Resistin and interleukin 6 as predictive factors for recurrence and long-term prognosis in renal cell cancer

ORIGINAL ARTICLE U ologic Oncology: Semina s and O iginal In es iga ions Resis in and in e leukin-6 as p edic i e ac o s o ecu ence and long- e m p ognosis in enal cell cance J. Kallio1, M. Hämäläinen2, T. Luukkaala3, E. Moilanen2, T.L. Tammela1, 5, P-L. Kellokumpu-Leh inen4, 5 1) Depa men o U ology, Tampe e Uni e si y Hospi al, Tampe e, Finland 2) The Immunopha macology Resea ch G oup, Facul y o Medicine and Li e Sciences, Uni e si y o Tampe e and Tampe e Uni e si y Hospi al, Tampe e, Finland 3) Resea ch and Inno a ion Cen e, Tampe e Uni e si y Hospi al and Heal h Sciences, Facul y o Social Sciences, Uni e si y o Tampe e, Tampe e, Finland 4) Depa men o Oncology, Tampe e Uni e si y Hospi al, Tampe e, Finland 5) Facul y o Medicine and Li e Sciences, Uni e si y o Tampe e, Tampe e, Finland Co esponding au ho Ma i Hämäläinen, PhD The Immunopha macology Resea ch G oup Facul y o Medicine and Li e Sciences Uni e si y o Tampe e 33014 Tampe e Finland This is an accep ed manusc ip . The o iginal a icle has been published in U ologic Oncology: Semina s and O iginal In es iga ions. 2017, ol. 35, no. 9, pp. 544.e25-544.e31. DOI:h ps://doi.o g/10.1016/j.u olonc.2017.05.005. Abs ac Objec i es The aim o he p esen s udy was o in es iga e p ognos ic ac o s o long e m ou come o enal cell cance (RCC) in a coho o pa ien s ea ed be o e new an iangiogenic he apy modali ies we e in oduced. Ou speci ic aim was o explo e esis in and in e leukin-6 (IL-6) le els in o de o ind ou cy okines po en ial o p edic ecu ence and su i al in pa ien s wi h RCC. Ma e ials and me hods Ou p ospec i e s udy popula ion consis ed o 91 pa ien s who unde wen adical neph ec omy o pa ial esec ion o RCC a Tampe e Uni e si y Hospi al be ween 1994 and 2001. A he ime o su ge y, 25 pa ien s we e diagnosed o ha e an ad anced and 66 pa ien s a local umou ; 34 pa ien s in he la e g oup de eloped a ecu ence du ing he ollow up o 15 yea s. Se um samples we e collec ed p eope a i ely and a 3, 9 and 15 mon hs and a 2, 3, 4 and 5 yea s pos ope a i ely. IL-6 and esis in le els in se um we e measu ed by immunoassay. Resul s P eope a i e alues o IL-6 (p=0.006) and esis in (p<0.001) we e highe in pa ien s wi h ad anced RCC, when compa ed o pa ien s wi h local umou s. Pa ien s wi h local RCC who de eloped a ecu ence du ing he ollow-up pe iod had highe p eope a i e IL-6 alues (p=0.003) han pa ien s wi hou a ecu ence. Based on ajec o y analysis o IL-6 and esis in le els, he pa ien s we e di ided in o h ee ajec o y g oups, espec i ely. Acco ding o mul i a ia e analysis, he pa ien s in he ajec o y class o he inc easing esis in alues du ing he ollow-up had a s a is ically signi ican ly highe isk o RCC p og ession (HR: 3.73, 95% CI: 1.52-9.13) and o poo su i al (HR: 4.93, 95% CI: 1.79-13.6) han he pa ien s in he lowes ajec o y class. Also, he pa ien s in he ajec o y class o he highes IL-6 alues showed a signi ican ly ele a ed isk o RCC p og ession (HR: 7.03, 95% CI: 3.00-16.5) and o RCC- ela ed poo su i al (HR: 6.09, 95% CI: 2.53-14.7), when compa ed o he pa ien s in he ajec o y class o he lowes IL-6 alues. Conclusion In RCC pa ien s, he ele a ed p eope a i e esis in le els associa ed s ongly wi h an ad anced disease. Based on Cox eg ession models and ajec o y analysis, esis in alues we e associa ed wi h disease p og ession and a poo su i al. Key wo ds: enal cell cance , adipokines, esis in, IL-6, p ognosis In oduc ion Renal cell cance (RCC) has a ma ked challenge among u ological malignancies ha