Glucose Transporter 1 Overexpression Research Articles

Immunohistochemical Expression of GLUT-1 and HIF-1α in Tooth Germ, Ameloblastoma, and Ameloblastic Carcinoma.

Hypoxia-inducible factor-1α (HIF-1α) promotes proteins that enable cell survival during hypoxia, such as glucose transporter 1 (GLUT-1). Their coexpression has been associated with aggressiveness in malignancies and has not been studied in odontogenic tumors. Immunohistochemical expression of HIF-1α and GLUT-1 was analyzed in 13 tooth germs (TGs), 55 ameloblastomas (AMs), and 3 ameloblastic carcinomas (ACs). HIF-1α was negative in all TGs, and just 1 case of AM and 1 of AC had nuclear positivity. GLUT-1 expressed in ameloblastic cells of all TGs, AMs, and ACs, with an increasing intensity, respectively, and was significantly higher in solid AM than in unicystic AM (P = .041). Absence of nuclear HIF-1α in TGs and most AMs suggest that GLUT-1 may be induced by alternative pathways to hypoxia. However, in ACs, HIF-1α may be activated; however, to confirm this, additional cases are needed. GLUT-1 overexpression could be related to aggressiveness in AMs and ACs and must represent a normal metabolite in TGs.

Inhibition of glutamine utilization sensitizes lung cancer cells to apigenin-induced apoptosis resulting from metabolic and oxidative stress.

Recent studies have shown anticancer activity of apigenin by suppressing glucose transporter 1 (GLUT1) expression in cultured cancer cells; however, it is not clear whether apigenin can suppress glucose metabolism in lung cancer cells or sensitize them to inhibition of glutamine utilization-mediated apoptosis through metabolic and oxidative stress. We show that apigenin significantly decreases GLUT1 expression in mice. Furthermore, we demonstrate that apigenin induces growth retardation and apoptosis through metabolic and oxidative stress caused by suppression of glucose utilization in lung cancer cells. The underlying mechanisms were defined that the anticancer effects of apigenin were reversed by ectopic GLUT1 overexpression and galactose supplementation, through activation of pentose phosphate pathway-mediated NADPH generation. Importantly, we showed that severe metabolic stress using a glutaminase inhibitor, compound968, was involved in the mechanism of sensitization by apigenin. Taken together, the combination of apigenin with inhibitors of glutamine metabolism may provide a promising therapeutic strategy for cancer treatment.

Expression of hypoxic markers and their prognostic significance in soft tissue sarcoma.

Tumor hypoxia is significant in promoting tumor progression and resistance to therapy, and hypoxia-inducible factor 1α (HIF-1α) is essential in the adaptive response of cells to hypoxia. The aim of the present study was to investigate the expression of hypoxic markers and evaluate their prognostic significance in soft tissue sarcoma (STS). A retrospective analysis of 55 patients with STS from Pusan National University Hospital (Busan, Korea) between 1998 and 2007 was conducted, using immunohistochemistry to analyze the expression of HIF-1α, carbonic anhydrase 9 (CA9), glucose transporter-1 (GLUT1) and vascular endothelial growth factor (VEGF). The association between the overexpression of these markers and clinicopathological characteristics, including the overall survival (OS) and progression-free survival (PFS) in cases of STS, were investigated. Overexpression of HIF-1α, CA9, GLUT1 and VEGF was shown in 54.5, 32.7, 52.7 and 25.5% of tumors, respectively, and all exhibited a significant association with high French Federation of Cancer Centers (FNCLCC) grade and high American Joint Committee on Cancer (AJCC) stage. Overexpression of HIF-1α and CA9 was associated with a shorter OS and a shorter PFS. On multivariate analysis, AJCC stage and HIF-1α overexpression had independent prognostic significance. In the group receiving chemotherapy (n=27), HIF-1α overexpression was independently associated with a decreased OS. These results indicate that overexpression of HIF-1α and CA9 is associated with poor prognosis, and that HIF-1α overexpression is an independent unfavorable prognostic factor in STS.

