High expression of class III β tubulin in upper gastrointestinal cancer types

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1 ONCOLOGY LETTERS High expression of clss III β tubulin in upper gstrointestinl cncer types DORIS HÖFLMAYER 1*, ERAY ÖZTÜRK 1*, CORNELIA SCHROEDER 2, CLAUDIA HUBE MAGG 1, NICLAS C. BLESSIN 1, RONALD SIMON 1,2, DAGMAR S. LANG 1, EMILY NEUBAUER 1, COSIMA GÖBEL 1, MARIE CHRISTINE HEINRICH 1, CHRISTOPH FRAUNE 1, KATHARINA MÖLLER 1, MORITZ ARMBRUST 1, MORTON FREYTAG 1, ANDREA HINSCH 1, CLARA LÜHR 1, MAGDALENA NOACK 1, VIKTOR REISWICH 1, SÖREN WEIDEMANN 1, MAXIMILIAN BOCKHORN 2, DANIEL PEREZ 2, JAKOB R. IZBICKI 2, GUIDO SAUTER 1 nd FRANK JACOBSEN 1 1 Institute of Pthology; 2 Generl, Viscerl nd Thorcic Surgery Deprtment nd Clinic, University Medicl Center Hmburg Eppendorf, D Hmburg, Germny Received Jnury 4, 2018; Accepted September 10, 2018 DOI: /ol Abstrct. Clss III β tubulin (TUBB3) is component of microtubules of neuronl cells tht is upregulted in vrious cncer entities. To better understnd the role of TUBB3 in upper gstrointestinl trct cncer types, the present study ssessed TUBB3 expression in tissue microrrys including 189 gstric nd 428 esophgel cncer. TUBB3 expression ws detected in 62.4% of gstric cncer, 73.8% of esophgel denocrcinom nd 88.7% of esophgel squmous cell cncer, while control smples of norml esophgel nd gstric epithelium were TUBB3 negtive. TUBB3 positivity ws not ssocited with the Interntionl Union Aginst Cncer clssifiction, World Helth Orgniztion grding, lymph node involvement or distnt metstsis in ny entity. Of note, TUBB3 expression ws ssocited with tumor locliztion nd prognosis in gstric cncer, with the tumor stge in esophgel denocrcinom, nd with the resection mrgin in esophgel squmous cell cncer. In conclusion, the substntil rte of positivity for TUBB3 lredy in erly stges of gstric cncer in combintion with the lck of further increse in frequency with tumor stge, my suggest, tht TUBB3 upregultion is rther relevnt for cncer development thn for cncer progression. TUBB3 Correspondence to: Dr Ronld Simon, Institute of Pthology, University Medicl Center Hmburg Eppendorf, 52 Mrtinistrsse, D Hmburg, Germny E mil: r.simon@uke.de * Contributed eqully Abbrevitions: TUBB3, Clss III β tubulin; TMA, tissue microrry; UICC, Interntionl Union Aginst Cncer Key words: tubulin, gstric nd esophgel cncer, TMA might be suitble prognostic biomrker in gstric cncer types. Introduction Upper gstrointestinl cncers re mong the leding cuses of cncer ssocited mortlity worldwide. Approximtely 1.5 million people re dignosed with gstric nd esophgel cncer ech yer (1,2). Despite improvements in dignosis nd therpy in the lst decdes, the outcome for ptient with gstric nd esophgel cncers remins poor with 5 yer survivl rtes not exceeding 20 30% in Western societies (3 5). The moleculr mechnisms underlying crcinogenesis remin lrgely elusive. Accordingly, moleculr mrkers llowing for prediction of the clinicl course of these diseses re currently lcking. Hence, there is high demnd for moleculr mrkers to predict tumor ggressiveness nd response to therpy for these cncer types. Microtubules re multifunctionl cytoskeletl proteins involved in numerous cellulr processes including mintennce of cell shpe, intrcellulr trnsport nd chromosome segregtion during mitosis nd meiosis. Microtubules re composed of polymers of α nd β tubulin heterodimers. Clss III β tubulin (TUBB3) is typiclly expressed in cells of neuronl origin, where it contributes to the formtion of dynmic microtubules essentil for neurite formtion nd mintennce (6). Severl lines of evidence suggest tht TUBB3 lso hs n importnt role in tumor development. In fct, overexpression of TUBB3 hs been linked to poor clinicl outcome in numerous epithelium derived tumor types, including non smll cell lung (7), bldder (8), brest (9), ovrin (10) nd prostte cncer (11). Severl studies nlyzing gstric nd/or esophgel cncer specimens (n=29 149) hve lso suggested cliniclly relevnt roles of TUBB3 expression levels in upper gstrointestinl cncer (12 14). Of note, elevted levels of TUBB3 expression hve been ssocited with reduced response to txne bsed microtubule trgeting cncer therpy (7,10 12,15).

