MicroregionalExpressionofGlucoseTransporter ... · via activation of the hypoxia-inducible factor-1...

Microregional Expression of GlucoseTransporter-1and OxygenationStatus: Lackof Correlation in LocallyAdvanced Cervical CancersArnulf Mayer,1Michael Ho« ckel,2 Alexander Wree,1 and Peter Vaupel1

Abstract Purpose: Glucose transporter-1 (GLUT-1), a target gene of hypoxia-inducible factor-1, has beenconsidered a candidate endogenous marker of tumor hypoxia. Expression of GLUT-1may alsoserve as an indicator for the induction of the transcriptional response to hypoxia, which has beenlinked to enhanced proliferation, resistance to therapy, andmetastatic propagationof cancer cells.Overexpressionof GLUT-1has been shown to correlatewithpoor prognosis in several tumor enti-ties, among them cancers of theuterine cervix.The validity of these hypotheses is investigated.Experimental Design:The expression of GLUT-1was assessed in 80 biopsies of Eppendorfoxygenation measurement tracks from locally advanced cervical cancers in 47 patients usingimmunohistochemistry.Results:No correlationwas found between the expression of GLUT-1and oxygenation variables(median pO2, HF 2.5 and HF 5). Expression of GLUT-1was found greater in larger tumors(P = 0.0001) and to exhibit a linear increase with Fe¤ de¤ ration Internationale de Gyne¤ cologie et d’Obste¤ trique stage (P = 0.002). Overall survival (P = 0.004) and recurrence-free survival(P = 0.007) were significantly shorter for patients with expression of GLUT-1. In the subgroup ofpatients treated with surgery, this effect on prognosis was not independent when pTstage or pNstagewere included in amultivariate Cox proportional hazards model.Conclusions:The suitability of GLUT-1as an endogenous marker of tumor hypoxia seems ques-tionable.The associationwith prognosis may partially depend on confounding factors.

Under physiologic conditions, glucose transporter-1 (GLUT-1)is expressed most strongly in erythrocytes and blood-brain orblood-nerve barriers (1–3). Overexpression of GLUT-1 is foundin many types of solid malignancies (1), among them cancersof the uterine cervix (4). Overexpression of GLUT-1 signifi-cantly contributes to the phenomenon of increased glucoseuptake (as measured by positron emission tomographyimaging of 18F-fluorodeoxyglucose uptake) found in solidtumors which can also be exploited for diagnostic purposes(5, 6). Because expression of GLUT-1 is stimulated by hypoxiavia activation of the hypoxia-inducible factor-1 (HIF-1; ref. 7),the question arises as to whether GLUT-1 expression inmalignant tissue can be used as a surrogate measure of tissueoxygen (O2) depletion and could thus serve as an endogenousmarker of tumor hypoxia.

Hypoxia is a hallmark of solid tumors and has an effect bothon the effectiveness of cancer treatment and on the aggressivetraits of malignant cells. Reduced O2 availability diminishes theefficacy of ionizing radiation (8). Significantly higher radiation

doses are thus needed in hypoxic tissue to achieve equivalentcytotoxic effects compared with normoxic microenvironments.Additionally, severely hypoxic conditions (<0.1% O2) canpromote the accumulation of genomic mutations (9–11) andmay thus expedite malignant progression (e.g., via activation ofoncogenes or inactivation of tumor suppressor genes). Hypoxiaalso has a profound effect on gene expression (termed ‘‘hypoxicresponse’’; e.g., ref. 12), which is mediated via oxygen-regulatedtranscription factors (13), among which HIF-1 occupies apivotal position. GLUT-1 is one member of the broad range oftarget genes of HIF-1 which are believed to confer enhanced cellsurvival and proliferation under hypoxic conditions (for arecent review, see ref. 7) and are thus viewed as driving factorsfor tumor growth, at least when a net effect is considered.Consistent with such a concept, overexpression of GLUT-1 hasbeen shown to be associated with an adverse prognosis inseveral tumor entities (14–23), among them cancers of theuterine cervix (4). The present study examined the possibility ofassessing GLUT-1 expression to gain information on the extentof tumor hypoxia. Additionally, the role of GLUT-1 as aprognostic factor was assessed in this cohort of patients withlong-term follow-up.