Molecular mechanisms of [18F]fluorodeoxyglucose accumulation in liver cancer

To elucidate the molecular mechanisms underlying the insufficient sensitivity in the detection of hepatocellular carcinoma (HCC) by [18F] 2-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET), the characteristics of glucose metabolism-related protein expression in HCC were examined in liver metastasis from colorectal cancer (Meta). Thirty-four patients (14 Meta and 20 HCC) who underwent FDG-PET and hepatectomy were studied. The relationships between the maximum standardized uptake value (SUV) in tumors and the mRNA expression of glucose metabolism-related proteins [hexokinase (HK), glucose transporter 1 (GLUT1), and glucose-6-phosphatase (G6Pase)] and proliferating cell nuclear antigen (PCNA) were examined in snap-frozen specimens with quantitative PCR. Tumor detection rates were lower in HCC (15/20) compared to Meta (13/14) patients. HK and GLUT1 expression was lower and G6Pase expression was higher in HCC compared to Meta. In particular, GLUT1 overexpression was 92-fold in Meta and 11-fold in HCC compared to the surrounding liver. The SUV correlated with GLUT1 and PCNA expression in HCC, but not Meta patients. Of note, four cases of poorly differentiated (P/D) HCC compared to moderately differentiated (M/D) HCC produced completely different results for FDG uptake (SUV, 14.4 vs. 4.0) and mRNA expression (G6Pase expression, 0.007 vs. 1.5). Variations in the expression of glucose metabolism-related enzymes between HCC and Meta patients are attributed to origin or degree of differentiation. Low FDG uptake in M/D HCC reflected low GLUT1 and high G6Pase expression, while high FDG accumulation in P/D HCC could reflect increased GLUT1 and decreased G6Pase expression. These results may explain why M/D HCC is not detected as sensitively by FDG-PET.

Overexpression of Glucose Transporter-1 (GLUT-1) Predicts Poor Prognosis in Epithelial Ovarian Cancer

Illumina microarray was used to identify differentially expressed genes in three epithelial ovarian cancer (EOC) cells. To validate the microarray data, mRNA and protein level of glucose transporter-1 (GLUT-1) was examined. GLUT-1 had an EOC/normal cells ratio of 5.51 based on microarray. Real-time PCR and immunohistochemistry demonstrated that GLUT-1 expression was significantly increased in EOC (p = .029 and p < .001, respectively). On survival analysis, GLUT-1 overexpression (HR = 4.80, p = .027) and lymph node metastases (HR = 8.35, p = .016) conferred a significantly worse overall survival. In conclusion, GLUT-1 expression is remarkably upregulated in EOC and predicts a poor overall survival.

Abstract C60: Vitamin C inhibits the survival and growth of colorectal cancer cells with KRAS or BRAF mutations

Abstract Although more than half of colorectal cancer patients have either KRAS or BRAF mutations, targeted therapies for these subgroups of cancer patients are lacking. We previously showed that isogenic human colorectal cancer cell (CRC) lines harboring a KRAS or BRAF mutation up-regulate the expression of glucose transporter 1 (GLUT1), and increase glucose uptake and glycolysis. In this study, we go on to show that KRAS or BRAF mutant cells exhibit a significant increase in the uptake of vitamin C, mainly in its oxidized form, dehydroascorbic acid (DHA), relative to their wild-type counterparts through GLUT1. Notably, CRCs did not uptake vitamin C in its reduced form, possibly due to the fact that its known transporters, sodium vitamin C cotransporters (SVCTs) were generally not present in CRCs. Deletion of GLUT1 in mutant cells, overexpression of GLUT1 in wild-type cells and competition assays between glucose and DHA confirmed that GLUT1 is both necessary and sufficient for the uptake of vitamin C in CRCs. Both mutant and wild-type cells were able to grow in low glucose (1-2 mM) at a similar rate. In the same condition, we found vitamin C to be selectively toxic to KRAS and BRAF mutant cells, causing them to undergo apoptosis. In contrast, in high glucose levels (&amp;gt;10 mM), a similar concentration of vitamin C had no effect on the survival and growth of mutant cells. In addition, vitamin C significantly inhibited the growth of cancer cells with KRAS or BRAF mutations in vivo xenografts models. To find the mechanism by which vitamin C induces cell death in KRAS or BRAF mutant cells, we performed targeted metabolomics using LC/MS. Both unlabeled total metabolite analysis and flux analysis with C13-Glucose isotope strongly suggested that vitamin C re-routes glucose usage from aerobic glycolysis and non-oxidative pentose phosphate pathway (PPP) to the oxidative PPP to compensate for the lower levels of NADPH which was rapidly consumed to reduce GSSH to GSH. Having taken up exclusively DHA, the oxidized state of vitamin C, the mutant cells immediately use GSH to reduce Vitamin C, resulting in the accumulation of GSSH. Shunting glucose to the oxidative PPP reduces aerobic glycolysis, lowering ATP levels, and decreases glucose anabolism, disfavoring the synthesis of nucleic acids, lipid and amino acids, all needed for the survival and growth of mutant cells. Surprisingly the level of reactive oxidative stress (ROS) was largely unchanged following vitamin C treatment possibly because increased levels of vitamin C served as an anti-oxidant in mutant cells. There are currently more than three clinical trials phase I/II examining the effect of high dose vitamin C via intravenous administration in patients against lymphoma or solid cancers including CRCs. Our findings will provide proof of concept that KRAS or BRAF mutations in CRC can be predictive biomarkers for vitamin C therapy. Citation Format: Jihye Yun, Adam Kavalier, Jatin Roper, Steve Gross, Carlo Rago, Nickolas Papadopoulos, Bert Vogelstein, Lewis Cantley. Vitamin C inhibits the survival and growth of colorectal cancer cells with KRAS or BRAF mutations. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr C60.

