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Glucose Transporter GLUT1 Expression Is an Stage-Independent Predictor of Clinical Outcome in Adrenocortical Carcinoma

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Glucose Transporter GLUT1 Expression Is an Stage-Independent Predictor of Clinical Outcome in Adrenocortical Carcinoma Endocrine-Related Cancer (2009) 16 919–928 Glucose transporter GLUT1 expression is an stage-independent predictor of clinical outcome in adrenocortical carcinoma Wiebke Fenske1*, Hans-Ullrich Vo¨lker 2*, Patrick Adam 2, Stefanie Hahner 1, Sarah Johanssen1, Sebastian Wortmann1, Melanie Schmidt3, Michael Morcos4, Hans-Konrad Mu¨ller-Hermelink 2, Bruno Allolio1 and Martin Fassnacht1 1Endocrine and Diabetic Unit, Department of Internal Medicine I, University Hospital of Wu¨rzburg and 2Institute of Pathology, University of Wu¨rzburg, Josef-Schneider-Strasse 2, D-97080 Wu¨rzburg, Germany 3Department of Gynaecology, University Hospital of Wu¨rzburg, Wu¨rzburg, Germany 4Department of Internal Medicine I, University Hospital, University of Heidelberg, Heidelberg, Germany (Correspondence should be addressed to M Fassnacht; Email: [email protected]) *(W Fenske and H-U Vo¨lker contributed equally to this work) Abstract Owing to the rarity of adrenocortical carcinoma (ACC) no prognostic markers have been established beyond stage and resection status. Accelerated glycolysis is a characteristic feature of cancer cells and in a variety of tumour entities key factors in glucose metabolism like glucose transporter 1 and 3 (GLUT1 and -3), transketolase like-1 enzyme (TKTL1) and pyruvate kinase type M2 (M2-PK) are overexpressed and of prognostic value. Therefore, we investigated the role of these factors in ACC. Immunohistochemical analysis was performed on tissue microarrays of paraffin-embedded tissue samples from 167 ACCs, 15 adrenal adenomas and 4 normal adrenal glands. Expression was correlated with baseline parameters and clinical outcome. GLUT1 and -3 were expressed in 33 and 17% of ACC samples respectively, but in none of the benign tumours or normal adrenals glands. By contrast, TKTL1 and M2-PK were detectable in all benign tissues and the vast majority of ACCs. GLUT1 expression was strongly associated with prognosis in univariate and multivariate analysis (P!0.01), whereas GLUT3, TKTL1 and M2-PK did not correlate with clinical outcome. Patients with strong GLUT1 staining showed a considerably higher overall mortality (hazard ratio (HR) 6.34 (95% confidence interval 3.10–12.90) compared with patients with no GLUT1 staining. When analysing patients in their early stages and advanced disease separately, similar results were obtained. HR for survival was 5.31 (1.80–15.62) in patients with metatastic ACC and in patients after radical resection the HR for disease-free survival was 6.10 (2.16–16.94). In conclusion, GLUT1 is a highly promising stage-independent, prognostic marker in ACC. Endocrine-Related Cancer (2009) 16 919–928 Introduction Many patients present with locally advanced or meta- Adrenocortical carcinoma (ACC) is a rare disease static disease and up to 85% of patients with radically characterised by an aggressive behaviour with an resected tumours relapse (Allolio & Fassnacht 2006, overall 5-year survival ranging from 16 to 44% Fassnacht et al. 2006). Disease stage and completeness (Dackiw et al. 2001, Allolio et al. 2004, Allolio & of initial resection are currently the only widely Fassnacht 2006, Libe et al. 2007, Fassnacht et al. accepted determinants of outcome for this disease 2009). The precise pathogenesis of ACC is still poorly (Barzon et al. 1997, Vassilopoulou-Sellin & Schultz understood and due to the rarity of the disease 2001, Schteingart et al. 2005, Fassnacht et al. 2009). prognostic assessment and treatment strategies are However, these features are poorly applicable when not well standardised (Schteingart et al.2005). fronting patients at a given stage and only partly reflect Endocrine-Related Cancer (2009) 16 919–928 Downloaded from Bioscientifica.comDOI: 10.1677/ERC-08-0211 at 09/25/2021 08:38:42PM 1351–0088/09/016–919 q 2009 Society for Endocrinology Printed in Great Britain Online version via http://www.endocrinology-journals.orgvia free access W Fenske, H-U Vo¨lker et al.: GLUT1 in adrenal cancer the wide prognostic heterogeneity of the disease. TKTL1 and M2-PK in patients with ACC, with benign Therefore, histological and molecular features for adrenal adenomas, and in normal adrenal glands. In prediction of tumour behaviour would be of major addition, we have analysed the prognostic value of importance for tailored therapeutic decisions. these markers in ACC. However, till date reliable prognostic factors for survival in ACC are lacking. More than 80 years ago, Warburg (1956) described Material and methods that one of the most fundamental characteristics of cancer cells is an increased level of glucose Clinical data and specimen uptake and its anaerobic metabolism. Most recently, A total of 186 adrenocortical tissues were collected several key factors in glucose metabolism have from patients undergoing surgery for ACC (nZ167), been described to be overexpressed in different