Materials andMethods

Patients. All patients in this study were enrolled in a prospectiveclinical trial for the evaluation of the significance of tumor oxygenationin primary, locally advanced carcinomas of the uterine cervix thatcommenced at the Department of Obstetrics and Gynecology,University of Mainz Medical School, in June 1989. The study designwas approved by the local Medical Ethics Committee, with patients

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Authors’Affiliations: 1Institute of Physiology and Pathophysiology, University ofMainz and 2Department of Obstetrics and Gynecology, University of Leipzig,GermanyReceived11/17/04; revised1/4/05; accepted1/11/05.The costs of publication of this article were defrayed in part by the payment of pagecharges.This article must therefore be hereby marked advertisement in accordancewith18 U.S.C. Section1734 solely to indicate this fact.Requests for reprints: ArnulfMayer, Institute of PhysiologyandPathophysiology,University of Mainz, Duesbergweg 6, 55128 Mainz, Germany. Phone: 49-6131-392-5203; Fax: 49-6131-392-5774; E-mail: [email protected].

F2005 American Association for Cancer Research.

CancerTherapy: Preclinical

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giving informed written consent before being enrolled. All 47 patients

from the former study, for whom one or two tumor biopsy specimensof the oxygen measurement tracks were available, were included in the

present study. Patients of this subgroup had been recruited between

August 1991 and April 1997. Table 1 shows relevant patient and tumorcharacteristics at the time of pretreatment oxygen tension (oxygen

partial pressure, pO2) measurements.For correlations involving survival, only patients treated with

curative intent were included (n = 42). In 31 of these, the primary

therapy was surgical. Abdominal radical hysterectomy and pelvic/periaortic lymph node dissection was the standard surgical procedure.

In 5 of 31 patients, supralevator exenteration had to be done insteadof radical hysterectomy. The remaining 11 cases were treated by

radiation instead of surgery because their tumors were fixed to the

pelvic wall or their comorbidity excluded extensive operations. Primaryradiotherapy was given as combined teletherapy and brachytherapy.

External beam irradiation was applied with 10 MV photons producedby a linear accelerator at the Division of Radiotherapy. For

brachytherapy, a high–dose rate 192Ir afterloading machine at the

Department of Obstetrics and Gynecology was used (for details, seeref. 24). Adjuvant chemotherapy regimens are described in detail in

Ref. 31. Median follow-up time was 28 months (SD 28), ranging from

4 to 95 months.Tumor oxygen tension measurements. Tumor pO2 was measured

pretherapeutically with the computerized Eppendorf histographysystem (Eppendorf, Hamburg, Germany), using a protocol that hasbeen described in detail previously (25). Briefly, pO2 readings were

done in the conscious patient along linear tracks, first in the s.c. fat ofthe mons pubis followed by cervical measurements at the 12 and 6

o’clock sites in macroscopically vital tumor tissue. Within the tumortissue, up to 35 pO2 measurements were made along each electrodetrack (70 readings in total) starting at a tissue depth of 5 mm. The

individual pO2 measurement points were situated 0.7 mm apart,resulting in an overall measurement track length of f25 mm.

Immediately following pO2 measurements, needle core biopsies(obtained using Biopty, Radioplast, Uppsala, Sweden) of f2 mm indiameter and 20 mm in length were taken from those tumor areas

where pO2 readings had been obtained. Both the pO2 readings and theneedle core biopsies were done without general anesthesia in all

patients. Intravaginal temperature, arterial blood pressure, heart rate,hemoglobin concentration, hematocrit, and arterial oxyhemoglobinsaturation were monitored at the time when pO2 readings were taken.

The pretherapeutic pO2 measurements were usually done 1 to 5 daysbefore oncological treatment. After histologic examination of the

biopsy specimens, pO2 measurements in necrotic tissue areas wereexcluded from analysis.

Immunohistochemistry. Expression of GLUT-1 was assessed in 80biopsy specimens taken from the tumor pO2 measurement tracksobtained directly after pO2 measurement in 47 patients. Two biopsies,corresponding to the 6 and 12 o’clock positions of the tumor centerwere available for each of 33 patients and one biopsy for each of theremaining 14 cases. All material was fixed in formalin before beingembedded in paraffin. Histologic slides were prepared from theparaffin blocks and dried overnight at 37jC. Subsequently, specimenswere dewaxed in two changes of fresh xylene and rehydrated in adescending alcohol series. Retrieval of antigenic binding sites wasdone by heating specimens in 10 mmol/L citrate buffer (pH 6.0) in amicrowave oven for 17 minutes. GLUT-1 polyclonal rabbit anti-human GLUT-1 clone MYM (DakoCytomation, Hamburg, Germany)was used as the primary antibody at a concentration of f1 Ag/mL inantibody diluent (DakoCytomation, 1:200 dilution). Incubation tookplace overnight at 4jC. A biotinylated goat anti-mouse/rabbitsecondary antibody was applied for 30 minutes at room temperatureand further detection was carried out using a streptavidin-biotin-horseradish peroxidase system (Duet-Kit, DakoCytomation), inaccordance with the manufacturer’s instructions. Negative controlspecimens were treated with antibody diluent without the primary

