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00006231-201310000-0000300006231_2013_34_953_xu_transplanted_10article< 94_0_19_5 >Nuclear Medicine Communications© 2013 Wolters Kluwer Health | Lippincott Williams & WilkinsVolume 34(10)October 2013p 953–958Correlation between 18F-FDG uptake and the expression of glucose transporter-1 and hypoxia-inducible factor-1α in transplanted VX2 tumors[ORIGINAL ARTICLES]Xu, Huiqina; Li, Biaod; Yu, Wenjinga; Wang, Huia; Zhao, Xuefenga; Yao, Yuanchunc; Huang, DakebDepartments of aNuclear MedicinebPathology, The First Affiliated Hospital of Anhui Medical UniversitycDepartment of Pathology, Anhui Medical University, HefeidDepartment of Nuclear Medicine, Shanghai Ruijin Hospital, the Affiliated Hospital of Shanghai Jiaotong Medical University, Shanghai, ChinaCorrespondence to Biao Li, PhD, Department of Nuclear Medicine, Shanghai Ruijin Hospital, the Affiliated Hospital of Shanghai Jiaotong Medical University, 197 the Second Ruijin Road, Shanghai 200032, China Tel: +86 138 055 16109; fax: +86 216 433 3548; e-mail: Received March 5, 2013Accepted June 28, 2013AbstractObjective: We investigated the correlation between fluorine-18-fluorodeoxyglucose (18F-FDG) uptake and glucose transporter-1 (GLUT-1) and hypoxia-inducible factor-1α (HIF-1α) expression in a rabbit lung VX2 tumor model.Materials and methods: Twenty-four VX2 tumor-bearing rabbits underwent 18F-FDG PET/computed tomography (CT) at 4, 5, 6, and 7 weeks after implantation. PET/CT images were obtained to monitor the tumor/normal tissue (T/N) ratio in each period. Six rabbits were randomly killed after PET/CT, and immunohistochemical staining was used to assess GLUT-1 and HIF-1α expression. We investigated the correlations of 18F-FDG uptake with GLUT-1 and HIF-1α expression and the pathological tumor (p-tumor) size as well as those of the lymph node metastasis (p-N) stage with the T/N ratio, p-tumor size, and GLUT-1 and HIF-1α expression.Results: The T/N ratio increased gradually over time before subsequently decreasing. The T/N ratio was significantly influenced by time (F=54.63, P<0.05) and was significantly correlated with GLUT-1 (r=0.53, P<0.01) and HIF-1α (r=0.44, P<0.01) expression and p-tumor size (r=0.58, P<0.05). A significant positive correlation between GLUT-1 expression and HIF-1α expression was also identified (r=0.58, P<0.05). The p-N stage showed a significant association with the T/N ratio (P<0.05) but not with GLUT-1/HIF-1α expression (P>0.05).Conclusion: 18F-FDG uptake is closely correlated with GLUT-1 and HIF-1α expression, tumor size, and lymph node metastasis.IntroductionThe occurrence of hypoxic conditions within tumors is a frequent phenomenon that appears to be strongly associated with malignant progression and the development of radioresistance 1,2. Biological markers that determine tumor hypoxia may be useful in the selection of treatment modalities and prediction of patient prognosis 3–5. The transcription factor hypoxia-inducible factor-1α (HIF-1α) enables cells to respond to hypoxia and plays an important role in tumor growth, angiogenesis, glucose uptake, glycolytic metabolism, apoptosis, and iron metabolism 6,7. The glucose transporter (GLUT) family is associated with the tumor hypoxia status. In particular, GLUT-1 is considered a possible intrinsic marker of hypoxia that affects the prognosis of malignant tumors by promoting glucose translation and enhancing the growth of primary tumors.The anatomical extent of the disease, as expressed by the tumor node metastasis stage, is at present the most important prognostic indicator for survival in patients with cancer. Noninvasive molecular imaging techniques, especially fluorine-18-fluorodeoxyglucose (18F-FDG) PET/computed tomography (PET/CT), are useful for estimating the stage, local recurrence, and metastasis and can be used to evaluate tumor hypoxia. Although 18F-FDG uptake, as measured by PET/CT, has been reported to reflect the hypoxic status 8–10, there are conflicting results on the correlation between 18F-FDG uptake and the