ct and li ver). IK Kbe ta re gu la tes gas tric car ci no ge ne sis via IL-1α expres sion, whi ch is as so cia ted wi th an ti-a-pop to tic sig na li ng and ce ll pro li fe ra tion (44). Ac cu-mu la ti ng evi den ce sug ges ts that in ter sec tio ns and com pen sa to ry pat hways may exi st be tween the NFκB and HI F-1 syste ms (7,45,46) lin ki ng in na te im-mu ni ty to the hypoxic res pon se.
The NFκB pat hway is tig htly con trol led by in hi bi to-rs ac ti ng at diff e re nt le ve ls. To ll-in ter leu kin re cep-tor 8 (TI R8) is an exam ple of a mo le cu le that, by con trol li ng in fl am ma tion, may pro te ct again st can-cer. TI R8 al so known as sin gle im mu nog lo bu lin in-ter leu kin 1 re cep to r-re la ted pro tein (SIGIRR), is a frin ge mem ber of the IL-1 re cep tor fa mi ly wi th a sin gle Ig do main, a lo ng cytop las mic tail and an al-te red TIR do main. It in hi bi ts TLR and IL-1R sig nal li-ng and is hig hly expres sed in in tes ti nal mu co sa. TI-R8 ge ne de fi cien cy is as so cia ted wi th in crea sed sus cep ti bi li ty to in tes ti nal in fl am ma tion and car ci-no ge ne sis (47,48) as we ll as to B ce ll lymphop ro li-fe ra tion and au toim mu ni ty (49,50). Anot her ne ga-ti ve re gu la tor of in fl am ma ga-tion, na me ly A20 (al so known as TNFAI P3), has been pro po sed to fun-ction as tu mour sup pres sor in se ve ral hu man B-ce-ll lympho ma (51).
Thus, ba lan ci ng in hi bi to rs and ac ti va to rs tu nes the ac tion of the NFκB pat hway as an en do ge nous tu-mour pro mo ter, ac ti ng in in fi l tra ti ng leu ko cytes as we ll as in cel ls tar ge ted by car ci no ge ns. Evi den ce sug ges ts that p50 ho mo di me r-ne ga ti ve re gu la tor is res pon sib le for the slug gi sh NFκB ac ti va tion in tu mou r-as so cia ted mac rop ha ges (TAM) and for their pro-tu mour phe no type. Thus, NFκB ap pea rs to act as a rheos tat tu ned at diff e re nt le ve ls in fl o-rid in fl am ma to ry con di tio ns pre dis po si ng to can-cer (e.g. in fl am ma to ry bowel di sea se, IBD) and in TA Ms sus tai ni ng the smoul de ri ng in fl am ma to ry mi lieu of es tab lis hed me tas ta tic neop la sia (52,53). NFκB has al so been re cen tly in vol ved in dri vi ng the M2 (al ter na ti ve ly ac ti va ted mac rop ha ges) po-la ri za tion of TA Ms (54).
Alo ng wi th NFκB, STA T3 is a poi nt of con ver gen ce for nu me rous on co ge nic sig nal li ng pat hways (8). Con sti tu ti ve ly ac ti va ted STA T3 in crea ses tu mour ce ll pro li fe ra tion, sur vi val and in va sion whi le sup-pres si ng an ti-tu mour im mu ni ty. The per sis te nt ac-ti va ac-tion of STA T3 al so me dia tes tu mou r-pro mo ac-ti ng in fl am ma tion. STA T3 has this dual ro le in tu mour in fl am ma tion and im mu ni ty by pro mo ti ng pro-on-co ge nic in fl am ma to ry pat hways, in clu di ng NFκB and IL-6-gp130-JAK pat hways and by op po si ng STA T1 and NFκB-me dia ted Th1 an ti-tu mour im mu-ne res pon ses (55).