antibody under the same conditions. Slides were counterstained withMayer’s hematoxylin, dehydrated in an ascending alcohol series andcovered with a coverslip using Eukitt mounting medium (Riedel-deHaen, Seelze, Germany).

Assessment of GLUT-1 expression. A semiquantitative scoring systemwas used to assess the degree of GLUT-1 expression in entire biopsysections: score 0, no staining or only very few positive cells (‘‘absent’’);score 1, <10% positive (‘‘weak’’), score 2, 11% to 50% positive(‘‘moderate’’); score 3, >50% positive (‘‘strong’’). Each specimen wasscored by two independent observers (A.M. and A.W.). Discordant caseswere reevaluated and discussed using a conference microscope.

Statistical analysis. All statistical tests were done using the SPSSsoftware package (version 11.5; SPSS, Inc., Chicago, IL). The

www.aacrjournals.org Clin Cancer Res 2005;11(7) April 1, 20052769

Table 1. Patient and tumor characteristics at the timeof pretherapeutic oxygen tensionmeasurements

No.patients Median Range

FIGO stagesIB 6IIA 1IIB 26IIIA 1IIIB 9 (6)IVA 2 (0)IVB 2

Grading1 7 (6)2 19 (17)3 14 (13)ND 7 (6)

pTstagespT1b 5pT2a 2pT2b 20pT3b 3NA 17 (12)

pN stagesN0 10N1 18NX 2NA 17 (12)

Largest tumordiameter (mm)

60 (50) 0-150 (0-80)

Menopausal statusPremenopausal 24 (23)Postmenopausal 23 (19)

Patient age (y)<55 27 (26) 52 26-80z55 20 (16)

Hemoglobin concentration (g/dL)<12 g/dL 13 (11) 12.8 (12.9) 9.3-16.4z12 g/dL 33 (31)ND 1 (0)

NOTE: Numbers in brackets indicate deviations for the subgroup of patientstreated with curative intent (survival correlations).Abbreviations:ND, not documented;NA, not applicable, no surgical treatment(radiation only).

GLUT-1and Oxygenation Status in Cervical Cancers



significance level was set at a = 5% for all comparisons. Linearcorrelations between two variables were described by Spearman’srank correlation coefficient (U). Two-sided Mann Whitney U testsand Kruskal Wallis tests were used for comparison of categorizedvariables. Survival estimates were calculated using the Kaplan-Meiermethod and differences between groups were assessed with log-rank statistics. The Cox proportional hazards model was used forthe multivariate analysis of the effect of individual factors onsurvival.

Results

GLUT-1 expression. GLUT-1 expression exhibited a charac-teristic pattern, with staining intensity increasing as a function

of distance from the vascularized tumor stroma (Fig. 1), beingparticularly strong in the viable cell layers immediately adjacent

to necrotic areas. Erythrocytes and perineural tissue invariably

stained positive. Variation of erythrocyte staining intensity was


Fig. 1. Expression patterns and score ofGLUT-1expression (histologic photographs,20�magnification) with respective oxygentension (pO2) histograms for hypoxic (top)andnormoxic tumors (bottom). Examples ofhigh and low expression of GLUT-1aredepicted; n = number ofpO2 readings in therespective measurement track. Note thatpositive staining (bottom right) is foundalmost entirely in erythrocytes.




very low, indicating a neglectable batch to batch variation inoverall GLUT-1 immunoreactivity. No positive staining wasseen in the vascular tumor stroma. GLUT-1 expression waspresent in 59 of 80 biopsies (f74%). Of these, GLUT-1expression was weak in 37 cases (f63%), moderate in 18 cases(f30%), and strong in four cases (f7%).