Enhanced expression of glucose transporter-1 in vascular smooth muscle cells via the Akt/tuberous sclerosis complex subunit 2 (TSC2)/mammalian target of rapamycin (mTOR)/ribosomal S6 protein kinase (S6K) pathway in experimental renal failure

Chronic renal failure (CRF) is associated with increased cardiovascular mortality, and medial vascular smooth muscle cell (VSMC) hypertrophy, proliferation, and calcification play a pivotal role in uremic vasculopathy. Glucose transporter-1 (GLUT1) facilitates the transport of glucose into VSMCs, and GLUT1 overexpression associated with high glucose influx leads to a stimulation of VSMC proliferation. However, the role of GLUT1 in uremic vasculopathy remains unclear. This study aimed to identify changes in the expression of GLUT1 in VSMCs in the setting of experimental uremia and investigate whether Akt/tuberous sclerosis complex subunit 2 (TSC2)/mammalian target of rapamycin (mTOR)/ribosomal S6 protein kinase (S6K) signaling, which plays a crucial role in VSMC proliferation and glucose metabolism, is involved in the regulation of GLUT1 expression. In vivo experimental CRF was induced in Wistar rats by 5/6 nephrectomy, and the GLUT1 expression in aortic tissue was determined by the reverse transcriptase-polymerase chain reaction, immunoblotting, and immunohistochemical staining. Indoxyl sulfate (IS) is a uremic retention solute proven with pro-proliferative effect on rat VSMCs, and we further studied the expression of GLUT1 in rat A7r5 rat embryonic aortic cells stimulated by IS in the presence or absence of phloretin, a GLUT1 inhibitor, to explore the pathogenic role of GLUT1 in uremic vasculopathy. The contribution of Akt/TSC2/mTOR/S6K signaling in modifying the GLUT1 expression was also assessed. Eight weeks after 5/6 nephrectomy, aortic tissue obtained from CRF rats exhibited increased wall thickness and VSMC hypertrophy, hyperplasia, and degeneration. Compared with the sham-operated control group, the messenger (m)RNA and protein abundance of GLUT1 were both markedly increased in CRF rats. In vitro, IS induced a significant increase in expression of GLUT1 protein as well as pro-proliferative cyclin D1 and p21 mRNA and a modest increase in expression of antiapoptotic p53 mRNA in A7r5 cells, whereas inhibition of GLUT1 mediated glucose influx reduced the pro-proliferative and antiapoptotic effects of IS. In addition to increased GLUT1 expression, IS significantly suppressed Akt and TSC2 phosphorylation after 6-hour and 12-hour treatment, but increased S6K phosphorylation after 3-hour treatment. Inactivation of mTOR downstream signaling by rapamycin treatment inhibited S6K phosphorylation and abolished the stimulatory effect of IS on GLUT1 expression. In vivo and in vitro experimental CRF displayed prominent GLUT1 upregulation in VSMCs. The uremic toxin IS stimulated proliferation of VSMCs possibly through induction of GLUT1 expression. The Akt/TSC/mTOR/S6K signaling pathway may be one of the mechanisms underlying the upregulation of GLUT1 expression in uremic VSMCs.