So lub le me dia to rs of can ce r-re la ted
in fl am ma tion
TNF-α plays a key ro le in the per sis ten ce of in fl am-ma tion and es tab lis hed evi den ce de mon stra tes that tu mour de ri ved TNF-α sus tai ns the growth and prog res sion of synge nic, xe no ge nic and che-mi cal ly in du ced tu mou rs of skin, pan creas and bowe ls (31,56,57). In ad di tion to can cer cel ls, ot her TNF-α pro du ce rs ha ve been iden ti fi ed in tu mour mic roen vi ron me nt. Mac rop ha ges (58) and CD4+ cel ls (59) sec re te TNF-α and trig ger in fl am ma tion, as shown in a ge ne tic mo del of li ver can cer (43). TNF-α ini tia tes a com plex cro ss-ta lk be tween epit-he lial ova rian can cer cel ls and sur roun di ng tis sues, pro mo ti ng the co lo ni za tion of the pe ri to neum (59). Mo reo ver, the con sti tu ti ve pro duc tion of TNF-α was as so cia ted wi th in crea sed re lea se of che mo ki nes (CCL2, CXCL8, CXCL12), IL-6, VEGF and mac rop ha ge mig ra tion in hi bi to ry fac tor (MI F-1). The mec ha ni sm of TNF-α ac tion in clu des di re ct ef-fec ts on tu mour spread, via CXCR4; tu mour ce ll sur vi val, via CXCR4/CXCL12; but al so sti mu la tion of new blood ves se ls in the pe ri to neal tu mour co lo-nies, due to in duc tion of CXCL12 and VEGF expres-sion (60). A ma jor sour ce of in fl am ma to ry cyto ki-nes in the tu mour mic roen vi ron me nt are tu mou r-as so cia ted mac rop ha ges (TAM) (61,62). TA Ms pro-mo te wnt sig nal li ng throu gh TNF in gas tric can cer (63). The se fi n din gs pro vi de a ra tio na le for the de-ve lop me nt of cli ni cal pro to co ls em ployi ng TNF an-ta go nis ts in can cer the ra py (64). De coy re cep tor 3 (DcR3) is a mem ber of the TNF re cep tor su per fa mi-ly and has been in vol ved in the con trol of MHC
cla-ss II in TA Ms (65). IL-1, IL-6, TNF-α, and the re la ted re cep tor ac ti va tor of NFκB li ga nd (RANKL) ha ve lo-ng been known to aug me nt the ca pa ci ty to me-tas ta ti ze by aff ec ti ng mul tip le ste ps in the dis se mi-na tion and in fl am ma tion cas ca de (2,66,67). TA Ms as si st tu mour be ha viour in ma ny ways, in clu di ng pro du ci ng cyto ki nes, growth fac to rs, and mat rix-deg ra di ng en zymes (68-70). Kim et al. re cen tly showed that tu mour ce ll su per na tan ts con tai ned an in du cer of cyto ki ne pro duc tion in mac rop ha-ges. Unexpec ted ly, the tu mou r-de ri ved mac rop-ha ge ac ti va tion was iden ti fi ed as a com po ne nt of the extra cel lu lar mat rix: ver si can, whi ch is frequen-tly up-re gu la ted in hu man tu mou rs. Ver si can, re-lea sed by tis sue da ma ge, was fou nd to be re cog ni-zed by to ll-li ke re cep tor 2 and 6 (TLR2/TLR6). Thus, in the Lewis lu ng car ci no ma mo del this stu dy iden-ti fi es a cas ca de of am pli fi ca iden-tion of me tas ta sis ini-tia ted by tu mou r-de ri ved ver si can ac ti ng on mye-loid cel ls via TLR2/TLR6, lea di ng to in fl am ma to ry cyto ki ne pro duc tion (71).
