Virchows Archiv

, Volume 462, Issue 1, pp 83–93 | Cite as

Expression and role of GLUT-1, MCT-1, and MCT-4 in malignant pleural mesothelioma

  • Ai Mogi
  • Kaori Koga
  • Mikiko Aoki
  • Makoto Hamasaki
  • Noriko Uesugi
  • Akinori Iwasaki
  • Takayuki Shirakusa
  • Kazuo Tamura
  • Kazuki NabeshimaEmail author
Original Article


Malignant cells supply their energy needs through increased glucose consumption, producing large quantities of lactic acid via glycolysis. Glucose transporters (GLUTs) and monocarboxylate transporters (MCTs) are therefore commonly up-regulated in human malignancies to mediate glucose influx and lactic acid efflux, respectively. However, their roles in malignant pleural mesothelioma (MPM) have not been fully elucidated. Here, we evaluated GLUT-1, MCT-1, and MCT-4 expression in human MPM and reactive mesothelial hyperplasia (RMH) and elucidated their biological role in vitro. GLUT-1, MCT-1, and MCT-4 expression was determined in human MPM (n = 35) and RMH (n = 20) specimens by immunohistochemistry and in frozen tissue, and MPM cell lines, by real-time reverse transcription-polymerase chain reaction and western blot analysis. GLUT-1, MCT-1, and MCT-4 functions in MPM were evaluated by transfection with small interfering RNA. Immunohistochemical analysis revealed higher levels of GLUT-1, MCT-1, and MCT-4 in MPM than in RMH. Additionally, GLUT-1, MCT-1, and MCT-4 mRNA levels were higher in MPM than in non-neoplastic mesothelial cell lines. The siRNA-mediated knockdown of GLUT-1 or MCT-1 significantly suppressed tumor cell proliferation, and MCT-1 silencing inhibited invasion and induced apoptosis. Taken together, these results indicate that combined application of GLUT-1, MCT-1, and MCT-4 immunohistochemistry might be useful in differentiating MPM from RMH and suggest that MCT-1plays an important biological role.


Malignant mesothelioma GLUT-1 MCT-1 MCT-4 



We acknowledge the expert technical assistance of Ms. M. Onitsuka in immunohistochemical and in vitro studies. This work was supported in part by a grant from the Research Center for Advanced Molecular Medicine, Fukuoka University.

Conflict of interest

The authors declare no conflict of interest.