presence of tumor hypoxia 11–14. To our knowledge, most studies thus far have not characterized such correlations in a dynamic and sequential manner. To determine whether 18F-FDG PET/CT could be used as a predictive marker for tumor hypoxia, the present study attempted to evaluate the correlation between 18F-FDG uptake and HIF-1α and GLUT-1 expression at different periods in a VX2 tumor model and investigate the relationships of these biological parameters with the pathological tumor node metastasis staging classification.Materials and methodsVX2 animal modelThe animal experiments were approved by the Animal Care Committee of Anhui Province. Adult New Zealand white rabbits weighing 2.5–3.0 kg were used in the study. The rabbit VX2 tumor model is an optimal animal lung tumor model because of its rapid growth and large tumor size. VX2 cells were initially grown in the hind limb of a donor rabbit. To implant the VX2 tumor into the lung, the tumor was surgically removed from the donor rabbit under general anesthesia and minced into 1-mm3 fragments with a pair of scissors. After receiving anesthesia, the recipient rabbit was fixed on the operating table. Under CT guidance, an 18-G needle was percutaneously inserted into the lung and its tip was positioned in the right lower lobe. Through a 20-G aspiration needle placed coaxially, we implanted one 1-mm3 piece of VX2 tissue 15. Three weeks after tumor implantation, CT was used to detect tumor formation and determine the size of the tumor; tumors that grew to ∼10–20 mm in diameter were selected for the experiment.18F-FDG PET/CT18F-FDG PET/CT was performed on the rabbits at 4, 5, 6, and 7 weeks after implantation. All animals were fasted for at least 6 h before scanning.18F-FDG (37 MBq/kg) was injected into each rabbit through an indwelling catheter in the auricular vein; PET/CT (Siemens Medical Systems, Erlangen, Germany) was performed 1 h after the injection. The rabbits were imaged in the supine position after general anesthesia with 3% pentobarbital (30 mg/kg), and the CT component was performed before the emission component. The parameters for CT were 120 kV, 80 mA, and a 5.0 mm pitch. Emission data were acquired at 7 min per bed position. The images were reconstructed using an iterative reconstruction algorithm to obtain CT, PET, and PET/CT fusion images of the VX2 lung-implanted tumor model. Two experienced nuclear medicine physicians blinded to all information independently evaluated the whole-body PET images for the presence of an abnormally increased uptake in the transplanted tumor. The maximum standardized uptake value (SUVmax) was calculated by measuring the maximal concentration of radioactivity in a region of interest and correcting it for body weight and the injected dose. The tumor tissue SUVmax, the contralateral normal lung tissue SUVmax, and the ratio of the two values (T/N ratio) were monitored using 18F-FDG PET/CT in each period and recorded.GLUT-1 and HIF-1α immunohistochemical stainingSix rabbits were humanely killed each week after 18F-FDG PET/CT imaging. Tumor samples and corresponding samples of normal lung tissue were collected, fixed in 10% buffered neutral formalin, and embedded in paraffin; 4-μm-thick slices were then cut from the tumor or tissue samples and mounted on glass slides for histological staining. The slides were heated in citrate buffer (0.01 M, pH 6.0) for 20 min in a microwave oven and blocked with methanol containing 3% hydrogen peroxide for 10 min at room temperature. For immunohistochemical detection of GLUT-1 and HIF-1α, the specimens were incubated overnight at 4°C with GLUT-1 (dilution, 1 : 200; Boaosheng Biologicals, Beijing, China) and HIF-1α (dilution, 1 : 200; Novus Biologicals, Littleton, Colorado, USA). The slides were then incubated with a secondary horseradish peroxidase-labeled immunoglobulin and washed with Tris-buffered saline Tween solution three times for 5 min each. Hematoxylin was used as a nuclear counterstain.Data analysisThe immunohistochemical staining was evaluated by two pathologists in a blinded