GLUT-1 expression, clinical, and pathohistologic data. GLUT-1expression increased linearly with Federation Internationale deGynecologie et d’ Obstetrique (FIGO) stage (r = 0.35, P = 0.002;see Fig. 2). Significantly higher expression of GLUT-1 was alsofound in larger tumors (r = 0.42, P = 0.0001) and in tumorswith a higher pT stage (r = 0.34, P = 0.015). GLUT-1 expressionshowed no correlation with histologic grading, pN stage,patient age, parity, and pretherapeutic hemoglobin level.

GLUT-1 expression and oxygenation data. The Kruskal-Wallis test showed no differences in median pO2, hypoxicfraction V2.5 mm Hg (HF 2.5) and hypoxic fraction V5 mm Hg(HF 5) between the four GLUT-1 expression scores. There werealso no statistically significant differences in GLUT-1 expressionbetween individual categories (e.g., absent expression versusstrong expression; Fig. 3). A subgroup analysis of squamous cellcarcinomas only (n = 60) also showed no differences in any ofthe oxygenation variables between the four classes of intensityof GLUT-1 expression. A weak trend (r = 0.34; P = 0.14, n = 20)was seen for higher values of HF 5 in non–squamous cellhistology cases with higher GLUT-1 expression. As Fig. 3 shows,some severely hypoxic tumors had weak to absent expression ofGLUT-1 and normoxic tumors repeatedly showed moderate tostrong GLUT-1 expression.

GLUT-1 expression and survival. Univariate Kaplan-Meiersurvival analysis showed significantly improved overall (P =0.004) and recurrence-free (P = 0.007) survival for patientswhose tumors entirely lacked (both biopsies negative in caseswhere two biopsies were available) expression of GLUT-1 (seeFig. 4). In addition, correlations with poorer overall andrecurrence-free survival, respectively, were found for thepresence of lymph node metastasis (P = 0.0002 and P =0.0001), higher pT stage (P = 0.02 and P = 0.0367) and higherFIGO stage (P = 0.0067 and P = 0.0248). When either pT stage

or pN stage were included in a multivariate Cox proportionalhazards analysis (only applicable in cases treated with surgery),there was no significant independent influence of GLUT-1expression on prognosis. Only pN stage remained a significantprognostic factor for overall (P = 0.015) and recurrence-free(P = 0.007) survival.

Discussion

The primary aim of this study was to evaluate the suitabilityof GLUT-1 as an endogenous marker of tumor hypoxia. Theexpression of GLUT-1 was analyzed using immunohistochem-istry in biopsy specimens taken from oxygenation measurementtracks done with the Eppendorf microsensor system. The factthat both measurements originate from identical tissue micro-areas is a novel feature of this study. Using this methodology,no correlation of GLUT-1 expression and oxygenation variables(median pO2, HF 2.5 and HF 5) were found. Several severelyhypoxic tissue biopsies showed weak or no expression ofGLUT-1, whereas moderate to strong expression was repeatedlyfound in normoxic specimens. In a recent study, Airley et al. (4)described a weak, albeit statistically significant, correlation ofhigher GLUT-1 expression in cases with higher values of HF 2.5.This finding may in the first instance be interpreted as beingcontradictory to our results. On closer examination however,the suitability of GLUT-1 as an endogenous hypoxia markerseems highly questionable from the data of both studies. Inagreement with our own results, Airley et al. (4) found nocorrelation of GLUT-1 expression with HF 5 and the study alsodoes not mention a correlation with the median pO2. Bothstudies show that GLUT-1 expression may be absent in asignificant amount of severely hypoxic tumors and that well-oxygenated tumors may exhibit very strong expression ofGLUT-1. Two recent studies compared GLUT-1 (and carbonicanhydrase IX) expression with the accumulation of the‘‘hypoxia-marker’’ pimonidazole and found a strong spatialcolocalization and correlation between the two variables,concluding that both proteins may be regarded as endogenoushypoxia markers (17, 26). This interpretation is problematic


Fig. 2. GLUT-1score as a function of FIGO stage (significantly positive correlation,P < 0.002).