ing he highes mo ali y, up o 50% in a long- e m ollow-up. I s clinical beha iou is e y a iable and i can ecu ence in an unp edic able manne e en a e se e al yea s since he p ima y ea men [1,2]. Clinical s age and his ological g ade con inue o be he mos powe ul independen p ognos ic ac o s, e en hough newe candida es o p ognos ic and p edic i e ac o s ha e been igo ously in es iga ed [1,2]. Ma ke s o cell p oli e a ion, apop osis, in asion and angiogenesis ha e shown p ognos ic alue in ea lie s udies [3-6]. Immunological egula ion has a majo ole in he beha iou o RCC and immuno he apy was he main ea men s a egy in a me as a ic RCC be o e newe ea men modali ies like an iangiogenic agen s and mTOR-inhibi o s became a ailable [7]. High IL-6 le els ha e been associa ed wi h poo p ognosis in RCC [8]. In addi ion, oday new ype o immunomodula ion wi h PD-3 (ipilimumab) and PD-l monoclonal an ibodies ia immuno egula o y cells seems o be a new p omising ea men modali y o he me as a ic RCC [9,10]. Obesi y has consis en ly been associa ed wi h ele a ed isk o RCC, bu he mechanisms h ough which obesi y ac s o inc ease RCC isk emain unclea [11]. Adipose issue has se e al endoc ine unc ions. I s ho mones a e collec i ely called as adipokines o adipocy okines. These p o eins ha e an e ec on a wide a ie y o complex, o en p oneoplas ic p ocesses such as in lamma ion, insulin esis ance, cell g ow h, p oli e a ion, and ascula and blood p essu e egula ion [12]. Some o hese adipokines ha e demons a ed p omising esul s as p edic o s o isk and/o p og ession in obesi y- ela ed cance s: b eas cance [13], colo ec al cance [14], endome ial cance [15], and p os a e cance [16]. In enal cell cance i has been shown ha low adiponec in le els a e associa ed wi h an ele a ed isk [17] and high adiponec in le els wi h a educed isk o RCC [18]. Resis in is an adipocy okine shown o ha e a ole in many in lamma o y condi ions associa ed wi h oxida i e / ni osa i e s ess. Resis in is p oduced p ima ily by mac ophages and i ac i a es TLR4 and in lamma o y signalling cascades in a ious cell ypes including umou cells. Resis in has been shown o ac i a e umou cell p oli e a ion and mig a ion in i o and i may p omo e cance dissemina ion h ough inc easing he exp ession o ma ix me allop o eases, adhesion molecules and p o-angiogenic ac o s. [19] Howe e , i s impac in RCC has no been in es iga ed. In he p esen s udy, we aimed o explo e RCC pa ien s bo h p e- and pos ope a i ely in o de o ind ou cy okines po en ial o p edic ecu ence and su i al. Ou main in e es was ocused on one o he adipocy okines, namely esis in because o i s po en ial ole in umou p og ession. Ma e ial and me hods Ou p ospec i e s udy popula ion consis ed o 91 pa ien s who unde wen adical neph ec omy o pa ial esec ion o RCC a Tampe e Uni e si y Hospi al be ween 1994 and 2001. Pa ien s wi h o he malignan diseases o ch onic in lamma o y diseases we e excluded. Th ee g oups o pa ien s we e iden i ied: pa ien s wi h local umou s wi hou ecu ence du ing he ollow-up (n=32), pa ien s wi h local umou s wi h ecu ence du ing he ollow-up (n=34) and pa ien s wi h ad anced umou s a he ime o diagnosis (n=25). Se um samples we e collec ed p eope a i ely and a 3, 9 and 15 mon hs and a 2, 3, 4 and 5 yea s pos ope a i ely and s o ed a -70 ⁰C un il analysed. Clinical ollow-up and da a collec ion we e pe o med a ou uni e si y clinic up o 5 yea s, a e which he ollow-up was done by gene al p ac i ione s a pa ien ’s home own. Indi idual su i al s a us, da e o dea h, and clinical diagnoses we e collec ed om he pa ien ’s eco ds up o 15 yea