aldosterone-producing adenoma (nZ5), cortisol- human carcinomas (for e.g. glioblastoma, colorectal, producing adenoma (nZ5) and endocrine inactive gastric, pancreatic and breast cancer (Reske et al. adenomas (nZ5). The normal adrenal tissue was 1997, Grover-McKay et al. 1998, Urano et al. 2006, derived from adrenal glands removed as part of tumour Wincewicz et al. 2007). Especially, the hypoxia- nephrectomy (nZ4). Table 1 summarises the charac- responsive glucose transporters isoforms 1 and 3 teristics of patients and tissue samples included in this (GLUT1 and -3) have been shown to be associated study. A total of 134 ACC samples were derived from with shortened survival in several tumour entities (as surgery of the primary tumour; 19 of local recurrence in colon, urethelial, oral squamous cell, and head and and 14 of distant metastasis. The diagnosis of ACC was neck carcinomas (Smith 1999, Langbein et al. 2006, based on established clinical, biochemical and Eckert et al. 2008, Zhou et al. 2008)) and may morphological criteria (Allolio & Fassnacht 2006). possibly assist in the selection of patients for more aggressive therapy. In addition, high expression of All histological diagnoses were confirmed by the transketolase like-1 enzyme (TKTL1) in tumour cells reference pathologist of the German ACC Registry is correlated with poor clinical outcome in colon and (Wolfgang Saeger, Hamburg, Germany) and malig- R urothelial cancer (Langbein et al. 2006). TKTL1 nancy was established by a Weiss score 3(Weiss encodes an alternative transketolase transcript, open- et al. 1989). Clinical data of ACC patients, including ing a new energy source for the tumour cell by follow-up and survival data, were collected in a enabling oxygen-independent glucose degradation structured manner by the German ACC Registry and allowing glucose conversion to ribose for nucleic (www.nebennierenkarzinom.de; Koschker et al. acid synthesis (Coy et al. 2005). Specific transketo- 2006, Fassnacht et al. 2009). Tumour staging was lase inhibitors slow down tumour cell proliferation based on imaging studies and findings during surgery, (Comin-Anduix et al. 2001), whereas the activation and was reported according to the UICC/WHO of transketolase stimulates tumour growth (Rais et al. classification 2004 (DeLellis et al. 2004). Owing to 1999). In many tumour cells, the pyruvate kinase the retrospective data collection, pre-surgical endo- equilibrium is dysregulated at the cost of ATP crine work-up and imaging intervals during follow-up production by expression of the dimeric pyruvate were not standardised. However, in the majority of kinase type M2 (M2-PK). This mechanism allows patients glucocorticoid and/or androgen excess was tumour cells to invade areas with low oxygen and investigated with at least three of the following tests: glucose concentrations (Mazurek et al. 2005) and serum cortisol; plasma ACTH; 24-h urinary free might be relevant for the clinical behaviour of the cortisol; 1 mg dexamethasone suppression test; serum tumour (Yoo et al. 2004). dehydroepiandrosteronsulfat (DHEA-S); androsten- Owing to the rarity of ACC, single centres were not dione; 17-OH progesterone; and testosterone able to collect an adequate sample of tumours for (Fassnacht et al. 2004). Surgery of the primary tumour investigating the role of glucose metabolism in ACC was judged as radical resection if surgical, pathological carcinogenesis and to correlate factors in glucose and imaging; reports did not provide evidence for metabolism with clinical outcome. Owing to the macroscopically remaining disease. The database for efforts of the German ACC Registry Group, we were follow-up information was locked in May 2008. able to collect 167 clinically annotated ACC tumour Patients gave informed consent for collecting tissue samples. In the present study, we have used tissue and clinical data and the study was approved by the microarrays (TMAs) and immunohistochemistry ethics committee of the University of Wu¨rzburg analysis to investigate expression of GLUT1, -3, (Germany, board approval number 92/02 and 86/03). Downloaded from Bioscientifica.com at 09/25/2021 08:38:42PM via free access 920 www.endocrinology-journals.org Endocrine-Related Cancer (2009) 16 919–928 Table 1 Patients and tumour characteristics Primary tumour Age (years) Sex (M/F) size (cm) ACC Primary tumour (nZ134) 49 (16) (48/86) 12 (4.4) WHO I (nZ5)a 54 (24) (2/3) 4.5 (0.2) WHO II (nZ53) 48 (16) (20/33) 11.5 (4.4) WHO III (nZ26) 52 (14) (10/16) 11.4 (3.8) WHO IV (nZ45) 49 (17) (14/31) 13.4 (4) Local recurrence (nZ19)b 46 (17) (9/10) – Distant metastases (nZ14)b 44 (11) (3/11) – Adenoma Aldosterone-producing adenoma (nZ5) 47 (14) 2/3 2.0 (0.1) Cortisol-producing adenoma (nZ5) 52 (22) 0/5 2.6 (0.3) Inactive adenoma (nZ5) 67 (20) 2/3 1.8 (0.3) Normal adrenal gland (nZ4) 63 (18) 3/1 – Data are mean (S.D.) or numbers. WHO, World Health Organization/international union against cancer UICC; f, female; m, male. aIn six cases tumour stage was not determined. bNineteen out of the 33 samples from surgery for recurrence or distant metastases derived from patients with more than one analysed sample.
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