High Monocarboxylate Transporter 4 Protein Expression in Stromal Cells Predicts Adverse Survival in Gastric Cancer

  • Yan, Ping (Department of Occupational and Environmental Health, School of Public Health, Wuhan University) ;
  • Li, Yu-Hong (Department of Pathology, Medical College, Wuhan University of Science and Technology) ;
  • Tang, Zhi-Jiao (Department of Pathology, Wuhan Health and Medical Technology Co., Ltd.) ;
  • Shu, Xiang (Department of Pathology, Wuhan Health and Medical Technology Co., Ltd.) ;
  • Liu, Xia (Department of Pathology, Wuhan Health and Medical Technology Co., Ltd.)
  • Published : 2014.11.06


Background: Increasing evidence suggests that stromal monocarboxylate transporter 4 (MCT4) and carbonic anhydrase IX (CA IX) may play key roles in tumor development. However, their clinical value remains largely unexplored in gastric cancer (GC). The present study aimed to determine clinicopathological significance and prognostic values of stromal MCT4 and CA IX in GC. Materials and Methods: Specimens from 143 GC patients were immunohistochemically stained using polyclonal anti-MCT4 and anti-CA IX antibodies. Expression was correlated with patient clinicopathologic characteristics and survival data. Results: High stromal MCT4 expression was detected in 72 of 143 (50.3%) GCs and high CA IX in 74 (51.7%). Both high stromal MCT4 and CA IX were correlated with advanced TNM stage (p=0.000; p=0.000). High CA IX expression was positively related to depth of invasion (p=0.022) and positive lymph nodes (p=0.002) as well. Survival analysis indicated high expression of stromal MCT4 to be an independent factor in predicting poor overall survival (OS) (HR and 95%CI=1.962, 1.032-3.729, p=0.040) and disease free survival (DFS) (HR and 95%CI=2.081, 1.158-3.741, p=0.014) of GC patients. However, high CA IX expression exhibited no significant predictive value. Conclusions: These findings suggest that high expression of stromal MCT4 and CA IX proteins is significantly correlated with GC progression. High stromal MCT4 heralds worse outcome of GC patient, suggesting a novel candidate prognostic marker and therapeutic target.