Fig. 3. Fraction of pO2 readings V 5 mm Hg (HF 5) and GLUT-1scores in identicalmicroareas of locally advanced cancers of the uterine cervix. Note that somecircles represent more than one measurement.




since pimonidazole, as well as another ‘‘extrinsic’’ hypoxiamarker, EF5, have been shown not to correlate with theoxygenation status, as directly measured with microelectrodes(27–30). It also has to be kept in mind that prognosticcorrelations have thus far only been shown for the ‘‘snapshot’’picture of hypoxia acquired with the Eppendorf microsensortechnique, assessing all pathophysiologically relevant types ofhypoxia (acute and chronic), provided measurements innecrotic tissue areas can be excluded as done in our study.Similar to our findings, Hedley et al. (31) in a recent studyfound no correlation between a further HIF-1a target gene,carbonic anhydrase IX, and the oxygenation status measured bymicroelectrodes in cervical cancers. Applying the same experi-mental setup as that used in this study, we recently showed thatthere is also no direct correlation between HIF-1a expressionand oxygenation status in squamous cell carcinomas of theuterine cervix (32). HIF-1a data originating from this formerstudy were available for most of the cases reported in thepresent study and a preliminary analysis revealed no correlationbetween the two proteins. However, these data are not shown,because the methods for assessment were different and the twomarkers were not always analyzed in consecutive sections.

Expression of GLUT-1, much like HIF-1a, is induced by avariety of stimuli besides hypoxia. For GLUT-1, establishedinducing factors are glucose deprivation (33), oncogenictransformation (e.g., overexpression of c-MYC; ref. 34),inhibition of oxidative phosphorylation (35), angiotensin II(in mesangial cells; ref. 36), and osmotic stress (37, 38).According to our interpretation of the data, induction of HIF-1a and subsequent transactivation of GLUT-1 by hypoxia,although undoubtedly present, cannot be selectively identifieddue to the heterogeneous occurrence of the other above-mentioned factors in human cancer specimens.

Another important issue is the prognostic effect of GLUT-1 as amarker of the hypoxic response. In univariate analysis, animproved overall and recurrence-free survival in patients withcompletely absent GLUT-1 expression (i.e., two negativebiopsies) was found. Multivariate Cox regression analysisrevealed that both correlations were independent of FIGO stage,clinical tumor size, histologic grading, patient age, andpretherapeutic hemoglobin concentration. Inclusion of pT stageor pN stage into the model, however, abrogated the independentprognostic effect of GLUT-1 expression. The dependency of theprognostic relevance of GLUT-1 expression on T stage and Nstage has been described for other tumor entities (e.g., breastcarcinoma; ref. 23) and colorectal cancer (16, 22). The only studythat evaluated the prognostic effect of GLUT-1 expression incancers of the uterine cervix found a significant correlation withprognosis only for metastasis-free survival. A possible depen-dency of this correlation on nodal status could not be analyzed,as only patients treated with radiotherapy were examined (4).

A remarkable finding in the present study is the correlation ofGLUT-1 expression with FIGO stage, T stage, and maximumclinical tumor size. Correlations between GLUT-1 expressionand tumor size have also been described by others (14, 39–41)and may have important pathophysiologic implications.Because it is known (24) that tumor oxygenation is indepen-dent of tumor size, the finding is consistent with a partialGLUT-1 activation by factors other than hypoxia. Because theexpression pattern of GLUT-1 shows increasing intensitytowards areas of necrosis and with increasing distance fromthe stroma (containing the microvessels), it is probable thatenvironmental factors (e.g., glucose deprivation) are importantfor the expression of the protein. Activated oncogenes may havean effect on the degree of activation by these factors. Thisinfluence is likely to become more relevant in higher stages andlarger tumors, because oncogenic mutations, accumulatedduring malignant progression, may become more prevalent.

In conclusion, from the data of the present study as well asfrom recent findings by other groups, the role of GLUT-1 as anendogenous marker of tumor hypoxia is questionable, at leastfor cancers of the uterine cervix. There is an association ofGLUT-1 expression with prognosis, although correlations werenot independent, but instead were due to the association ofGLUT-1 expression with established factors of dominantprognostic relevance.

Acknowledgments

We thank Prof. Dr. M.A. Konerding (Department of Anatomy, University ofMainz) for providing the DISKUS image acquisition system, Beate Ko« hler for excel-lent technical assistance, and Dr. Debra K. Kelleher for her valuable assistance inpreparing this article.


Fig. 4. Kaplan-Meier plots for overall (top) and recurrence-free (bottom) survival ofGLUT-1-negative and GLUT-1-positive cases.





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2005;11:2768-2773. Clin Cancer Res Arnulf Mayer, Michael Höckel, Alexander Wree, et al. Cervical Cancers

AdvancedOxygenation Status: Lack of Correlation in Locally Microregional Expression of Glucose Transporter-1 and

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