Virchows Archiv

, Volume 452, Issue 2, pp 139–146 | Cite as

Increased expression of monocarboxylate transporters 1, 2, and 4 in colorectal carcinomas

  • Céline Pinheiro
  • Adhemar Longatto-Filho
  • Cristovam Scapulatempo
  • Luísa Ferreira
  • Sandra Martins
  • Luc Pellerin
  • Mesquita Rodrigues
  • Venancio A. F. Alves
  • Fernando Schmitt
  • Fátima Baltazar
Original Article

Abstract

Tumour cells are known to be highly glycolytic, thus producing high amounts of lactic acid. Monocarboxylate transporters (MCTs), by promoting the efflux of the accumulating acids, constitute one of the most important mechanisms in the maintenance of tumour intracellular pH. Since data concerning MCT expression in colorectal carcinomas (CRC) are scarce and controversial, the present study aimed to assess the expressions of MCT1, 2, and 4 in a well characterized series of CRC and assess their role in CRC carcinogenesis. CRC samples (126 cases) were analyzed for MCT1, MCT2, and MCT4 immunoexpression and findings correlated with clinico-pathological parameters. Expression of all MCT isoforms in tumour cells was significantly increased when compared to adjacent normal epithelium. Remarkably, there was a significant gain of membrane expression for MCT1 and MCT4 and loss of plasma membrane expression for MCT2 in tumour cells. Plasma membrane expression of MCT1 was directly related to the presence of vascular invasion. This is the larger study on MCT expression in CRC and evaluates for the first time its clinico-pathological significance. The increased expression of these transporters suggests an important role in CRC, which might justify their use, especially MCT1 and MCT4, as targets in CRC drug therapy.