Adrenal Myelolipoma: An Unusual Cause of Bilateral Highly 18F-FDG-Avid Adrenal Masses

A 77-yr-old man presented with rapidly progressive cerebellar syndrome,extrapyramidal signs,andcognitive impairment. Past medical history reported a prostate cancer treated by external radiotherapy and an essential thrombocytemia with sideroblastic anemia. Brain computed tomography (CT) scan was normal. The combination of positive antineutrophil antibodies and brain 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) uptake pattern was suggestive of paraneoplastic neurological syndrome. Whole-body PET imaging revealed bilateral hypermetabolic adrenal masses (right and left adrenal maximumstandardizeduptakevalue 11.4and8.0).Abdominal CTscanshowedbilateralheterogeneousadrenalmassescontaining soft tissue and adipose components (Fig. 1). Complete endocrinological workup (24-h urinary free cortisol, low-dose dexamethasone suppression test, plasma aldosterone level, dehydroepiandrosterone sulfate, and urinary and plasma methoxyamines) was normal. A CT scan-guided adrenal puncture was performed to rule out malignancy. Pathological analyses were concordant with the diagnosis of myelolipoma. Bilateral high 18F-FDG PET uptake is usually due to adrenal malignancies (i.e. metastases, primary adrenal lymphoma) (1). A recent study has also reported an intense glucose hypermetabolism in bilateral adrenal hyperplasia with Cushing’s syndrome, which was not observed in our patient (2).Wereporthereavery rare caseofbenignhypermetabolic masses secondary to adrenal myelolipomas. The few reported cases of adrenal myelolipoma have usually shown no significant 18F-FDG uptake. An unusual case of giant adrenal myelolipoma with increased 18F-FDG uptake has been reported (3). In another case, high tracer avidity was due to a lung cancer metastasis within a myelolipoma (4). Interestingly, in our case, increased 18F-FDG avidity could be explained by overexpression of glucose transporter-1 within the myeloid tissue component of the mass (5). Myelolipomas should be considered as potential differential diagnoses of high 18F-FDG avid adrenal lesions, which consequently do not necessarily require adrenalectomy. A CT-guided biopsy directed at the focal area of hypermetabolism may be needed to rule out malignancy.

Overexpression of GLUT1 correlates with Kras mutations in lung carcinomas

Glucose is the major source of energy for cells, and glucose transporter 1 (GLUT1) is the most common glucose transporter. GLUT1 has been found to be aberrantly expressed in several tumor types. From the results of the microarray and serial analysis of gene expression (SAGE), GLUT1 transcript expression was found to be higher in clones with mutant Kras alleles. We hypothesized that GLUT1 overexpression might be correlated with clinicopathological features of Japanese lung cancers. Immunohistochemistry for GLUT1 was performed in 283 surgically treated non-small cell lung cancer (NSCLC) cases from Nagoya City University Hospital. Thirty-six Kras mutant carcinoma cases were included. GLUT1 overexpression was found in 138 (48.8%) lung cancer patients. The GLUT1 overexpression status was significantly correlated with gender (women 31.9% vs. men 54.5%, P<0.0001), smoking status (never smoker 31.4% vs. smoker 59.4%, P<0.0001) and pathological subtypes (adenocarcinoma 36.4% vs. non‑adenocarcinoma 74.5%, P<0.0001). In addition, the GLUT1 overexpression status was significantly correlated with gene mutation status, including EGFR (mutation-positive 23.4% vs. -negative 58.3%, P<0.0001) and Kras (mutation-positive 66.7% vs. -negative 46.6%, P=0.038). The survival of patients with GLUT1 overexpression (n=137, 50 were deceased) was significantly worse when compared to the patients with normal expression of GLUT1 (n=142, 31 were deceased) (Log-rank test, P=0.0009). Thus, GLUT-1 overexpression correlates with an aggressive phenotype of lung carcinoma.