The in vol ve me nt of IL-1 in tu mour prog res sion is we ll es tab lis hed. IL-1 expres sion is ele va ted in hu-man brea st, co lon, lu ng, head and ne ck can ce rs, me la no mas, and pa tien ts wi th IL-1 pro du ci ng tu-mou rs ha ve ge ne ral ly bad prog no sis (72). IL-1 pro-mo tes tu pro-mour growth and me tas ta sis by in du ci ng se ve ral pme tas ta tic ge nes su ch as me tal lop ro-tei na ses, che mo ki nes, growth fac to rs and TGF-β (73). IL-1 is al so ab le to sti mu la te the expres sion of en dot he lial ad he sion mo le cu les su ch as ICA M-1 and VCA M-1 (74). Of par ti cu lar im por tan ce are its eff ec ts on an gio ge ne sis: IL-1 is a po te nt proan gio-ge nic cyto ki ne and VEGF re lea se is al so IL-1 de pen-de nt (75). In a pan crea tic is let tu mour mo pen-del, a fi r st wa ve of myc-dri ven an gio ge ne sis is in du ced by the in fl am ma to ry cyto ki ne IL-1 (76). IL-1α was al so shown to play a pi vo tal ro le in the pat ho ge ne sis of li ver can cer (77). On the ot her ha nd, IL-1α is pos sib-ly of im por tan ce in 3-methylcholantrene-induced fi b ro sar co ma, due to its effi cien cy in ac ti va ti ng an-ti-tu mour in na te and spe ci fi c im mu ne res pon ses, by ac ti ng as a fo cu sed ad ju va nt, throu gh bin di ng to IL-1R1 on im mu ne sur veil lan ce cel ls (78,79). Mo-reo ver, sma ll amoun ts of IL-1α, whi ch is ho meos ta-ti cal ly expres sed in cel ls, but not sec re ted, can be pou red out from nec ro ti zi ng cel ls and ser ve as a
‘dan ger sig nal’ for moun ti ng an ti-tu mour ce ll im-mu ni ty (80). In 1993 the fi r st stu dy usi ng IL-1R an ta-go ni st (IL-1Ra) treat me nt in mi ce tran splan ted wi th hu man me la no ma cel ls de mon stra ted a stro ng re-duc tion in the num ber of lu ng me tas ta sis (81). Si-mi lar fi n din gs we re re por ted in a mo del of he pa tic me tas ta sis: a sin gle injec tion of IL-1Ra re du ced tu-mor co lo nies by 50% and tu tu-mor vo lu me by 70% (82). The re is evi den ce of the ra peu tic effi ca cy in bloc ki ng the IL-1 pat hway in hu ma ns wi th IL-1Ra and IL-1 in hi bi to rs. In mye lo ma pa tien ts trea ted wi-th dexa met ha so ne and Ana kin ra (IL-1Ra) lo ng prog res sio n-free in ter va ls of over 3 yea rs or 4 yea rs we re ob tai ned in so me pa tien ts (83) in di ca ti ng a lo ng sta bi li za tion of the di sea se. Mo re po te nt IL-1 in hi bi to rs are reac hi ng cli ni cal eva lua tion, in par ti-cu lar for au toim mu ne di sea ses, ope ni ng a pos sib le fu tu re use in an ti can cer the ra pies (84).