s. Clinical s age was assigned using he 1997 TNM classi ica ion o malignan umou s. Because o he es ic ed numbe o pa ien s in he s udy, TNM-classes we e di ided in o wo g oups o he s a is ical analysis: local (T1-T3N0M0) and ad anced (T4 and/o N1-2 and/o M1). His ology o umou s was classi ied acco ding o he Heidelbe g classi ica ion and g aded acco ding o he WHO classi ica ion. Eigh y ou o 91 we e clea cell umou s, six papilla y, h ee ch omophobe and wo collec ing duc ca cinomas. P og ession o he disease was conside ed o happen when umou mass was ecognized in he ollow-up imaging s udies a e su ge y (local umou s) o when exis ing umou masses we e enla ging and/o de eloping new ocus (ad anced umou s) [20]. IL-6 and esis in concen a ions we e de e mined by enzyme-linked immunoassay by using he eagen s om eBioscience Inc. (San Diego, CA, USA) and R&D Sys ems Eu ope L d (Abingdon, U.K.), espec i ely. The de ec ion limi and in e -assay coe icien o a ia ion we e 0.2 pg/ml and 4.2% o IL-6 and 15.6 pg/ml and 3.4% o esis in. E hics The esea ch plan was app o ed by he E hical Commi ee o Tampe e Uni e si y Hospi al (code R94144) and an in o med consen was ob ained om e e y pa ien . S a is ics Resis in and IL-6 alues we e clus e ed by ajec o y analysis o iginally p esen ed by Nagin 2005 [21]. T ajec o y g oups a e clus e s o indi iduals ollowing simila ajec o ies on an ou come o e ime [22]. The ajec o ies we e c ea ed acco ding o all measu emen s o esis in o IL-6 in each pa ien as a con inuous ou come measu e. Resis in and IL-6 we e modelled sepa a ely. The ajec o ies a e p esen ed in Fig. 1. The analyses unde aken we e la en class mix u e models o quad a ic ajec o ies including a andom in e cep and concomi an a iables. Models we e i ed by using lexmix package [23] o he s a is ical p og am R, e sion 2.13.0, om he R Founda ion o S a is ical Compu ing [24]. Rela i e goodness o i was assessed using Bayesian in o ma ion C i e ia (BIC). Di e ences (p) be ween g oups we e es ed by Mann-Whi ney es , Pea son chi-squa e es o Fishe ’s exac es . Associa ion o explana o y ac o s (age, gende , umou s age, his ological g ade o he umou , umou diame e , esis in ajec o ies and IL-6 ajec o ies) wi h p og ession and su i al we e examined by uni a ia e (su i al as age-adjus ed) and mul i a ia e Cox eg ession p opo ionally haza ds models (Table 2). The analyses we e pe o med by IBM SPSS S a is ics o Windows, Ve sion 20.0. A monk, NY: IBM Co p. Released 2011. P- alues <0.05 we e conside ed s a is ically signi ican . Resul s The p eope a i e pa ien cha ac e is ics: The median (Md) age o he pa ien s a he ime o ope a ion was 65 yea s (in e qua ile ange(IQR) 55-73, ange 33-85) and he median umou diame e was 7cm ( ange 2.3-25cm). As expec ed, he e was a clea di e ence in su i al be ween pa ien s wi h a local o an ad anced disease, Md 9.2 yea s (IQR 4.5-13.7; ange 0.9-17.9) and Md 1.1 yea s (IQR 0.54-2.68; ange 0-15.7), espec i ely (p<0.001). In e leukin-6: P eope a i e alues o IL-6 we e highe in pa ien s wi h an ad anced RCC han in pa ien s wi h a local umou , Md 6.5 (IQR 2.8-18.6; ange 0.5-39.5) pg/ml and Md 2.2 (IQR 1.1-6.1; ange 0.5-36.9) pg/ml, espec i ely (p=0.006, Mann-Whi ney U- es ). In addi ion, he pa ien s wi h a local umou who de eloped a ecu ence du ing he ollow-up pe iod had highe p eope a i e IL-6 alues han pa ien s wi hou a ecu ence, Md 4.9 (IQR 1.5-7.7; ange 0.5-36.9) pg/ml and Md 1.4 (IQR 0.9-2.8; ange 0.6-29.0) pg/ml, espec i ely (p=0.003) (Table 1). T ajec o y analysis di ided he pa ien s in o h ee g oups based on he le el o IL-6 alues (Fig. 1A). Acco