The BRAF V600E Mutation in Papillary Thyroid Carcinoma Is Associated with Glucose Transporter 1 Overexpression

The glucose transporter 1 (GLUT1) is a key protein that facilitates the extensive glucose uptake of cancer cells, and its overexpression is associated with more aggressive tumor phenotypes. In cases of BRAF mutations, GLUT1 seems to be a target of the constitutive activation of the RAF/MEK/ERK pathway. In this study, we hypothesized that the common BRAF V600E mutation was associated with GLUT1 overexpression and proliferation in papillary thyroid carcinomas (PTCs). A total of 57 cases of paraffin-embedded PTC (31 BRAF V600E, 26 wild-type BRAF) were investigated using immunohistochemistry with antibodies against GLUT1 and Ki-67 (MK167) protein. The BRAF V600E mutations were detected using direct sequencing of genomic DNA that was isolated from formalin-fixed paraffin-embedded tumor tissues. GLUT1 expression was assessed using the Remmele immunoreactive score and subdivided into three groups (I=negative, II=weakly positive, and III=positive). The Ki-67 labeling index (Ki-67 LI) was determined by counting Ki-67-positive nuclei. GLUT1 expression was found in 39/57 (68.4%) samples of PTC. The occurrence of the BRAF V600E genetic variant was significantly correlated with GLUT1 overexpression (p=0.007) and showed a trend toward higher proliferation, which was indicated by Ki-67 LI (p=0.06). Moreover, GLUT1 overexpression was positively associated with Ki-67 labeling (p=0.023). The V600E BRAF mutation in PTC may contribute to the initiation of the glycolytic phenotype and confers growth advantages in cancer cells. Better understanding of the molecular mechanisms of cancer cell energy metabolism may lead to the implementation of targeted treatment modalities, which regulate cancer glucose uptake.

Modulation of Glucose Transporter 1 (GLUT1) Expression Levels Alters Mouse Mammary Tumor Cell Growth In Vitro and In Vivo

Tumor cells exhibit an altered metabolism characterized by elevated aerobic glycolysis and lactate secretion which is supported by an increase in glucose transport and consumption. We hypothesized that reducing or eliminating the expression of the most prominently expressed glucose transporter(s) would decrease the amount of glucose available to breast cancer cells thereby decreasing their metabolic capacity and proliferative potential.Of the 12 GLUT family glucose transporters expressed in mice, GLUT1 was the most abundantly expressed at the RNA level in the mouse mammary tumors from MMTV-c-ErbB2 mice and cell lines examined. Reducing GLUT1 expression in mouse mammary tumor cell lines using shRNA or Cre/Lox technology reduced glucose transport, glucose consumption, lactate secretion and lipid synthesis in vitro without altering the concentration of ATP, as well as reduced growth on plastic and in soft agar. The growth of tumor cells with reduced GLUT1 expression was impaired when transplanted into the mammary fat pad of athymic nude mice in vivo. Overexpression of GLUT1 in a cell line with low levels of endogenous GLUT1 increased glucose transport in vitro and enhanced growth in nude mice in vivo as compared to the control cells with very low levels of GLUT1.These studies demonstrate that GLUT1 is the major glucose transporter in mouse mammary carcinoma models overexpressing ErbB2 or PyVMT and that modulation of the level of GLUT1 has an effect upon the growth of mouse mammary tumor cell lines in vivo.

Overexpression of GLUT1 in Colorectal Cancer is Independently Associated with Poor Prognosis

To investigate the expression of glucose transporter 1 (GLUT1) in colorectal cancer (CRC) and its relationship to clinicopathological variables. The expression of GLUT1 in 163 primary tumors together with the corresponding normal mucosa, and 36 liver metastases was examined using real-time PCR. The mean value of GLUT1 was higher in primary tumors (50.390 ± 68.648) than in the corresponding normal mucosa (20.437 ± 28.703, p<0.0001), while there was no significant difference in GLUT1 expression between CRC and liver metastasis (50.390 ± 68.648 vs 52.277 ± 52.482, p=0.190). In CRCs, GLUT1 expression was higher in poorly differentiated than in well and moderately differentiated tumors (p=0.022), and higher in stage III + IV than in stage I + II tumors (p=0.035). The patients with high-expressed GLUT1 had a worse prognosis than those with low-expressed GLUT1 independently of gender, age, tumor site, stage and differentiation (p=0.026, RR 2.737, 95% CI 1.126-6.651) in stage I-III CRCs. In liver metastasis, GLUT1 expression was higher in larger tumors than in smaller ones (p=0.025). Overexpression of GLUT1 in stage I-III CRCs was independently associated with poor prognosis.