IL-6 is a key growth-pro mo ti ng and an ti-a pop to tic in fl am ma to ry cyto ki ne (85,86) and is al so one of the eff ec tor sig na ls of ac ti va ted NFκB in the pro-mo tion of neop la sia. A clear pro-tu pro-mo ral ro le for IL-6 has been de mon stra ted in mul tip le mye lo ma (87). Anot her exam ple of IL-6-de pen de nt tu mour is the He pa to cel lu lar car ci no ma (HCC), the mo st com mon type of li ver can cer. Naug ler et al. (88) explo red the mo le cu lar mec ha nis ms to explain the hig her in ci den ce of li ver can cer in ma le pa tien ts. It tur ned out that in fe ma les es tro ge ns blo ck IL-6 pro duc tion in lo cal im mu ne cel ls (li ver Kup ff er cel-ls). In IL-6 de fi cie nt mi ce or mi ce lac ki ng the adap-tor pro tein MyD88 (lin ked to NFκB sig nal li ng) the sex diff e ren ce in sus cep ti bi li ty to can cer was ab se-nt (89). The im por tan ce of the au toc ri ne IL-6 is con-fi r med al so in ot her can cer types whe re it is de-mon stra ted that IL-6 is an im por ta nt ac ti va tor of on co ge nic STA T3 in lu ng ade no car ci no mas and Jag ge d-1/Notch sig nal li ng in brea st tu mour mam-mos phe res (90-92). New lig ht was shed on the ro le of IL-6 in co li ti s-as so cia ted can cer (93,94). It was fou nd that IL-6 pro du ced by mye loid cel ls is a cri ti-cal tu mour pro mo ter du ri ng in tes ti nal car ci no ge-ne sis. IL-6 pro tec ts nor mal and pre-ma lig na nt in-tes ti nal epit he lial cel ls from apop to sis and pro mo-tes the pro li fe ra tion of tu mou r-i ni tia ti ng cel ls. The-se ac tio ns are me dia ted by gp130 and STA T3. Thus, the NFκB/IL-6/STAT3 cas ca de plays a key ro le in
in-tes ti nal car ci no ge ne sis. In te res tin gly, STAT3 al so re gu la tes the ba lan ce be tween IL-12 and IL-23 in the tu mour mic roen vi ron me nt (95).
Anot her so lub le com po ne nt stric tly as so cia ted wi-th wi-the rec ruit me nt of leu ko cytes in tu mou rs is rep-re sen ted by che mo ki nes (2,9,96,97). Re ce nt rep-re sul ts wi th ge ne-tar ge ted mi ce have pro vi ded unequi-vo cal evi den ce for a ro le of CC che mo ki nes in car-ci no ge ne sis. Mi ce de fi car-cie nt in D6, a de coy and sca-ven ger re cep tor for in fl am ma to ry CC che mo ki nes, show in crea sed sus cep ti bi li ty to skin car ci no ge ne-sis and co li ti s-as so cia ted can cer (98). The con tri bu-tion of che mo ki nes to an gio ge ne sis and tu mour pro mo tion has been the ob je ct of in ten si ve in ves-ti ga ves-tion. A va rie ty of che mo ki nes, in clu di ng CCL2, CXCL12, CXCL8, CXCL1, CXCL13, CCL5, CCL17, and CCL22, ha ve been de tec ted in neop las tic tis sues as pro duc ts of eit her tu mour cel ls or stro mal ele men-ts (96,99). CXCL1 and re la ted mo le cu les (CXCL2, CXCL3, CXCL8, or IL-8) ha ve an im por ta nt ro le in me la no ma prog res sion by sti mu la ti ng neop las tic growth, pro mo ti ng in fl am ma tion, and in du ci ng an gio ge ne sis. Stro ng evi den ce de mon stra tes that le ve ls of CCL2 are as so cia ted wi th TAM ac cu mu la-tion and that CCL2 may play an im por ta nt ro le in the re gu la tion of an gio ge ne sis (1). Che mo ki nes are al so in vol ved in the ra pid tur no ver of mye loi d-de-ri ved sup pres sor cel ls (100). Expres sion of che mo-ki ne re cep to rs plays an im por ta nt ro le in gui di ng me tas ta sis. CXCR4 is the mo st frequen tly up-re gu-la ted che mo ki ne re cep tor in can cer cel ls, and it is as so cia ted wi th ad van ced sta ges and me tas ta sis (2). Re cen tly, the che mo ki ne re cep tor CX3CR1 has been re por ted to be up-re gu la ted in hu man pan-crea tic can cer and to be in vol ved in the pe ri neu ral dis se mi na tion of this neop la sia alo ng lo cal ner ve ter mi na tio ns (101).