ding o he mul i a ia e analysis, he pa ien s in he ajec o ies 2 (p=0.004) and 3 (p<0.001) had poo e su i al han pa ien s in he ajec o y 1 (i.e. pa ien s wi h he lowes IL-6 alues) (Fig. 2 and Table 2). Resis in: P eope a i e alues o esis in we e signi ican ly highe in pa ien s wi h an ad anced RCC han in pa ien s wi h a local umou , Md 21.7 (IQR 17.9-27.5; ange 9.7-80.9) ng/ml and Md 14.8 (IQR 11.3-18.6; ange 7.0-34.9) ng/ml, espec i ely (p<0.001, Mann-Whi ney U- es ). In con as o IL-6, he p eope a i e esis in alues did no di e be ween local RCC pa ien s wi h o wi hou ecu ence, Md 14.7 (IQR 11.3-17.6; ange 8.7-34.9) ng/ml and Md 15.0 (IQR 11.3-18.9; ange 7.0- 31.1) ng/ml, espec i ely (p=0.647) (Table 1). Based on ajec o y analysis o esis in alues o e ime he pa ien s we e di ided in o h ee g oups (Fig. 1B). Acco ding o he mul i a ia e analysis, he pa ien s in he esis in ajec o ies 2 (0.047) and 3 (p=0.002) had poo e su i al han pa ien s in he ajec o y 1 (Fig.3 and Table 2). P og ession: Table 2 shows uni a ia e and mul i a ia e analysis o isk ac o s o RCC p og ession. In mul i a ia e analysis, an ad anced disease (HR: 6.32, 95% CI: 2.90-13.8), a high his ological g ade (2.30, 1.28-4.12), a high umou diame e (3.58, 1.90-6.74), a highe IL-6 ajec o y class (class 2: 3.02, 1.47-6.21; class 3: 7.03, 3.00-16.5) and esis in ajec o y class 3, (3.73, 1.52-9.13) we e s a is ically signi ican p ognos ic ac o s o disease p og ession. Su i al: Risk ac o s, based on uni a ia e and mul i a ia e analysis, o RCC-speci ic su i al a e shown in Table 2. In he mul i a ia e analysis, an ad anced disease (HR: 10.7, 95% CI: 4.60-24.9), a high his ological g ade (2.79, 1.55-5.04), a high umou diame e (3.64, 1.86-7.12), IL-6 ajec o y class 2 (3.10, 1.44-6.66) and class 3 (6.09, 2.53-14.7), and esis in ajec o y classes 2 and 3 (class 2: 2.93, 1.01-8.45; class 3: 4.93, 1.79-13.6) we e independen p ognos ic ac o s o poo su i al. Discussion To he bes o ou knowledge, his is he i s p ospec i e s udy o e alua e esis in as a p ognos ic ac o in a clinical popula ion o RCC pa ien s. The esul s showed ha ele a ed p eope a i e esis in le els we e s ongly associa ed wi h an ad anced disease. Fu he mo e, based on Cox eg ession models and ajec o y analysis, esis in alues we e associa ed wi h disease p og ession and poo su i al. In addi ion, as epo ed also ea lie [25], highe IL-6 le els showed a clea associa ion wi h dissemina ing disease and poo su i al. In e es ingly, p eope a i e IL-6 le els we e highe no only in he pa ien s wi h ad anced / me as a ic disease bu also in hose pa ien s who we e o iginally diagnosed o ha e a local disease bu de eloped a ecu ence du ing he ollow-up. Obesi y has been associa ed wi h ele a ed isk o RCC. Findings in he la ge US coho s udy by Adams e al. sugges complexi y in he ela ion be ween weigh his o y and enal cell cance [11]. Especially adul hood (midli e) weigh gain inc eased ma kedly RCC isk. Wais - o-hip a io (abdominal adiposi y) was associa ed wi h an ele a ed isk o RCC, especially in women. Fac o s associa ed wi h excessi e body mass index (BMI) can damage he kidneys in di e en ways and a he same ime possibly aise he isk o RCC o o RCC p og ession e.g. ia oxida i e s ess [26], hype ension-induced inju y o he enal ubules [27], enal a he oscle osis [28] and al e ed ci cula ing concen a ions o es ogen and o he ho mones [29]. Resis in is an adipocy okine which has been shown o ha e a ole in se e al pa hophysiological condi ions. In a h i is ele a ed le els o esis in ha e been obse ed [30] and i has been sugges ed o play a ole in he pa