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Molecular Imaging and Biology

, Volume 21, Issue 2, pp 375–381 | Cite as

Linked Hexokinase and Glucose-6-Phosphatase Activities Reflect Grade of Ovarian Malignancy

  • Birgitte Brinkmann OlsenEmail author
  • Albert Gjedde
  • Mie Holm Vilstrup
  • Iben Birgit Gade Johnsen
  • Gudrun Neumann
  • Drew Avedis Torigian
  • Abass Alavi
  • Poul Flemming Høilund-Carlsen
Research Article

Abstract

Purpose

Malignant cells exhibit increased rates of aerobic glycolysis. Here, we tested whether the accumulation of fluoro-deoxyglucose-6-phosphate (FDG6P) in ovarian cancers of differential malignancy reflects inversely correlated elevations of hexokinase (HK) and glucose-6-phosphatase (G6Pase) activities.

Procedures

Twenty-nine women with suspected ovarian cancer had positron emission tomography (PET) prior to surgery. From fresh-frozen tissue, we determined the activities of HK and G6Pase, and from the PET images, we determined the tumor maximum standardized uptake value (SUVmax) of 2-deoxy-2-[18F]fluoro-D-glucose.

Results

The SUVmax of malignant lesions significantly exceeded the SUVmax of benign (p < 0.005) and borderline lesions (p < 0.0005) that did not differ significantly. We found no significant correlation between measured HK or G6Pase activities and histological tumor type or SUVmax except that G6Pase activities were higher in malignant than borderline lesions (p < 0.05). Measured HK and G6Pase activities correlated inversely (p < 0.05). The slopes from the regression lines of the three correlations yielded positively correlated abscissa and ordinate intercepts, designated HKmax and G6Pasemax, respectively (r = 0.67, p < 0.0001). The positive correlations between the abscissa and ordinate intercepts with SUVmax had regression coefficients of r = 0.44, p < 0.05; and r = 0.39, p < 0.05, respectively.

Conclusions

The results distinguished two ovarian cancer phenotypes, one with elevated HK activity and low G6Pase activity, and another with the opposite characteristics.

Key Words

Ovarian cancer FDG Glucose-6-phosphatase Hexokinase Positron emission tomography (PET) 

Notes

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Ethics Approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed Consent

Twenty-three patients were enrolled prospectively after both oral and written information and signed consent. Six patients were enrolled retrospectively, with previously obtained formal consent to retroactive use of tissue still valid.

Supplementary material

11307_2018_1247_MOESM1_ESM.pdf (463 kb)
ESM 1 (PDF 463 kb)