  1. 1.
    Vogelzang NJ, Rusthoven JJ, Symanowski J et al (2003) Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol 21:2636–2644PubMedCrossRefGoogle Scholar
  2. 2.
    Warburg O (1956) On the origin of cancer cells. Science 123:309–314PubMedCrossRefGoogle Scholar
  3. 3.
    Younes M, Brown RW, Stephenson M, Gondo M, Cagle PT (1997) Overexpression of Glut1 and Glut3 in stage I nonsmall cell lung carcinoma is associated with poor survival. Cancer 80:1046–1051PubMedCrossRefGoogle Scholar
  4. 4.
    Idrees MT, Schlosshauer P, Li G, Burstein DE (2006) GLUT1 and p63 expression in endometrial intraepithelial and uterine serous papillary carcinoma. Histopathology 49:75–81PubMedCrossRefGoogle Scholar
  5. 5.
    Brown RS, Wahl RL (1993) Overexpression of Glut-1 glucose transporter in human breast cancer. An Immunohistochemical Study. Cancer 72:2979–2985PubMedCrossRefGoogle Scholar
  6. 6.
    Wang BY, Kalir T, Sabo E, Sherman DE, Cohen C, Burstein DE (2000) Immunohistochemical staining of GLUT1 in benign, hyperplastic, and malignant endometrial epithelia. Cancer 88:2774–2781PubMedCrossRefGoogle Scholar
  7. 7.
    Halestrap AP, Price NT (1999) The proton-linked monocarboxylate transporter (MCT) family: structure, function and regulation. Biochem J 343(Pt 2):281–299PubMedCrossRefGoogle Scholar
  8. 8.
    Fang J, Quinones QJ, Holman TL et al (2006) The H+-linked monocarboxylate transporter (MCT1/SLC16A1): a potential therapeutic target for high-risk neuroblastoma. Mol Pharmacol 70:2108–2115PubMedCrossRefGoogle Scholar
  9. 9.
    Froberg MK, Gerhart DZ, Enerson BE, Manivel C, Guzman-Paz M, Seacotte N, Drewes LR (2001) Expression of monocarboxylate transporter MCT1 in normal and neoplastic human CNS tissues. Neuroreport 12:761–765PubMedCrossRefGoogle Scholar
  10. 10.
    Pinheiro C, Albergaria A, Paredes J et al (2010) Monocarboxylate transporter 1 is up-regulated in basal-like breast carcinoma. Histopathology 56:860–867PubMedCrossRefGoogle Scholar
  11. 11.
    Pinheiro C, Longatto-Filho A, Scapulatempo C et al (2008) Increased expression of monocarboxylate transporters 1, 2, and 4 in colorectal carcinomas. Virchows Arch 452:139–146PubMedCrossRefGoogle Scholar
  12. 12.
    Koukourakis MI, Giatromanolaki A, Harris AL, Sivridis E (2006) Comparison of metabolic pathways between cancer cells and stromal cells in colorectal carcinomas: a metabolic survival role for tumor-associated stroma. Cancer Res 66:632–637PubMedCrossRefGoogle Scholar
  13. 13.
    Rofstad EK, Mathiesen B, Kindem K, Galappathi K (2006) Acidic extracellular pH promotes experimental metastasis of human melanoma cells in athymic nude mice. Cancer Res 66:6699–6707PubMedCrossRefGoogle Scholar
  14. 14.
    Kato Y, Tsuta K, Seki K et al (2007) Immunohistochemical detection of GLUT-1 can discriminate between reactive mesothelium and malignant mesothelioma. Mod Pathol 20:215–220PubMedCrossRefGoogle Scholar
  15. 15.
    Shen J, Pinkus GS, Deshpande V, Cibas ES (2009) Usefulness of EMA, GLUT-1, and XIAP for the cytologic diagnosis of malignant mesothelioma in body cavity fluids. Am J Clin Pathol 131:516–523PubMedCrossRefGoogle Scholar
  16. 16.
    Monaco SE, Shuai Y, Bansal M, Krasinskas AM, Dacic S (2011) The diagnostic utility of p16 FISH and GLUT-1 immunohistochemical analysis in mesothelial proliferations. Am J Clin Pathol 135:619–627PubMedCrossRefGoogle Scholar
  17. 17.
    Travis WD, World Health Organization, International Agency for Research on Cancer, International Association for the Study of Lung Cancer, International Academy of Pathology (2004) Pathology and genetics of tumours of the lung, pleura, thymus and heart. IARC Press, LyonGoogle Scholar
  18. 18.
    Al-Haddad S, Zhang Z, Leygue E et al (1999) Psoriasin (S100A7) expression and invasive breast cancer. Am J Pathol 155:2057–2066PubMedCrossRefGoogle Scholar