  1. Aomatsu N, Yashiro M, Kashiwagi S, et al (2014). Carbonic anhydrase 9 is associated with chemosensitivity and prognosis in breast cancer patients treated with taxane and anthracycline. BMC Cancer, 14, 400.
  2. Birner P, Jesch B, Friedrich J, et al (2011). Carbonic anhydrase IX overexpression is associated with diminished prognosis in esophageal cancer and correlates with Her-2 expression. Ann Surg Oncol, 18, 3330-7.
  3. Bissell MJ, Radisky D (2001). Putting tumours in context. Nature Reviews Cancer, 1, 46-54.
  4. Castello-Cros R, Bonuccelli G, Molchansky A, et al (2011). Matrix remodeling stimulates stromal autophagy, “fueling” cancer cell mitochondrial metabolism and metastasis. Cell Cycle, 10, 2021-34.
  5. de Oliveira J, Felipe AV, Neto RA, et al (2014). Association between ABCB1 immunohistochemical expression and overall survival in gastric cancer patients. Asian Pac J Cancer Prev, 15, 6935-8.
  6. Chen J, Rocken C, Hoffmann J, et al (2005). Expression of carbonic anhydrase 9 at the invasion front of gastric cancers. Gut, 54, 920-7.
  7. Chiche J, Ilc K, Laferriere J, et al (2009). Hypoxia-inducible carbonic anhydrase IX and XII promote tumor cell growth by counteracting acidosis through the regulation of the intracellular pH. Cancer Res, 69, 358-68.
  8. Chiche J, Ricci JE, Pouyssegur J (2013). Tumor hypoxia and metabolism -- towards novel anticancer approaches. Ann Endocrinol, 74, 111-4.
  9. Deng W, Long L, Li JL, et al (2014). Mortality of major cancers in Guangxi, China: sex, age and geographical differences from 1971 and 2005. Asian Pac J Cancer Prev, 15, 1567-74.
  10. Dvorak HF, Weaver VM, Tlsty TD, et al (2011). Tumor microenvironment and progression. J Surg Oncol, 103, 468-74.
  11. Fock KM, Ang TL (2010). Epidemiology of Helicobacter pylori infection and gastric cancer in Asia. J Gastroenterol Hepatol, 25, 479-86.
  12. Gao XH, Yang XQ, Wang BC, et al (2013). Overexpression of twist and matrix metalloproteinase-9 with metastasis and prognosis in gastric cancer. Asian Pac J Cancer Prev, 14, 5055-60.
  13. Gee HE, Camps C, Buffa FM, et al (2010). Hsa-mir-210 is a marker of tumor hypoxia and a prognostic factor in head and neck cancer. Cancer, 116, 2148-58.
  14. Group G, Paoletti X, Oba K, et al (2010). Benefit of adjuvant chemotherapy for resectable gastric cancer: a meta-analysis. JAMA, 303, 1729-37.
  15. Kim MJ, Kim DH, Jung WH, et al (2014). Expression of metabolism-related proteins in triple-negative breast cancer. Int J Clin Exp Pathol, 7, 301-12.
  16. Halestrap AP, Price NT (1999). The proton-linked monocarboxylate transporter (MCT) family: structure, function and regulation. Biochem J, 343, 281-99.
  17. 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, 1007-13.
  18. Jemal A, Bray F, Center MM, et al (2011). Global cancer statistics. CA Cancer J Clin, 61, 69-90.
  19. Kononen J, Bubendorf L, Kallioniemi A, et al (1998). Tissue microarrays for high-throughput molecular profiling of tumor specimens. Nat Med, 4, 844-7.
  20. Li M, Chen H, Diao L, et al (2010). Caveolin-1 and VEGF-C promote lymph node metastasis in the absence of intratumoral lymphangiogenesis in non-small cell lung cancer. Tumori, 96, 734-43.
  21. Lin WL, Sun JL, Chang SC, et al (2014). Factors predicting survival of patients with gastric cancer. Asian Pac J Cancer Prev, 15, 5835-8.
  22. Lorusso G, Ruegg C (2008). The tumor microenvironment and its contribution to tumor evolution toward metastasis. Histochem Cell Biol, 130, 1091-103.
  23. Lou Y, McDonald PC, Oloumi A, et al (2011). Targeting tumor hypoxia: suppression of breast tumor growth and metastasis by novel carbonic anhydrase IX inhibitors. Cancer Res, 71, 3364-76.
  24. Martinez-Outschoorn UE, Pavlides S, Howell A, et al (2011). Stromal-epithelial metabolic coupling in cancer: integrating autophagy and metabolism in the tumor microenvironment. Int J Biochem Cell Biol, 43, 1045-51.
  25. Moreira TJ, Pierre K, Maekawa F, et al (2009). Enhanced cerebral expression of MCT1 and MCT2 in a rat ischemia model occurs in activated microglial cells. J Cereb Blood Flow Metab, 29, 1273-83.
  26. Martinez-Outschoorn UE, Trimmer C, Lin Z, et al (2010). Autophagy in cancer associated fibroblasts promotes tumor cell survival: Role of hypoxia, HIF1 induction and NFkappaB activation in the tumor stromal microenvironment. Cell Cycle, 9, 3515-33.