manner and discrepancies were resolved in conference. We investigated GLUT-1 and HIF-1α expression using scoring analysis. For the immunohistochemistry results, cytoplasm/membrane reactivity was considered positive for GLUT-1 and nuclear reactivity was considered positive for HIF-1α. The levels of cytoplasm/membrane/nuclear reactivity were classified as follows: 0+, no staining; 1+, positivity in 1–10% of cells; 2+, positivity in 10–50% of cells (weak staining); 3+, positivity staining in 50–80% of cells (moderate staining); and 4+, positive staining in more than 80% of cells (strong staining). Scores of 2+ or above were considered to indicate positivity for HIF-1α and GLUT-1. The tumor sample on each slide was divided evenly into 10 regions, and in each region one field of high magnification (×100 for GLUT-1, ×200 for HIF-1α) was chosen. The percentage of positively stained cells for each field was calculated by dividing the number of stained cells by the total area containing tumor cells. The average obtained from all of the selected fields was taken as the final expression level of GLUT-1 and HIF-1α for each rabbit. Normal lung tissue samples were analyzed using the same method to determine the percentage of normal lung cells that were positively stained for GLUT-1 and HIF-1α. Each period’s T/N and its corresponding staining goals were recorded for each rabbit, which were then categorized as groups A, B, C, or D.Statistical analysisStatistical analyses were performed using SPSS Software (version 17.0; SPSS Inc., Chicago, Illinois, USA). The results are expressed as mean±SD. One-way analysis of variance was used to compare the T/N ratio among the four groups. Spearman’s rank correlation coefficient was used to evaluate associations between the T/N ratio and expression of the hypoxia-related markers and the pathological tumor (p-tumor) size. The association between the lymph node metastasis (p-N) stage and the T/N ratio and GLUT-1 and HIF-1α expression was investigated using logistic regression analysis. A P value of less than 0.05 was considered statistically significant.ResultsVX2 tumor model and PET/CT imagingAs shown on 18F-FDG PET/CT images, we successfully grew a solitary VX2 tumor in the right lung lobes of 24 animals. Compared with the tumors in animals of groups A, B, and C, an obvious increase was observed in the uneven distribution of radioactivity, with cavity formation and pervasive lymph node metastasis in group D. The average T/N ratios of the four groups were 9.12±0.54, 13.09±0.49, 14.27±1.05, and 11.76±0.72, respectively (Fig. 1). Significant differences in the T/N groups were detected between any two group pairs with the exception of groups B and D. The median p-tumor sizes in the four groups were 1.31±0.17, 2.25±0.35, 2.40±0.51, and 2.67±0.43 cm, respectively. Of the 24 rabbits, 12 were confirmed to have lymph node metastasis (p-N1) stage.Fig. 1. Fluorine-18-fluorodeoxyglucose (18F-FDG) PET/computed tomography images of a VX2 transplant tumor in a rabbit at different periods. (a) Fourth week, 18F-FDG accumulation was observed in the right lung lobe [tumor/normal tissue (T/N) ratio=9.12]. (b) Fifth week, a visible increase in 18F-FDG accumulation was detected (T/N ratio=13.09). (c) Sixth week, an additional increase in 18F-FDG accumulation with lymph node metastasis was observed (T/N ratio=14.27). (d) Seventh week, a decline in 18F-FDG accumulation with an uneven distribution of radioactivity and pervasive lymph node metastasis was observed (T/N ratio=11.76).VX2 tumor histopathologyImmunohistochemical analysis was performed to assess GLUT-1 and HIF-1α expression in tumors. Nine tumors (37.5%) were moderately positive for HIF-1α and six tumors (25%) were strongly positive for HIF-1α. GLUT-1 was moderately expressed in 10 tumors (41.7%) and strongly expressed in five tumors (20.8%; Table 1). Varying degrees of necrosis were observed in the four groups. For GLUT-1, positivity was indicated as cytoplasmic expression. Compared with the expression in group C, a decrease in GLUT-1 expression