Cel lu lar com po nen ts of can ce r-re la ted
in fl am ma tion
TAM rep re se nt the ma jor in fl am ma to ry com po ne-nt of the stro ma of ma ny tu mou rs, ab le to aff e ct diff e re nt as pec ts of the neop las tic tis sue (102,103). In se ve ral stu dies of hu man can cer, TAM ac cu mu la-tion has been as so cia ted wi th an gio ge ne sis and wi th the pro duc tion of an gio ge nic fac to rs su ch as
VEGF and pla te let deri ved en dot he lial ce ll growth fac tor (1,104-109). TA Ms ac cu mu la te in hypoxic re-gio ns of tu mou rs, and hypoxia trig ge rs a pro-an-gio ge nic prog ram me in the se cel ls (104). A num-ber of mo le cu les wi th pos sib le im pa ct on an gio-ge ne sis ha ve been shown to be expres sed by mac-rop ha ges in low-oxygen con di tio ns, su ch as VEGF, TNF-α, ba sic fi b rob la st growth fac tor (bFGF), and CXCL8. The re fo re, mac rop ha ges rec rui ted in si tu rep re se nt an in di re ct pat hway of am pli fi ca tion of an gio ge ne sis, in con ce rt wi th an gio ge nic mo le cu-les di rec tly pro du ced by tu mour cel ls (2,23). Un der hypoxic con di tio ns, tu mou r-sec re ted lac tic acid pro mo tes a IL-23/IL-17-mediated pro-in fl am ma to ry pat hway in TA Ms (110).
Mye loid cel ls in the tu mour mic roen vi ron me nt are re la ted to the an gio ge nic swit ch at diff e re nt le ve ls (111). VEGF and the re la ted an gio ge nic fac tor pla-cen ta de ri ved growth fac tor (PlDGF) ha ve lo ng been known to be po te nt mo no cyte at trac tan ts and to con tri bu te to TAM rec ruit me nt (112). VEG-F1R+ he ma to poie tic bo ne-mar row cel ls ho me to
tu mou r-spe ci fi c pre me tas ta tic si tes. The re, they fo-rm a re ci pie nt nic he whi ch fa vou rs se con da ry lo ca-li za tion of can cer. Bv8, al so known as pro ki ne tic 2, mo du la tes rec ruit me nt of an gio ge nic Gr+Ma c1+
cel ls from bo ne-mar row (113) and pro mo tes an gio-ge ne sis. Mo reo ver, Gr+Ma c1+ cel ls, pre su mab ly
MDSC, ha ve re cen tly been shown to me dia te re sis-tan ce to an ti-an gio ge nic the ra py in va rious mo de-ls (113). Howe ver, al so ma st cel de-ls, neut rop hi de-ls and even eff ec to rs of the adap ti ve im mu ni ty (e.g. an ti-bo dy-pro du ci ng B cel ls ac ti va ti ng mac rop ha ges) may sus tain in fl am ma to ry reac tio ns that pro mo te can cer prog res sion (114,115). In ad di tion to pro du-ci ng an gio ge nic fac to rs, su ch as che mo ki nes and VEGF it se lf, mye loid cel ls are al so a sour ce of mat-rix-deg ra di ng en zymes (MMP) whi ch mo bi li ze VEGF from extra cel lu lar mat rix sto res. Re ce nt re-sul ts sug ge st that TA Ms can pro mo te tu mour an-gio ge ne sis al so via se map ho rin 4D (116). Thus TA-Ms and re la ted cel ls (MDSC, DC, po lymor pho nuc-lear cel ls (PMN)) rep re se nt an im por ta nt in di re ct and al ter na ti ve pat hway of an gio ge ne sis in the tu-mour mic roen vi ron me nt (117).
Con clu di ng re mar ks
The li nk be tween in fl am ma tion and can cer is now we ll es tab lis hed, even in tho se ca ses whe re un der-lyi ng chro nic in fec tio ns are ab se nt. Two mo le cu lar pat hways ha ve been re cog ni zed and con si st of an in trin sic pat hway, dri ven by ge ne tic al te ra tio ns that cau se neop la sia and ac ti va te the in fl am ma-tion cas ca de, and an extrin sic pat hway whe re in-fl am ma to ry con di tio ns fa ci li ta te can cer de ve lop-me nt. At the cros sroa ds, the key or ches tra to rs are rep re sen ted by tran scrip tion fac to rs (e.g. NFκB) that coor di na te cyto ki ne (e.g. TNF), che mo ki ne and en zyme pro duc tion. The se fac to rs rec ruit and ac ti va te leu ko cytes, main ly of the mye lo mo no-cytic li nea ge (112), pro du ci ng and am pli fyi ng the in fl am ma to ry res pon ses. Smoul de ri ng in fl am ma-tion con tri bu tes to pro li fe ra ma-tion and sur vi val of ma lig na nt cel ls, an gio ge ne sis, me tas ta sis, sub ver-sion of adap ti ve im mu ni ty and re du ced res pon se to che mot he ra peu tic agen ts.