  19. 19.
    Usami N, Fukui T, Kondo M et al (2006) Establishment and characterization of four malignant pleural mesothelioma cell lines from Japanese patients. Cancer Sci 97:387–394PubMedCrossRefGoogle Scholar
  20. 20.
    Aoki M, Nabeshima K, Koga K, Hamasaki M, Suzumiya J, Tamura K, Iwasaki H (2007) Imatinib mesylate inhibits cell invasion of malignant peripheral nerve sheath tumor induced by platelet-derived growth factor-BB. Lab Investig 87:767–779PubMedCrossRefGoogle Scholar
  21. 21.
    Pinheiro C, Longatto-Filho A, Soares TR et al (2012) CD147 immunohistochemistry discriminates between reactive mesothelial cells and malignant mesothelioma. Diagn Cytopathol 40:478–483PubMedCrossRefGoogle Scholar
  22. 22.
    Baba M, Inoue M, Itoh K, Nishizawa Y (2008) Blocking CD147 induces cell death in cancer cells through impairment of glycolytic energy metabolism. Biochem Biophys Res Commun 374:111–116PubMedCrossRefGoogle Scholar
  23. 23.
    Mathupala SP, Parajuli P, Sloan AE (2004) Silencing of monocarboxylate transporters via small interfering ribonucleic acid inhibits glycolysis and induces cell death in malignant glioma: an in vitro study. Neurosurgery 55:1410–1419, discussion 1419PubMedCrossRefGoogle Scholar
  24. 24.
    Sonveaux P, Vegran F, Schroeder T et al (2008) Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice. J Clin Invest 118:3930–3942PubMedGoogle Scholar
  25. 25.
    Izumi H, Takahashi M, Uramoto H et al (2011) Monocarboxylate transporters 1 and 4 are involved in the invasion activity of human lung cancer cells. Cancer Sci 102:1007–1013PubMedCrossRefGoogle Scholar
  26. 26.
    Harvey P, Clark IM, Jaurand MC, Warn RM, Edwards DR (2000) Hepatocyte growth factor/scatter factor enhances the invasion of mesothelioma cell lines and the expression of matrix metalloproteinases. Br J Cancer 83:1147–1153PubMedCrossRefGoogle Scholar
  27. 27.
    Hasteh F, Lin GY, Weidner N, Michael CW (2010) The use of immunohistochemistry to distinguish reactive mesothelial cells from malignant mesothelioma in cytologic effusions. Cancer Cytopathol 118:90–96PubMedCrossRefGoogle Scholar
  28. 28.
    Ozbudak IH, Shilo K, Tavora F et al (2009) Glucose transporter-1 in pulmonary neuroendocrine carcinomas: expression and survival analysis. Mod Pathol 22:633–638PubMedCrossRefGoogle Scholar
  29. 29.
    Macheda ML, Rogers S, Best JD (2005) Molecular and cellular regulation of glucose transporter (GLUT) proteins in cancer. J Cell Physiol 202:654–662PubMedCrossRefGoogle Scholar
  30. 30.
    Fan J, Zhou JQ, Yu GR, Lu DD (2010) Glucose transporter protein 1-targeted RNA interference inhibits growth and invasion of the osteosarcoma cell line MG63 in vitro. Cancer Biother Radiopharm 25:521–527PubMedCrossRefGoogle Scholar
  31. 31.
    Amann T, Maegdefrau U, Hartmann A et al (2009) GLUT1 expression is increased in hepatocellular carcinoma and promotes tumorigenesis. Am J Pathol 174:1544–1552PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  • Ai Mogi
    • 1
    • 2
  • Kaori Koga
    • 1
  • Mikiko Aoki
    • 1
  • Makoto Hamasaki
    • 1
  • Noriko Uesugi
    • 4
  • Akinori Iwasaki
    • 3
  • Takayuki Shirakusa
    • 5
  • Kazuo Tamura
    • 2
  • Kazuki Nabeshima
    • 1
    Email author
  1. 1.Department of PathologyFukuoka University School of Medicine and HospitalFukuokaJapan
  2. 2.Department of Internal Medicine, Division of Medical Oncology, Hematology and Infectious DiseaseFukuoka University School of Medicine and HospitalFukuokaJapan
  3. 3.Thoracic SurgeryFukuoka University School of Medicine and HospitalFukuokaJapan
  4. 4.Department of Pathology, Institute of Basic Medical ScienceGraduate School of Comprehensive Human Sciences, University of TsukubaTsukubaJapan
  5. 5.Department of SurgeryFukusei-Kai HospitalFukuokaJapan

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