was observed in group D. In this group, positive GLUT-1 staining was detected mainly in viable tumor cells distributed at the fringe of areas of spontaneous focal necrosis. Further, the HIF-1α expression was seen to be principally nuclear, although it was also observed in the cytoplasm. Moreover, in this group, a lower HIF-1α expression was detected, similar to what was observed for GLUT-1. Areas of densely packed tumor cells intermixed with areas of necrotic cells were also detected in this group (Fig. 2). Positively stained VX2 tumor cells were usually located in the periphery of the necrotic tumor regions, and this staining distribution was consistent with the results of previous reports on other non-VX2 tumors 16,17.Table 1 Immunohistochemical staining of hypoxic markers in the rabbit VX2 tumorFig. 2. Immunohistochemical expression of glucose transporter-1 (GLUT-1) and hypoxia-inducible factor-1α (HIF-1α) in the rabbit VX2 transplanted tumor model (original magnification, ×400). (a1–d1) Expression of GLUT-1 in groups A, B, C, and D, respectively. (a2–d2) Expression of HIF-1α in groups A, B, C, and D, respectively.Correlation between the T/N ratio and GLUT-1/HIF-1α expressionThe correlations between the T/N ratio and hypoxic marker expression are shown in Fig. 3. In VX2 tumors, the T/N ratio was significantly correlated with both GLUT-1 (r=0.53, P<0.01) and HIF-1α expression (r=0.44, P<0.01). A positive correlation between GLUT-1 and HIF-1α was also observed (r=0.57, P<0.01).Fig. 3. Correlations among the tumor/normal tissue (T/N) ratio, tumor size, and immunostaining indices of hypoxic markers. Significant correlations were noted between the T/N ratio and pathological tumor (p-tumor) size (r=0.58, P<0.05) and the staining indices of hypoxia-inducible factor-1α (HIF-1α) (r=0.44, P<0.05) and glucose transporter-1 (GLUT-1) (r=0.53, P<0.05) in VX2 tumors. A positive correlation between GLUT-1 and HIF-1α expression was also noted (r=0.57, P<0.05). r indicates Spearman’s correlation coefficient.Correlation between the T/N ratio and p-tumor sizeAs the tumors grew in size, the T/N ratio significantly increased from groups A to C. The probability of T/N ratios greater than 12 was 76.9% in rabbits with tumor diameters exceeding 20 mm, whereas this probability decreased to 27.2% when the tumor diameter was less than 20 mm (Fig. 3).The relationships between the p-N stage and the T/N ratio and GLUT-1/HIF-1α expressionThe T/N ratio was positively correlated with the p-N stage. Animals with elevated T/N ratios tended to have p-N1 stage tumors. The probability of a p-N1 stage was 64.3% in rabbits with T/N ratios higher than 12, whereas it was 16.7% in rabbits with T/N ratios less than 10. The GLUT-1 and HIF-1α expression was not associated with the p-N stage (Table 2).Table 2 Logistic regression analysis of the correlations between the p-N stage and the T/N ratio and GLUT-1/HIF-1α expressionDiscussionAlthough the high 18F-FDG uptake observed in malignant tumors is due to increased glucose metabolism, data on the relationship between hypoxia and 18F-FDG uptake have been limited and inconsistent in the clinical setting 18. In the present study, we succeeded in visualizing the hypoxic status in rabbits with VX2 tumors using 18F-FDG PET/CT and confirmed it histologically by means of immunostaining. We found that 18F-FDG accumulation was significantly correlated with GLUT-1 and HIF-1α expression. It has been hypothesized that adaptation to the tumor microenvironment is important because proliferating cancer cells often have an insufficient blood supply 19. Tumor cells activate HIF-1 to survive under hypoxic stress. HIF-1 is a heterodimer that functions as the master regulator of oxygen homeostasis. It is composed of two constitutively expressed subunits: HIF-1α and HIF-1β. HIF-1β is ubiquitously expressed, whereas HIF-1α is destabilized under normoxic conditions. Previous studies reported that HIF-1α controls oxygen delivery by means of angiogenesis and metabolic adaptation to hypoxia through glycolysis 20. Izuishi