hogenesis o os eoa h i is [31]. Ci cula ing esis in le els ha e been shown o be up egula ed in in lamma o y bowel diseases [32], ch onic kidney disease [33] and in as hma [34]. Resis in has been p oposed as a bioma ke o s e oid-sensi i e as hma [35] and as a p edic i e ma ke o he deg ee o ischemia- epe usion inju y du ing ca diac su ge y [36]. Resis in is exp essed in adipocy es in oden s, whe eas in humans i is p ima ily syn hesized by mac ophages [37, 38] and i is no eadily associa ed wi h obesi y and BMI [39]. Se e al issues and cell ypes a e esponsi e o esis in including adipose issue, li e , muscle, ascula endo helium and leukocy es. The main biological e ec s o esis in a e associa ed wi h insulin esis ance in mice, and enhancemen o in lamma ion in humans [37, 38]. Resis in has been shown o media e i s p o-in lamma o y p ope ies e.g. h ough p omo ing he exp ession o TNF and IL-6 in human mononuclea cells [40] and by inducing he exp ession o adhesion molecules in ascula endo helial cells [41]. Speci ic ecep o s o esis in ha e no been iden i ied, bu i has been shown ha esis in ac s as an endogenous ligand o Toll-like ecep o 4 (TLR4) [42]. TLR4 igge s majo in lamma o y pa hways and is also ac i a ed by bac e ial p oduc s such as lipopolysaccha ides. In acellula signalling cascades o esis in include NF-kB and PI3K-Ak pa hways as well as mi ogen-ac i a ed p o ein kinase cascades [37]. Ele a ed le els o esis in ha e been epo ed in pa ien s wi h b eas cance [43], colo ec al cance [44] and in non-small cell lung cance [45]. Resis in has been shown o ac i a e umou cell p oli e a ion and mig a ion in i o and i has been sugges ed o p omo e cance p og ession, in asion and me as asis h ough inc easing he exp ession o ma ix me allop o eases, adhesion molecules and p o-angiogenic ac o s [19,46-49]. The p esen s udy ex ends he p e ious knowledge o he pa hophysiological oles o esis in by showing ha ele a ed esis in le els in RCC pa ien s a e associa ed wi h an ad anced / me as a ic disease, and wi h disease p og ession and poo su i al. Limi a ions o he p esen s udy include he limi ed numbe o pa ien s in each g oup. Fo he i s i e yea s he ollow-up was pe o med acco ding o p ede ined schedule a he Tampe e Uni e si y Hospi al, and a e ha he da a is based on he egis y collec ed om he pa ien s’ isi s o he gene al p ac i ione s. Imaging echniques ha e de eloped since 1994 and nowadays ecu ence and p og ession a e likely o be obse ed ea lie . In conclusion, he p esen s udy shows ha esis in le els in RCC pa ien s a e associa ed wi h dissemina ed disease, umou p og ession and poo su i al. Ou indings o e an in e es ing in oduc ion o possible mechanisms o p og ession and me as asis o RCC. This is an in iguing opic o u he esea ch, which may esul in clinical implica ions o esis in as a bioma ke . Fu he mo e, he knowledge o he exac mechanism o ac ion o esis in may also o e he apeu ic possibili ies in he u u e. Acknowledgemen s Ms Te hi Salonen and Salla Hie akangas a e wa mly acknowledged o excellen echnical assis ance. 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Adipocy okine esis in co ela es wi h oxida i e s ess and myoca dial inju y in pa ien s unde going ca diac su ge y. Eu J Ca dio ho ac Su g 2014;46(4):729-36. Figu e 1 A B Figu e legend: Figu e 2 Su i al cu es om Cox haza d eg ession mul i a ia e models o enal cell ca cinoma pa ien s in di e en IL-6 ajec o y analysis g oups Figu e 2 Figu e legend: Figu e 3 Su i al cu es om Cox haza d eg ession mul i a ia e models o enal cell ca cinoma pa ien s in di e en esis in ajec o y analysis g oups Figu e 3