2 2 HÖFLMAYER et l: TUBULIN EXPRESSION IN GASTRIC AND ESOPHAGEAL CANCER Here we tested retrospectively TUBB3 expression in upper gstrointestinl cncers from 230 gstric nd 594 esophgel cncers on tissue microrrys (TMA) nd report the clinicl follow up from 189 gstric nd 428 esophgel cncers. Ptients nd methods Ptients. The 230 ptients [men ge (± SD), 67 yers (±12); femle/mle rtio, 0.51] with gstric nd 594 ptients [men ge (± SD), 62 yers (±10); femle/mle rtio, 0.25] with esoph gel cncer received surgicl tretment t the Deprtment of Generl, Viscerl nd Thorcic Surgery, University Medicl Center Hmburg Eppendorf (Hmburg, Germny) between June 1994 nd October 2006, nd between Jnury 1992 nd December 2014, respectively. TUBB3 stining nd follow up dt ws vilble for 93 ptients with gstric cncer with medin time of 13 months nd for 393 esophgel cncer ptients with medin time of 41 months. Tumors were stged ccording to the sixth edition of the tumor nodes metstsis clssifiction, grded nd histologiclly subtyped ccording to the recommendtions of the Interntionl Union Aginst Cncer (UICC) (16). Dt on neodjuvnt or djuvnt cytotoxic therpy regimens or response to tretment were unvilble. The TMA mnufcturing ws performed s described in previous studies (17,18). Ech TMA block contined internl controls of norml esophgel nd gstric tissue tken from the sme ptient cohort. The Ethics Committee of the Ärztekmmer Hmburg pproved the present study (no. WF 049/09). According to locl lws (HmbKHG 12), informed consent ws not required. Ptient records/informtion were nonymized prior to nlysis. All work ws performed in complince with the Helsinki Declrtion. Immunohistochemistry. TUBB3 stining nd scoring ws performed s described in previous study (9). The recombinnt rbbit monoclonl nti TUBB3 ntibody clone EPR1568Y ws used t dilution 1:150 of (ct. no. b68193; Abcm, Cmbridge, UK). Stining ws observed in the cytoplsm of TUBB3 expressing cells nd scored s neg tive (0), wek (1+ in 70% of tumor cells or 2+ in 30% of tumor cells), moderte (1+ in >70% of tumor cells, or 2+ in 31 70% of tumor cells, or 3+ in 30% of tumor cells) or strong (2+ in >70% of tumor cells or 3+ in >30% of tumor cells) (Figs. 1 nd 2). Figure 1. Representtive imges of 600 µm tissue spots t mgnifiction, x100 nd x400, respectively, showing norml (A) gstric nd (B) esophgel tissue. Note tht glndulr cells in the gstric nd squmous epithelil cells in the esophgel tissue re not stined, while stroml cells re positive in both tissues. Figure 2. Representtive imges of 600 µm tissue spots showing (A) neg tive, (B) wek, (C) moderte nd (D) strong clss III β tubulin expression in gstric cncer (mgnifiction, x100). Sttisticl nlysis. JMP 12.0 softwre (SAS Institute Inc., Crey, NC, USA) ws used to clculte contingency tbles nd P vlues with the chi squred (likelihood) test. Kpln Meier curves were drwn nd significnt differences between groups were ssessed by the log rnk method. Cox regression nlysis ws used to compre hzrd rtios in univrite nd multivrite models. P 0.05 ws considered to indicte sttisticlly significnt difference. Results TUBB3 stining. The results of the TMA nlysis were interpre tble for totl of 189/230 (82%) of gstric nd 431/594 (73%) Figure 3. Representtive imges of 600 µm tissue spots showing (A) neg tive, (B) wek, (C) moderte nd (D) strong clss III β tubulin expression in esophgel squmous cell cncer (mgnifiction, x100).