CRI rep re sen ts a tar get for phar ma co lo gi cal stra te-gies that can mo du la te the ho st mic roen vi ron me-nt. Pri ma ry pro-in fl am ma to ry cyto ki nes, che mo ki-nes and their re cep to rs rep re se nt pri me tar ge ts of fu tu re bio lo gi cal the ra pies (57), and their cli ni cal use is bei ng expe ri men ted in can cer pa tien ts (118-120). Re cen tly, new stra te gies are ai med at tar ge ti-ng TAM rec ruit me nt and po la ri za tion (53). For ma-ny yea rs all eff or ts to treat can cer ha ve con cen tra-ted on ly on the des truc tion/inhibition of can cer cel ls, CRI may rep re se nt a com ple men ta ry per-spec ti ve that can he lp the de ve lop me nt of eff ec ti-ve an ti-tu mour res pon ses.
Ac knowled ge men ts
The aut ho rs are sup por ted by the Ita lian As so cia-tion for Can cer Re sear ch, Ita lian Mi nis try of Heal th, MIUR (Mi nis te ro de ll’Is tru zio ne Uni ver si tà e Ri cer-ca).
Po ten tial con fl i ct of in te re st
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Mo le ku lar ni pu to vi u upa li po ve za noj s kar ci no mom
SažetakSve vi še do ka za uka zu je da je kro nič na upa la po ve za na s po vi še nim ri zi kom od kar ci no ma. Upal na sas tav ni ca pri sut na je i u mik rook ru že nju tu-mo ra epi de mio loš ki ne po ve za nog s upa lom. Op sež na is tra ži va nja pro ve de na zad njih de set go di na ot kri la su mno ge me ha nič ke pu to ve ko ji su u pod lo zi upa le po ve za ne s kar ci no mom. Pro na đe ni su pu to vi ko ji po ve zu ju upa lu i kar ci nom: in trin zič ni (vo đe ni ge net skim do ga đa ji ma ko ji uz ro-ku ju neop la zi ju) i ek strin zič ni (vo đe ni upal nim uv je ti ma ko ji pre dod re đu ju kar ci nom). Ti nja ju ća upa la sas tav ni ca je tu mor skog mik rook ru že nja te je pre poz na ta kao znak kar ci no ma. Glav ni up rav lja či na pre si je ca nju in trin zič nih i ek strin zič nih pu to va obuh va ća ju tran skrip cij ske čim be ni ke, prim je ri ce nuk lear ni čim be nik kap pa-B (NFκB), ko ji mo du li ra upal ni od go vor preko top lji vih me di ja to ra (ci to ki na, ke mo ki na) i sta nič nih sas tav ni-ca (npr. mak ro fa ga po ve za nih s tu mo rom) pos pje šu ju ći stva ra nje tu mo ra. NFκB po maže kod pro li fe ra ci je i pre živ lja va nja ma lig nih sta ni ni-ca, pos-pje šu je an gio ge ne zu i me tas ta zu, na ru ša va adap tiv ni imu ni tet te mi je nja od go vo re na hor mo ne i ke mo te ra pij ske agen te. Sve je vi še do ka za ko ji uka zu ju da traj na upa la pos pje šu je ge net sku nes ta bil no st. Upa la po ve za na s kar ci no mom sto ga pred stav lja cilj ino va tiv ne di jag nos ti ke i te ra pij-skih stra te gi ja.