References

  1. 1.
    Siegel R, Ma J, Zou Z, Jemal A (2014) Cancer statistic 2014. CA Cancer J Clin 64:9–29CrossRefGoogle Scholar
  2. 2.
    Risum S, Høgdall C, Loft A, Berthelsen AK, Høgdall E, Nedergaard L, Lundvall L, Engelholm SA (2010) Does the use of diagnostic PET/CT cause stage migration in patients with primary advanced ovarian cancer? Gynecol Oncol 116:395–398CrossRefGoogle Scholar
  3. 3.
    Musto A, Rampin L, Nanni C, Marzola MC, Fanti S, Rubello D (2011) Present and future of PET and PET/CT in gynaecologic malignancies. Eur J Radiol 78:12–20CrossRefGoogle Scholar
  4. 4.
    Nakamura K, Hongo A, Kodama J, Hiramatsu Y (2012) The pretreatment of maximum standardized uptake values (SUVmax) of the primary tumor is predictor for poor prognosis for patients with epithelial ovarian cancer. Acta Med Okayama 66:53–60Google Scholar
  5. 5.
    Schwartz L, Supuran CT, Alfarouk KO (2017) The Warburg effect and the hallmarks of cancer. Anti Cancer Agents Med Chem 17:164–170CrossRefGoogle Scholar
  6. 6.
    Macheda ML, Rogers S, Best JD (2005) Molecular and cellular regulation of glucose transporter (GLUT) proteins in cancer. J Cell Physiol 202:654–662CrossRefGoogle Scholar
  7. 7.
    Shinohara Y, Yamamoto K, Kogure K, Ichihara J, Terada H (1994) Steady state transcript levels of the type II hexokinase and type 1 glucose transporter in human tumor cell lines. Cancer Lett 82:27–32CrossRefGoogle Scholar
  8. 8.
    Kurokawa T, Yoshida Y, Kawahara K, Tsuchida T, Okazawa H, Fujibayashi Y, Yonekura Y, Kotsuji F (2004) Expression of GLUT-1 glucose transfer, cellular proliferation activity and grade of tumor correlate with [F-18]-fluorodeoxyglucose uptake by positron emission tomography in epithelial tumors of the ovary. Int J Cancer 109:926–932CrossRefGoogle Scholar
  9. 9.
    Yen TC, See LC, Lai CH, Yah-Huei CW, Ng KK, Ma SY, Lin WJ, Chen JT, Chen WJ, Lai CR, Hsueh S (2004) 18F-FDG uptake in squamous cell carcinoma of the cervix is correlated with glucose transporter 1 expression. J Nucl Med 45:22–29Google Scholar
  10. 10.
    Nagamatsu A, Umesaki N, Li L, Tanaka T (2010) Use of 18F-fluorodeoxyglucose positron emission tomography for diagnosis of uterine sarcomas. Oncol Rep 23:1069–1076Google Scholar
  11. 11.
    Nakamura K, Kodama J, Okumura Y, Hongo A, Kanazawa S, Hiramatsu Y (2010) The SUVmax of 18F-FDG PET correlates with histological grade in endometrial cancer. Int J Gynecol Cancer 20:110–115CrossRefGoogle Scholar
  12. 12.
    Tsujikawa T, Yoshida Y, Kiyono Y, Kurokawa T, Kudo T, Fujibayashi Y, Kotsuji F, Okazawa H (2011) Functional oestrogen receptor α imaging in endometrial carcinoma using 16α-[18F]fluoro-17β-oestradiol PET. Eur J Nucl Med Mol Imaging 38:37–45CrossRefGoogle Scholar
  13. 13.
    Tong SY, Lee JM, Ki KD, Choi YJ, Seol HJ, Lee SK, Huh CY, Kim GY, Lim SJ (2012) Correlation between FDG uptake by PET/CT and the expressions of glucose transporter type 1 and hexokinase II in cervical cancer. Int J Gynecol Cancer 22:654–658CrossRefGoogle Scholar
  14. 14.
    Park SI, Suh DS, Kim SJ, Choi KU, Yoon MS (2013) Correlation between biological marker expression and F-fluorodeoxyglucose uptake in cervical cancer measured by positron emission tomography. Onkologie 36:169–174CrossRefGoogle Scholar
  15. 15.
    Zhao Z, Yoshida Y, Kurokawa T, Kiyono Y, Mori T, Okazawa H (2013) 18F-FES and 18F-FDG PET for differential diagnosis and quantitative evaluation of mesenchymal uterine tumors: correlation with immunohistochemical analysis. J Nucl Med 54:499–506CrossRefGoogle Scholar
  16. 16.
    Jo MS, Choi OH, Suh DS, Yun MS, Kim SJ, Kim GH, Jeon HN (2014) Correlation between expression of biological markers and [18F]fluorodeoxyglucose uptake in endometrial cancer. Oncol Res Treat 37:30–34CrossRefGoogle Scholar
  17. 17.
    Marcolongo P, Fulceri R, Gamberucci A et al (2012) Multiple roles of glucose-6-phosphatases in pathophysiology: state of the art and future trends. Biochim Biophys Acta 1830:2608–2618CrossRefGoogle Scholar
  18. 18.
    Robey RB, Hay N (2006) Mitochondrial hexokinases, novel mediators of the antiapoptotic effects of growth factors and Akt. Oncogene 25:4683–4696CrossRefGoogle Scholar
  19. 19.
    Van Schaftingen E, Gerin I (2002) The glucose-6-phosphatase system. Biochem J 362:513–532CrossRefGoogle Scholar
  20. 20.