  27. Meijer TW, Schuurbiers OC, Kaanders JH, et al (2012). Differences in metabolism between adeno- and squamous cell non-small cell lung carcinomas: spatial distribution and prognostic value of GLUT1 and MCT4. Lung Cancer, 76, 316-23.
  28. Migneco G, Whitaker-Menezes D, Chiavarina B, et al (2010). Glycolytic cancer associated fibroblasts promote breast cancer tumor growth, without a measurable increase in angiogenesis: evidence for stromal-epithelial metabolic coupling. Cell Cycle, 9, 2412-22.
  29. Mueller MM, Fusenig NE (2004). Friends or foes - bipolar effects of the tumour stroma in cancer. Nat Rev Cancer, 4, 839-49.
  30. Nakayama Y, Torigoe T, Inoue Y, et al (2012). Prognostic significance of monocarboxylate transporter 4 expression in patients with colorectal cancer. Exp Ther Med, 3, 25-30.
  31. Pavlides S, Vera I, Gandara R, et al (2012). Warburg meets autophagy: cancer-associated fibroblasts accelerate tumor growth and metastasis via oxidative stress, mitophagy, and aerobic glycolysis. Antioxid Redox Signal, 16, 1264-84.
  32. Pertega-Gomes N, Vizcaino JR, Miranda-Goncalves V, et al (2011). Monocarboxylate transporter 4 (MCT4) and CD147 overexpression is associated with poor prognosis in prostate cancer. BMC Cancer, 11, 312.
  33. Robertson N, Potter C, Harris AL (2004). Role of carbonic anhydrase IX in human tumor cell growth, survival, and invasion. Cancer Res, 64, 6160-5.
  34. Pinheiro C, Reis RM, Ricardo S, et al (2010). Expression of monocarboxylate transporters 1, 2, and 4 in human tumours and their association with CD147 and CD44. J Biomed Biotechnol, 2010, 427694.
  35. Rademakers SE, Lok J, van der Kogel AJ, et al (2011). Metabolic markers in relation to hypoxia; staining patterns and colocalization of pimonidazole, HIF-1alpha, CAIX, LDH-5, GLUT-1, MCT1 and MCT4. BMC Cancer, 11, 167.
  36. Rattigan YI, Patel BB, Ackerstaff E, et al (2012). Lactate is a mediator of metabolic cooperation between stromal carcinoma associated fibroblasts and glycolytic tumor cells in the tumor microenvironment. Exp Cell Res, 318, 326-35.
  37. Sedlakova O, Svastova E, Takacova M, et al (2014). Carbonic anhydrase IX, a hypoxia-induced catalytic component of the pH regulating machinery in tumors. Front Physiol, 4, 400.
  38. Sergeant G, Lerut E, Ectors N, et al (2011). The prognostic relevance of tumor hypoxia markers in resected carcinoma of the gallbladder. Eur J Surg Oncol, 37, 80-6.
  39. Sotgia F, Martinez-Outschoorn UE, Howell A, et al (2012). Caveolin-1 and cancer metabolism in the tumor microenvironment: markers, models, and mechanisms. Annu Rev Pathol, 7, 423-67.
  40. Tostain J, Li G, Gentil-Perret A, et al (2010). Carbonic anhydrase 9 in clear cell renal cell carcinoma: a marker for diagnosis, prognosis and treatment. Eur J Cancer, 46, 3141-8.
  41. Ullah MS, Davies AJ, Halestrap AP (2006). The plasma membrane lactate transporter MCT4, but not MCT1, is up-regulated by hypoxia through a HIF-1alpha-dependent mechanism. J Biol Chem, 281, 9030-7.
  42. Zhao X, He Y, Chen H (2013a). Autophagic tumor stroma: mechanisms and roles in tumor growth and progression. Int J Cancer, 132, 1-8.
  43. Whitaker-Menezes D, Martinez-Outschoorn UE, Lin Z, et al (2011). Evidence for a stromal-epithelial “lactate shuttle” in human tumors: MCT4 is a marker of oxidative stress in cancer-associated fibroblasts. Cell Cycle, 10, 1772-83.
  44. Witkiewicz AK, Whitaker-Menezes D, Dasgupta A, et al (2012). Using the “reverse Warburg effect” to identify high-risk breast cancer patients: stromal MCT4 predicts poor clinical outcome in triple-negative breast cancers. Cell Cycle, 11, 1108-17.
  45. Zhang ZG, Zhang QN, Wang XH, et al (2013). Hypoxiainducible factor 1 alpha (HIF-1alpha) as a prognostic indicator in patients with gastric tumors: a meta-analysis. Asian Pac J Cancer Prev, 14, 4195-8.
  46. Zhao X, He Y, Gao J, et al (2013b). Caveolin-1 expression level in cancer associated fibroblasts predicts outcome in gastric cancer. PLoS One, 8, 59102.

Cited by

  1. Glycolysis-related protein expression in thyroid cancer vol.39, pp.3, 2017,
  2. Downregulation of MCT4 for lactate exchange promotes the cytotoxicity of NK cells in breast carcinoma vol.7, pp.9, 2018,