Glucose Transporter-1 in the Hypothalamic Glial Cells Mediates Glucose Sensing to Regulate Glucose Production In Vivo

OBJECTIVECirculating glucose inhibits glucose production in normal rodents and humans, but this glucose effectiveness is disrupted in diabetes due partly to sustained hyperglycemia. We hypothesize that hyperglycemia in diabetes impairs hypothalamic glucose sensing to lower glucose production, and changes of glucose transporter-1 (GLUT1) in the hypothalamic glial cells are responsible for the deleterious effects of hyperglycemia in vivo.RESEARCH DESIGN AND METHODSWe tested hypothalamic glucose effectiveness to increase hypothalamic glucose concentration and lower glucose production in rats induced with streptozotocin (STZ) uncontrolled diabetes, STZ and phlorizin, and whole-body and hypothalamic sustained hyperglycemia. We next assessed the content of glial GLUT1 in the hypothalamus, generated an adenovirus expressing GLUT1 driven by a glial fibrillary acidic protein (GFAP) promoter (Ad-GFAP-GLUT1), and injected Ad-GFAP-GLUT1 into the hypothalamus of rats induced with hyperglycemia. Pancreatic euglycemic clamp and tracer-dilution methodologies were used to assess changes in glucose kinetics in vivo.RESULTSSustained hyperglycemia, as seen in the early onset of STZ-induced diabetes, disrupted hypothalamic glucose sensing to increase hypothalamic glucose concentration and lower glucose production in association with reduced GLUT1 levels in the hypothalamic glial cells of rats in vivo. Overexpression of hypothalamic glial GLUT1 in STZ-induced rats with reduced GLUT1 acutely normalized plasma glucose levels and in rats with selectively induced hypothalamic hyperglycemia restored hypothalamic glucose effectiveness.CONCLUSIONSSustained hyperglycemia impairs hypothalamic glucose sensing to lower glucose production through changes in hypothalamic glial GLUT1, and these data highlight the critical role of hypothalamic glial GLUT1 in mediating glucose sensing to regulate glucose production.

Expression of hypoxia inducible factor-1α (HIF-1α) and glucose transporter-1 (GLUT-1) in ovarian adenocarcinomas: Difference in hypoxic status depending on histological character

The expression of hypoxia inducible factor-1alpha (HIF-1alpha) and glucose transporter-1 (GLUT-1) was immunohistochemically analyzed in ovarian adenocarcinomas with the aim of elucidating whether hypoxic status is associated with histological type or structural character. The following ovarian adenocarcinomas were used: serous adenocarcinoma (SEA), 21 cases; mucinous adenocarcinoma (MUA), 19 cases; endometrioid adenocarcinoma (ENA), 16 cases; clear cell adenocarcinoma (CLA), 19 cases. High-level expression (3+) of HIF-1alpha was observed in 100% of SEAs, 58% of MUAs, 100% of ENAs and 89% of CLAs, and high-level expression of GLUT-1 in 76% of SEAs, 26% of MUAs, 50% of ENAs and 67% of CLAs. Heterogeneous or localized staining was relatively evident for GLUT-1. Immunohistochemical profiles were in accord with the immunoblotting and mRNA levels of both markers. ELISA for the detection of active HIF-1 demonstrated that HIF-1 is strongly activated in SEAs, ENAs and CLAs as compared to MUAs. Our results show that GLUT-1 overexpression is to some extent regulated by HIF-1alpha and is also strongly associated with histological features, i.e., papillary or stratified structure accompanied by little or no vascular stroma. In conclusion, hypoxic status differs according to the histological type of ovarian adenocarcinoma and the micro-environmental conditions of each type.