3 ONCOLOGY LETTERS 3 Tble I. Assocition between TUBB3 expression nd gstric cncer phenotype. TUBB3 (%) Prmeter No. evluble Negtive Wek Moderte Strong P vlue All cncers Tumor stge pt pt UICC clssifiction I II III IV Lurén clssifiction Diffuse Mixed Intestinl WHO grding G G G Tumor locliztion Antrum b Corpus Crdi Other/not further specified Lymph node metstsis N N Distnt metstsis M M Ctegory with some missing dt, b significnt result. UICC, Interntionl Union Aginst Cncer; TUBB3, clss III β tubulin; WHO, World Helth Orgniztion. of esophgel tumor smples. In the non informtive TMA spots (18% for gstric cncer nd 27% for esophgel cncer), the tissue smple ws lcking or no unequivocl cncer tissue ws observed. Norml gstric nd esophgel tissues exhibited no stining under the selected experimentl conditions. Fig. 1 shows representtive imges of norml gstric nd esophgel tissue. TUBB3 expression in gstric cncer. In gstric cncer, positive stining for TUBB3 ws detected in 118 of 189 nlyzble spots (62.4%) nd ws rted wek in 11.1%, moderte in 18% nd strong in 33.3% of these smples. Representtive imges of TUBB3 stining in gstric cncers re given in Fig. 2. TUBB3 expression ws unrelted to tumor stge, UICC stge, Luren clssifiction, WHO grding, nd presence of lymph node or distnt metstsis (P>0.05 ech; Tble I). TUBB3 expression vried from 53.8 to 83.0% with the tumor locliztion (P=0.0012; Tble I). TUBB3 expression in esophgel cncer. In esophgel cncer, cytoplsmic TUBB3 stining ws detected in 345 of 428 nlyzble tumors (80.7%), including 233 denocrcinoms nd 195 squmous cell cncers. TUBB3 stining in denocrcinoms (squmous cell cncers) ws considered wek in 18.0% (11.8%), moderte in 19.7% (19.0%) nd strong in 36.1% (57.9%) of these smples. Representtive imges of TUBB3 stining in esophgel cncers re given in Fig. 3. In esophgel denocrcinoms, no ssocition between TUBB3 nd UICC stge, WHO grding, or the presence of lymph node or distnt metstsis ws identified (P>0.05 ech; Tble II). Only the tumor stge ws significntly ssocited with TUBB3 expression (P=0.0289; Tble II). In esophgel squmous cell crcinoms, only the resection mrgin

4 4 HÖFLMAYER et l: TUBULIN EXPRESSION IN GASTRIC AND ESOPHAGEAL CANCER Tble II. Assocition between TUBB3 expression nd esophgel denocrcinom phenotype. TUBB3 (%) Prmeter No. evluble Negtive Wek Moderte Strong P vlue All cncers Tumor stge pt1 b b pt pt pt4 b UICC clssifiction I II III IV WHO grding G G G G Resection mrgin Lymph node metstsis pn pn pn pn Distnt metstsis Ctegory with some missing dt, b significnt result. UICC, Interntionl Union Aginst Cncer; TUBB3, clss III β tubulin; WHO, World Helth Orgniztion. ws significntly ssocited with TUBB3 (P<0.05; Tble III). For the ssocition of TUBB3 with the tumor stge similr trend s in the denocrcinoms ws observed. Kpln meier nlysis. Follow up dt were vilble from 93 ptients with gstric cncer nd 393 ptients with esophgel cncer (204 denocrcinoms nd 189 squmous cell cncers) with interpretble TUBB3 stining on the TMA. While in gstric cncer TUBB3 expression ws ssocited with shorter overll survivl (Fig. 4A nd B), TUBB3 expression hd no impct on the survivl of esophgel cncer ptients (P>0.05; Fig. 4C nd D). Multivrite nlysis. Hzrd rtios for overll survivl were clculted. In gstric cncer, TUBB3 expression ws n independent risk fctor for shorter survivl (P<0.05; Tble IV). Discussion The results of the present study demonstrte tht TUBB3 is frequently expressed in upper gstrointestinl cncer types ssocited with ptient prognosis only in gstric cncer, but not in esophgel denocrcinom nd esophgel squmous cell cncer. TUBB3 expression ws identified in 62.4% of the 189 gstric cncer tissues, in 73.8% of the 233 esophgel denocrcinom tissues nd 88.7% of the 195 esophgel squmous cell cncer tissues in the present study, but ws undetectble in the respective norml tissue smples. In principle, these immunohistochemicl results re comptible with erlier studies on these tumor types. This prticulrly pplies to gstric tumors, where two erlier studies on gstric cncer tissues (n=115 nd 146) reported comprble dt,

5 ONCOLOGY LETTERS 5 Tble III. Assocition between TUBB3 expression nd esophgel squmous cell cncer phenotype. TUBB3 (%) Prmeter No. evluble Negtive Wek Moderte Strong P vlue All cncers Tumor stge pt1 b pt pt pt4 b UICC clssifiction I II III IV WHO grding G G G Resection mrgin b Lymph node metstsis pn pn pn pn Distnt metstsis Ctegory with some missing dt, b significnt result. UICC, Interntionl Union Aginst Cncer; TUBB3, clss III β tubulin; WHO, World Helth Orgniztion. Tble IV. Hzrd rtio for overll survivl of estblished prognostic prmeter nd TUBB3 expression in gstric cncer types. Vrible Univrite nlysis Multivrite nlysis Tumor stge pt3+4 vs. pt ( ) c 1.67 ( ) WHO grding G3 vs. G ( ) 2.22 ( ) Lymph node metstsis Positive vs. negtive 4.43 ( ) c 3.11 ( ) b TUBB3 expression Positive vs. negtive 2.23 ( ) 2.18 ( ) P 0.05, b P 0.001, c P Confidence intervl (95%) in brckets. TUBB3, clss III β tubulin; WHO, World Helth Orgniztion.