et al. 21 and Kaira et al. 22 observed a significant correlation between SUV and HIF-1α expression. Our data support previous findings that HIF-1α expression contributes to 18F-FDG uptake in VX2 tumors. In our study, the T/N ratio was significantly correlated with HIF-1α expression. The increased expression level of HIF-1α coincided with the increasingly larger T/N ratio across groups A to C, further supporting the hypothesis that tumor hypoxia contributes to 18F-FDG uptake.GLUT-1 expression has been investigated in various cancers. Recent studies revealed that hypoxia can regulate GLUT-1 expression by elevating the HIF-1α translation rate to adapt to the increasing energy needs and to promote tumor cell survival 6. However, Tohma et al. 23 reported that the correlation between GLUT-1 expression and 18F-FDG uptake was low. In contrast, Kato et al. 24 and Taylor et al. 25 observed a significant correlation between SUV and GLUT-1 expression. Kaira et al. 26 reported that 18F-FDG uptake is determined by glucose metabolism, angiogenesis, and HIF-1 and p53 expression in thymic epithelial tumors. In this study, increases in both the T/N ratio and HIF-1α expression were positively correlated with GLUT-1 expression, which suggests that a GLUT-1 overexpression mediated by activated HIF-1α was responsible for the increased energy supply. Taking into consideration our data and the data reported in previous studies, we suspect that GLUT-1 is responsible for the regulation of 18F-FDG uptake.In this study, we observed statistically significant differences in the T/N ratio among the four groups. Similar to the trend for tumor size, the average T/N ratio of tumors increased from groups A to C, which was indicative of rapid tumor growth with increasing energy needs and extremely hypoxic conditions within the tumor. Compared with the findings in group C, the mean T/N ratio and expression levels of HIF-1α and GLUT-1 were slightly lower in group D, in addition to the findings of a lower number of viable tumors and obvious necrosis. Excessive cell necrosis and autocytolysis were responsible for the decreases in the T/N ratio and hypoxic marker expression. However, no significant difference in the T/N ratio was observed between groups B and C, suggesting that proliferation in the tumor and cell necrosis achieved a rough balance during this period. Furthermore, the scanning interval between adjacent groups was limited (7 days), thereby making it potentially difficult to detect differences using PET/CT.A relationship between SUVmax and tumor size has been reported in many studies and has been observed in various organs, such as the colon 27, pancreas 28, and breast 29. Our result agrees with the theory that SUV is correlated with tumor size. However, in our study, the T/N ratio was significantly correlated with lymph node metastasis (p-N1). Kato et al. 30 reported that tumors with high SUVmax values tend to be categorized as p-N1, which is consistent with our data. However, Taylor et al. 25 reported that the SUVmax of a primary tumor is associated with the p-tumor size but not with p-N staging. Further, no statistically significant differences were noted in GLUT-1 and HIF-1α expression according to the p-N stage.Our data suggest that SUVmax reflects tumor size and the presence of lymph node metastasis in malignant tumors. In conclusion, our molecular-based analysis suggests that 18F-FDG uptake is closely related to the expression of GLUT-1 and HIF-1α. SUVmax, as measured using 18F-FDG PET/CT, may be a good noninvasive biomarker for predicting the hypoxic status; further, the SUVmax of a primary tumor is related to tumor size and lymph node metastasis.AcknowledgementsThis study was supported by Anhui Science and Technology Planning Project (No. 10021303025).Conflicts of interestThere are no conflicts of interest.References1. Brown JM.Exploiting the hypoxic cancer cell: mechanisms and therapeutic strategies.Mol Med Today2000;6:157–162. [CrossRef] [Medline Link] [Context Link]2. 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