Correlation of GLUT-1 Overexpression, Tumor Size, and Depth of Invasion with 18F-2-fluoro-2-deoxy-d-glucose Uptake by Positron Emission Tomography in Colorectal Cancer

We investigated the wide variability of 18F-2-fluoro-2-deoxy-D: -glucose (FDG) uptake, semiquantified as standardized uptake value (SUV), in positron emission tomography (PET) scanning, in 20 patients with colorectal cancer (CRC), including 1 with synchronous hepatic metastasis. The sensitivity of PET in CRC diagnosis was 100%, with a mean SUV of 8.0 (3.1-11.9). Tumor size and depth of invasion were associated with higher SUVs (P=.0004, .042, respectively). Strong glucose transporter-1 (GLUT-1) expression had significantly positive correlation with the SUV (r=.619, P=.003). GLUT-1 expression revealed positive staining in 17 (85%) of the 20 primary lesions. The central part of the tumor, thought to be relatively hypoxic, had stronger GLUT-1 expression and a higher SUV than the periphery, in both the primary tumor and hepatic metastatic foci. Our data suggest that the SUVs of FDG uptake in PET may be a noninvasive biomarker for advanced CRC, indicative of a large hypoxic tumor with deep invasion.

Evaluation of 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography in gastric carcinoma: relation to histological subtypes, depth of tumor invasion, and glucose transporter-1 expression

Variable uptake of 2-deoxy-2-[18F]fluoro-D-glucose (FDG) has been noticed in positron emission tomography (PET) studies of gastric carcinoma patients, with low uptake occurring especially in some particular histological subtypes and early carcinomas. But this phenomenon has not been adequately explained. The aim of the present study is to clarify FDG uptake in gastric carcinomas especially focusing on histological subtypes, the depth of tumor invasion, and glucose transporter-1 (GLUT-1) expression which is considered to be one of the major factors for higher FDG uptake in human malignant tumors. FDG-PET was performed on 35 preoperative patients with gastric carcinoma. Forty macroscopically distinguishable lesions on a surgical specimen were histologically classified into two subtypes: Cohesive type (papillary adenocarcinoma, tubular adenocarcinoma, and solid type poorly differentiated adenocarcinoma) or Noncohesive type (signet-ring cell carcinoma and non-solid type poorly differentiated carcinoma). GLUT-1 expression was immunohistochemically determined. Histological parameters (GLUT-1 expression, histological subtypes, the depth of invasion, lymphatic permeation, venous invasion and tumor size) were evaluated, and factors for FDG uptake (detectability and the degree) and GLUT-1 overexpression were determined by multiple regression analysis. Nineteen of 40 gastric carcinomas showed detectable FDG uptake (48%), multiple regression analysis revealed that both the depth of invasion and histological subtypes are independent factors that influence the detectable FDG uptake in gastric carcinoma (R2 = 0.66). GLUT-1 expression was seen from an early cancer stage and the cohesive type was an independent factor influencing the overexpression of GLUT-1 (R2 = 0.66). GLUT-1 expression was the most influential factor for the degree of FDG uptake in gastric carcinoma (R2 = 0.68). This study provided important information on the clinical application of FDG-PET in gastric carcinoma that early or non-cohesive gastric carcinoma may show lower FDG uptake. Therefore, the usefulness of FDG-PET for the detection of gastric carcinoma is limited. But there is a possibility that FDG uptake associated with GLUT-1 expression may serve as a prognostic factor of gastric carcinoma representing tumor metabolism.

Human T-Cell Leukemia Virus Type 1 (HTLV-1) and HTLV-2 Use Different Receptor Complexes To Enter T Cells

Studies using adherent cell lines have shown that glucose transporter-1 (GLUT-1) can function as a receptor for human T-cell leukemia virus type 1 (HTLV). In primary CD4(+) T cells, heparan sulfate proteoglycans (HSPGs) are required for efficient entry of HTLV-1. Here, the roles of HSPGs and GLUT-1 in HTLV-1 and HTLV-2 Env-mediated binding and entry into primary T cells were studied. Examination of the cell surface of activated primary T cells revealed that CD4(+) T cells, the primary target of HTLV-1, expressed significantly higher levels of HSPGs than CD8(+) T cells. Conversely, CD8(+) T cells, the primary target of HTLV-2, expressed GLUT-1 at dramatically higher levels than CD4(+) T cells. Under these conditions, the HTLV-2 surface glycoprotein (SU) binding and viral entry were markedly higher on CD8(+) T cells while HTLV-1 SU binding and viral entry were higher on CD4(+) T cells. Binding studies with HTLV-1/HTLV-2 SU recombinants showed that preferential binding to CD4(+) T cells expressing high levels of HSPGs mapped to the C-terminal portion of SU. Transfection studies revealed that overexpression of GLUT-1 in CD4(+) T cells increased HTLV-2 entry, while expression of HSPGs on CD8(+) T cells increased entry of HTLV-1. These studies demonstrate that HTLV-1 and HTLV-2 differ in their T-cell entry requirements and suggest that the differences in the in vitro cellular tropism for transformation and in vivo pathobiology of these viruses reflect different interactions between their Env proteins and molecules on CD4(+) and CD8(+) T cells involved in entry.