    Boellaard R, Delgado-Bolton R, Oyen WJ, Giammarile F, Tatsch K, Eschner W, Verzijlbergen FJ, Barrington SF, Pike LC, Weber WA, Stroobants S, Delbeke D, Donohoe KJ, Holbrook S, Graham MM, Testanera G, Hoekstra OS, Zijlstra J, Visser E, Hoekstra CJ, Pruim J, Willemsen A, Arends B, Kotzerke J, Bockisch A, Beyer T, Chiti A, Krause BJ, European Association of Nuclear Medicine (EANM) (2015) FDG PET/CT: EANM procedure guidelines for tumour imaging: version 2.0. Eur J Nucl Med Mol Imaging 42:328–354CrossRefGoogle Scholar
  21. 21.
    Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254CrossRefGoogle Scholar
  22. 22.
    Taussky HH, Shorr E (1953) A microcolorimetric method for the determination of inorganic phosphorus. J Biol Chem 202:675–685Google Scholar
  23. 23.
    Yamamoto Y, Oguri H, Yamada R, Maeda N, Kohsaki S, Fukaya T (2008) Preoperative evaluation of pelvic masses with combined 18F-fluorodeoxyglucose positron emission tomography and computed tomography. Int J Gynaecol Obstet 102:124–127CrossRefGoogle Scholar
  24. 24.
    Kitajima K, Suzuki K, Senda M, Kita M, Nakamoto Y, Onishi Y, Maeda T, Yoshikawa T, Ohno Y, Sugimura K (2011) FDG-PET/CT for diagnosis of primary ovarian cancer. Nucl Med Commun 32:549–553CrossRefGoogle Scholar
  25. 25.
    Tanizaki Y, Kobayashi A, Shiro M, Ota N, Takano R, Mabuchi Y, Yagi S, Minami S, Terada M, Ino K (2014) Diagnostic value of preoperative SUVmax on FDG-PET/CT for the detection of ovarian cancer. Int J Gynecol Cancer 24:454–460CrossRefGoogle Scholar
  26. 26.
    Jin Z, Gu J, Xin X, Li Y, Wang H (2014) Expression of hexokinase 2 in epithelial ovarian tumors and its clinical significance in serous ovarian cancer. Eur J Gynaecol Oncol 35:519–524Google Scholar
  27. 27.
    Pedersen P, Mathupala S, Rempel A et al (2002) Mitochondrial bound type II hexokinase: a key player in the growth and survival of many cancers and an ideal prospect for therapeutic intervention. Biochim Biophys Acta 1555:14–20CrossRefGoogle Scholar
  28. 28.
    Gejl M, Egefjord L, Lerche S, Vang K, Bibby BM, Holst JJ, Mengel A, Møller N, Rungby J, Brock B, Gjedde A (2012) Glucagon-like peptide-1 decreases intracerebral glucose content by activating hexokinase and changing glucose clearance during hyperglycemia. J Cereb Blood Flow Metab 32:2146–2152CrossRefGoogle Scholar
  29. 29.
    Gejl M, Lerche S, Egefjord L et al (2013) Glucagon-like peptide-1 (GLP-1) raises blood-brain glucose transfer capacity and hexokinase activity in human brain. Front Neuroenerg 5:2CrossRefGoogle Scholar
  30. 30.
    Abbadi S, Rodarte JJ, Abutaleb A, Lavell E, Smith CL, Ruff W, Schiller J, Olivi A, Levchenko A, Guerrero-Cazares H, Quinones-Hinojosa A (2014) Glucose-6-phosphatase is a key metabolic regulator of glioblastoma invasion. Mol Cancer Res 12:1547–1559CrossRefGoogle Scholar
  31. 31.
    Guo T, Chen T, Gu C, Li B, Xu C (2015) Genetic and molecular analyses reveal G6PC as a key element connecting glucose metabolism and cell cycle control in ovarian cancer. Tumour Biol 36:7649–7658CrossRefGoogle Scholar
  32. 32.
    Hart WR (2005) Borderline epithelial tumors of the ovary. Mod Pathol 18:S33–S50CrossRefGoogle Scholar
  33. 33.
    Patra KC, Wang Q, Bhaskar PT, Miller L, Wang Z, Wheaton W, Chandel N, Laakso M, Muller WJ, Allen EL, Jha AK, Smolen GA, Clasquin MF, Robey RB, Hay N (2013) Hexokinase 2 is required for tumor initiation and maintenance and its systemic deletion is therapeutic in mouse models of cancer. Cancer Cell 24:213–228CrossRefGoogle Scholar

Copyright information

© World Molecular Imaging Society 2018

Authors and Affiliations

  • Birgitte Brinkmann Olsen
    • 1
    • 2
    Email author
  • Albert Gjedde
    • 1
    • 2
  • Mie Holm Vilstrup
    • 1
  • Iben Birgit Gade Johnsen
    • 3
  • Gudrun Neumann
    • 4
  • Drew Avedis Torigian
    • 5
  • Abass Alavi
    • 5
  • Poul Flemming Høilund-Carlsen
    • 1
    • 2
  1. 1.Department of Nuclear MedicineOdense University HospitalOdenseDenmark
  2. 2.Department of Clinical ResearchUniversity of Southern DenmarkOdenseDenmark
  3. 3.Department of Clinical PathologyOdense University HospitalOdenseDenmark
  4. 4.Department of Gynecology and ObstetricsOdense University HospitalOdenseDenmark
  5. 5.Department of Radiology, University of Pennsylvania School of MedicineHospital of the University of PennsylvaniaPhiladelphiaUSA

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