Keywords

Monocarboxylate transporter Colorectal carcinoma 

References

  1. 1.
    Brizel DM, Schroeder T, Scher RL, Walenta S, Clough RW, Dewhirst MW, Mueller-Klieser W (2001) Elevated tumour lactate concentrations predict for an increased risk of metastases in head-and-neck cancer. Int J Radiat Oncol Biol Phys 51:349–353PubMedGoogle Scholar
  2. 2.
    Broer S, Broer A, Schneider HP, Stegen C, Halestrap AP, Deitmer JW (1999) Characterization of the high-affinity monocarboxylate transporter MCT2 in Xenopus laevis oocytes. Biochem J 341:529–535PubMedCrossRefGoogle Scholar
  3. 3.
    Dang CV, Semenza GL (1999) Oncogenic alterations of metabolism. Trends Biochem Sci 24:68–72PubMedCrossRefGoogle Scholar
  4. 4.
    Dimmer KS, Friedrich B, Lang F, Deitmer JW, Broer S (2000) The low-affinity monocarboxylate transporter MCT4 is adapted to the export of lactate in highly glycolytic cells. Biochem J 1:219–227CrossRefGoogle Scholar
  5. 5.
    Fang J, Quinones QJ, Holman TL, Morowitz MJ, Wang Q, Zhao H, Sivo F, Maris JM, Wahl ML (2006) The H+-linked monocarboxylate transporter (MCT1/SLC16A1): a potential therapeutic target for high-risk neuroblastoma. Mol Pharmacol 70:2108–2115PubMedCrossRefGoogle Scholar
  6. 6.
    Fishbein WN, Merezhinskaya N, Foellmer JW (2002) Relative distribution of three major lactate transporters in frozen human tissues and their localization in unfixed skeletal muscle. Muscle Nerve 26:101–112PubMedCrossRefGoogle Scholar
  7. 7.
    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
  8. 8.
    Fukumura D, Xu L, Chen Y, Gohongi T, Seed B, Jain RK (2001) Hypoxia and acidosis independently up-regulate vascular endothelial growth factor transcription in brain tumors in vivo. Cancer Res 61:6020–6024PubMedGoogle Scholar
  9. 9.
    Halestrap AP, Meredith D (2004) The SLC16 gene family—from monocarboxylate transporters (MCTs) to aromatic amino acid transporters and beyond. Pflugers Arch 447:619–628PubMedCrossRefGoogle Scholar
  10. 10.
    Helmlinger G, Sckell A, Dellian M, Forbes NS, Jain RK (2002) Acid production in glycolysis-impaired tumors provides new insights into tumor metabolism. Clin Cancer Res 8:1284–1291PubMedGoogle Scholar
  11. 11.
    Izumi H, Torigoe T, Ishiguchi H, Uramoto H, Yoshida Y, Tanabe M, Ise T, Murakami T, Yoshida T, Nomoto M, Kohno K (2003) Cellular pH regulators: potentially promising molecular targets for cancer chemotherapy. Cancer Treat Rev 29:541–549PubMedCrossRefGoogle 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.
    Ladanyi M, Antonescu CR, Drobnjak M, Baren A, Lui MY, Golde DW, Cordon-Cardo C (2002) The precrystalline cytoplasmic granules of alveolar soft part sarcoma contain monocarboxylate transporter 1 and CD147. AJP 160:1215–1221PubMedGoogle Scholar
  14. 14.
    Lambert DW, Wood IS, Ellis A, Shirazi-Beechey SP (2002) Molecular changes in the expression of human colonic nutrient transporters during the transition from normality to malignancy. Br J Cancer 86:1262–1269PubMedCrossRefGoogle Scholar
  15. 15.
    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 55:1410–1419PubMedCrossRefGoogle Scholar
  16. 16.
    Philp NJ, Yoon H, Lombardi L (2001) Mouse MCT3 gene is expressed preferentially in retinal pigment and choroid plexus epithelia. Am J Physiol Cell Physiol 280:1319–1326Google Scholar
  17. 17.
    Ritzhaupt A, Wood IS, Ellis A, Hosie KB, Shirazi-Beechey SP (1998) Identification and characterization of a monocarboxylate transporter (MCT1) in pig and human colon: its potential to transport l-lactate as well as butyrate. J Physiol 513:719–732PubMedCrossRefGoogle Scholar
  18. 18.
    Vaupel P (2004) The role of hypoxia-induced factors in tumor progression. Oncologist 9:10–17PubMedCrossRefGoogle Scholar
  19. 19.
    Wahl ML, Owen JA, Burd R, Herlands RA, Nogami SS, Rodeck U, Berd D, Leeper DB, Owen CS (2002) Regulation of intracellular pH in human melanoma: potential therapeutic implications. Mol Cancer Ther 1:617–628PubMedGoogle Scholar
  20. 20.
    Walenta S, Wetterling M, Lehrke M, Schwickert G, Sundfor K, Rofstad EK, Mueller-Klieser W (2000) High lactate levels predict likelihood of metastases, tumor recurrence, and restricted patient survival in human cervical cancers. Cancer Res 60:916–921PubMedGoogle Scholar
  21. 21.
    Walenta S, Schroeder T, Mueller-Klieser W (2004) Lactate in solid malignant tumors: potential basis of a metabolic classification in clinical oncology. Curr Med Chem 11:2195–2204PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Céline Pinheiro
    • 1
  • Adhemar Longatto-Filho
    • 1
    • 2
  • Cristovam Scapulatempo
    • 3
  • Luísa Ferreira
    • 1
  • Sandra Martins
    • 1
    • 4
  • Luc Pellerin
    • 5
  • Mesquita Rodrigues
    • 4
  • Venancio A. F. Alves
    • 3
  • Fernando Schmitt
    • 6
    • 7
  • Fátima Baltazar
    • 1
  1. 1.Life and Health Sciences Research Institute (ICVS), School of Health SciencesUniversity of MinhoBragaPortugal
  2. 2.Instituto Adolfo LutzSão PauloBrazil
  3. 3.Department of PathologyUniversity of São Paulo School of MedicineSão PauloBrazil
  4. 4.S. Marcos HospitalBragaPortugal
  5. 5.Faculty of Biology and MedicineUniversity of LausanneLausanneSwitzerland
  6. 6.Institute of Pathology and Immunology of University of Porto (IPATIMUP)PortoPortugal
  7. 7.Medical Faculty of the University of PortoPortoPortugal

Personalised recommendations