P300 and p53 levels determine activation of HIF-1 downstream targets in invasive breast cancer

In previous studies, we noted that overexpression of hypoxia-inducible factor (HIF)-1alpha in breast cancer, especially the diffuse form, does not always lead to functional activation of its downstream genes. Transcriptional activity of HIF-1 may be repressed by p53 through competition for transcriptional coactivators such as p300. The aim of this study was therefore to explore the role of p53 and p300 in relation to overexpression of HIF-1alpha and activation of HIF-1 downstream genes in invasive breast cancer. p300 immunohistochemistry was performed in a group of 183 early-stage invasive breast cancers, and related to p53 accumulation, overexpression of HIF-1alpha, and several HIF-1 downstream genes. p300 was expressed in varying degrees in 84% of invasive breast cancers. p300 staining intensity correlated positively with HIF-1alpha expression (P = .04), p53 accumulation (P = .001), and overexpression of glucose transporter 1 (GLUT-1) (P < .001), a glucose transporter downstream target gene of HIF-1. GLUT-1 levels were significantly associated with p300 in HIF-1alpha positive patients (P = .02). p53 accumulation significantly positively correlated with carbonic anhydrase IX (CAIX)/GLUT-1 coexpression in HIF-1alpha-positive patients (P = .007). p53 accumulation/high p300 levels, the most favorable situation for HIF-1 downstream activation, were significantly associated with GLUT-1 overexpression (P = .01) and coexpression of CAIX/GLUT-1 (P = .03), compared with low p53/low p300 levels, the most unfavorable situation for HIF-1 downstream activation. p300 is a cofactor highly associated with p53 accumulation and HIF-1alpha levels in invasive breast cancer. Furthermore, low levels of p300 may explain absence of downstream effects in HIF-1alpha-overexpressing cancers, an effect that seems to be enhanced by wild-type levels of p53. This underlines the importance of p300 levels and p53 accumulation in the HIF-1-regulated response toward hypoxia.

Microregional Expression of Glucose Transporter-1 and Oxygenation Status: Lack of Correlation in Locally Advanced Cervical Cancers

Glucose transporter-1 (GLUT-1), a target gene of hypoxia-inducible factor-1, has been considered a candidate endogenous marker of tumor hypoxia. Expression of GLUT-1 may also serve as an indicator for the induction of the transcriptional response to hypoxia, which has been linked to enhanced proliferation, resistance to therapy, and metastatic propagation of cancer cells. Overexpression of GLUT-1 has been shown to correlate with poor prognosis in several tumor entities, among them cancers of the uterine cervix. The validity of these hypotheses is investigated. The expression of GLUT-1 was assessed in 80 biopsies of Eppendorf oxygenation measurement tracks from locally advanced cervical cancers in 47 patients using immunohistochemistry. No correlation was found between the expression of GLUT-1 and oxygenation variables (median pO2, HF 2.5 and HF 5). Expression of GLUT-1 was found greater in larger tumors (P = 0.0001) and to exhibit a linear increase with Federation Internationale de Gynecologie et d' Obstetrique 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 of patients treated with surgery, this effect on prognosis was not independent when pT stage or pN stage were included in a multivariate Cox proportional hazards model. The suitability of GLUT-1 as an endogenous marker of tumor hypoxia seems questionable. The association with prognosis may partially depend on confounding factors.

Differential prognostic impact of hypoxia induced and diffuse HIF-1α expression in invasive breast cancer

Background: Intratumorous hypoxia triggers a broad cellular response mediated by the transcription factor hypoxia inducible factor 1 (HIF-1). HIF-1α concentrations increase during breast carcinogenesis, and are associated with poor prognosis....