6 6 HÖFLMAYER et l: TUBULIN EXPRESSION IN GASTRIC AND ESOPHAGEAL CANCER Figure 4. Kpln Meier nlysis of overll survivl nd (A) negtive, wek, moderte, or strong TUBB3 expression in gstric cncer, (B) negtive vs. positive (wek, moderte, or strong) TUBB3 expression in gstric cncer, (C) in esophgel denocrcinom, nd in (D) esophgel squmous cell cncer. * Significnt overll P vlue. TUBB3, clss III β tubulin. nmely detectble TUBB3 expression in 36 nd 53% of tumor smples (12,19). The results of two erlier studies on esophgel squmous cell cncers were more conflicting, reporting TUBB3 positive rtes of 7 nd 95%, respectively (14,20). The striking discrepncy of these dt is typicl for studies using homemde immunohistochemicl protocols. It is known, tht the use of different ntibodies, immunohistochemistry protocols nd scoring criteri cn result in discrepnt dt (21). The importnt function of TUBB3 in the mintennce of the dynmic plsticity of microtubules (22,23) prerequisite for cell motility, invsive growth, mitotic spindle orienttion, nd cell cycle progression would be consistent with significnt role for TUBB3 in tumor development nd progression. The high frequency of detectble TUBB3 stining in erly gstric cncer in combintion with the lck of further elevtion in frequency with the tumor stge incresing, my suggest tht up regultion of TUBB3 is n event in crcinogenesis of gstric cncer nd hs relevnce in cncer development rther thn cncer progression. Other studies hve filed to identify n ssocition between TUBB3 expression nd clinico pthologicl prmeters or ptient prognosis in gstric or esophgel crcinoms (12,19,20). In the present study, nlysis of much lrger number of tumors did revel significnt ssocition with ptient outcome in gstric cncer providing some rguments for TUBB3 testing. This is in line to the results on the predictive vlue of TUBB3 in vriety of other cncer types. Using the sme stining protocol, nother recent study by our group identified the prognostic vlue of TUBB3 in prostte cncer, which ws independent of estblished pre nd post opertively vilble prognostic fetures (24). Others studies hve reported TUBB3 overexpression is linked to lte tumor stge nd poor prognosis in brest (25), lung (26,27), colon (28), ovrin (10,29,30), prostte (11,24) nd severl neurologicl cncers (28). The present study ws retrospective study. Thus it remins to be seen whether the prognostic vlue of TUBB3 expression in gstric cncer cn be vlidted in prospective study. In summry, the results of the present study demonstrte tht TUBB3 is frequently expressed in upper gstrointestinl cncer types, including esophgel nd gstric tumors. For gstric cncer, TUBB3 expression might be prognostic fctor. Acknowledgements The uthors would like to thnk Mrs. Jnett Lütgens, Mrs. Sünje Seekmp nd Mrs. Inge Brndt (Institute of Pthology, University Medicl Center Hmburg Eppendorf) for excellent technicl ssistnce. Funding No funding ws received. Avilbility of dt nd mterils All dt generted or nlyzed during this study re included in this published rticle.

7 ONCOLOGY LETTERS 7 Authors' contributions DH, FJ, RS nd GS designed the study nd drfted the mnuscript. EÖ, CS nd JRI prticipted in study design. EN, CG, MCH, CF, KM, MA, MF nd AH performed immunohistochemicl nlysis nd scoring. CL, VR, SW nd MN prticipted in pthology dt nlysis. CH M, NCB nd RS performed sttisticl nlysis. MB, DP, nd DSL prticipted in dt interprettion nd helped to drft the mnuscript. All uthors red nd pproved the finl mnuscript. Ethics pprovl nd consent to prticipte The Ethics Committee of the Ärztekmmer Hmburg pproved the study protocol (WF 049/09). According to locl lws (HmbKHG 12), ptient informed consent ws not required. Ptient records/informtion were nonymized nd de identified prior to nlysis. All procedures hve been performed in complince with the principles outlined in the Helsinki Declrtion. Ptient consent for publiction Not pplicble. Competing interests The uthors declre tht they hve no competing interests. References 1. Zhng Y: Epidemiology of esophgel cncer. 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