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Glucose transporter 1 (GLUT1) of anaerobic glycolysis as predictive and prognostic values in neoadjuvant chemoradiotherapy and laparoscopic surgery for locally advanced rectal cancer

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International Journal of Colorectal Disease Aims and scope Submit manuscript

Abstract

Purpose

We investigated the relationships between biomarkers related to anaerobic glycolytic metabolism (GLUT1, LDH5, PDK1, and HIF-1α proteins), pathologic response, and prognosis.

Methods

All stage II and stage III rectal cancer patients had 50.4 Gy (1.8 Gy/day in 28 fractions) over 5.5 weeks, plus 5-fluorouracil (425 mg/m2/day) and leucovorin (20 mg/m2/day) bolus on days 1 to 5 and 29 to 33, and surgery was performed at 7 to 10 weeks after completion of all therapies. Expression of GLUT1, LDH5, PDK1, and HIF-1α proteins was determined by immunohistochemistry and was assessed in 104 patients with rectal cancer treated with neoadjuvant chemoradiotherapy.

Results

This study included stage II and III rectal cancer patients, and each stage accounted for each 50 % of the total cases. A high expression of GLUT1 protein was associated with a significantly lower rate of ypCR compared with low expression of GLUT1 protein (4.0 % vs. 27.8 %, respectively; p = 0.012). GLUT1 expression was also significantly higher in the poor response group (Grade 0, 1) than in the good response group (Grade 2, 3) (34.0 % vs. 14.8 %, respectively; p = 0.022). In recurrence analysis, the expression of GLUT1 protein demonstrated a significant correlation with time to recurrence, based on a log-rank method (p = 0.016). When analyzed by multiple Cox regression, the positive expression of GLUT1 was the most significant and independent unfavorable prognostic factor (p = 0.004).

Conclusions

GLUT1 expression is a predictive and prognostic factor for pathologic complete response and recurrence in rectal cancer patients treated with 5-flurouracil and leucovorin neo-adjuvant chemoradiotherapy.

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References

  1. Kockerling F, Reymond MA, Altendorf-Hofmann A, Dworak O, Hohenberger W (1998) Influence of surgery on metachronous distant metastases and survival in rectal cancer. J Clin Oncol 16(1):324–329

    PubMed  CAS  Google Scholar 

  2. Gerard JP, Conroy T, Bonnetain F, Bouche O, Chapet O, Closon-Dejardin MT, Untereiner M, Leduc B, Francois E, Maurel J, Seitz JF, Buecher B, Mackiewicz R, Ducreux M, Bedenne L (2006) Preoperative radiotherapy with or without concurrent fluorouracil and leucovorin in T3-4 rectal cancers: results of FFCD 9203. J Clin Oncol 24(28):4620–4625. doi:24/28/462010.1200/JCO.2006.06.7629

    Article  PubMed  Google Scholar 

  3. Crane CH, Sargent DJ (2004) Substitution of oral fluoropyrimidines for infusional fluorouracil with radiotherapy: how much data do we need? J Clin Oncol 22(15):2978–2981. doi:10.1200/JCO.2004.04.953 JCO.2004.04.953

    Article  PubMed  CAS  Google Scholar 

  4. Bosset JF, Collette L, Calais G, Mineur L, Maingon P, Radosevic-Jelic L, Daban A, Bardet E, Beny A, Ollier JC (2006) Chemotherapy with preoperative radiotherapy in rectal cancer. N Engl J Med 355(11):1114–1123. doi:355/11/111410.1056/NEJMoa060829

    Article  PubMed  CAS  Google Scholar 

  5. Capirci C, Valentini V, Cionini L, De Paoli A, Rodel C, Glynne-Jones R, Coco C, Romano M, Mantello G, Palazzi S, Mattia FO, Friso ML, Genovesi D, Vidali C, Gambacorta MA, Buffoli A, Lupattelli M, Favretto MS, La Torre G (2008) Prognostic value of pathologic complete response after neoadjuvant therapy in locally advanced rectal cancer: long-term analysis of 566 ypCR patients. Int J Radiat Oncol Biol Phys 72(1):99–107. doi:S0360-3016(07)04759-110.1016/j.ijrobp. 2007.12.019

    Article  PubMed  Google Scholar 

  6. Rodel C, Martus P, Papadoupolos T, Fuzesi L, Klimpfinger M, Fietkau R, Liersch T, Hohenberger W, Raab R, Sauer R, Wittekind C (2005) Prognostic significance of tumor regression after preoperative chemoradiotherapy for rectal cancer. J Clin Oncol 23(34):8688–8696. doi:JCO.2005.02.132910.1200/JCO.2005.02.1329

    Article  PubMed  Google Scholar 

  7. Kim BC (2011) Prognostic significance of tumor regression grade after preoperative chemoradiotherapy for rectal cancer. J Korean Soc Coloproctol 27(1):1–2. doi:10.3393/jksc.2011.27.1.1

    Article  PubMed  Google Scholar 

  8. Suarez J, Vera R, Balen E, Gomez M, Arias F, Lera JM, Herrera J, Zazpe C (2008) Pathologic response assessed by Mandard grade is a better prognostic factor than down staging for disease-free survival after preoperative radiochemotherapy for advanced rectal cancer. Colorectal Dis 10(6):563–568. doi:CDI142410.1111/j.1463-1318.2007.01424.x

    Article  PubMed  CAS  Google Scholar 

  9. Theodoropoulos G, Wise WE, Padmanabhan A, Kerner BA, Taylor CW, Aguilar PS, Khanduja KS (2002) T-level downstaging and complete pathologic response after preoperative chemoradiation for advanced rectal cancer result in decreased recurrence and improved disease-free survival. Dis Colon Rectum 45(7):895–903

    Article  PubMed  Google Scholar 

  10. Yeo SG, Kim DY, Kim TH, Chang HJ, Oh JH, Park W, Choi DH, Nam H, Kim JS, Cho MJ, Kim JH, Park JH, Kang MK, Koom WS, Nam TK, Chie EK, Lee KJ (2010) Pathologic complete response of primary tumor following preoperative chemoradiotherapy for locally advanced rectal cancer: long-term outcomes and prognostic significance of pathologic nodal status (KROG 09-01). Ann Surg 252(6):998–1004. doi:10.1097/SLA.0b013e3181f3f1b100000658-201012000-00015

    Article  PubMed  Google Scholar 

  11. Warburg O (1956) On the origin of cancer cells. Science 123(3191):309–314

    Article  PubMed  CAS  Google Scholar 

  12. Semenza GL, Roth PH, Fang HM, Wang GL (1994) Transcriptional regulation of genes encoding glycolytic enzymes by hypoxia-inducible factor 1. The Journal of biological chemistry 269(38):23757–23763

    PubMed  CAS  Google Scholar 

  13. Semenza GL (2007) HIF-1 mediates the Warburg effect in clear cell renal carcinoma. Journal of bioenergetics and biomembranes 39(3):231–234. doi:10.1007/s10863-007-9081-2

    Article  PubMed  CAS  Google Scholar 

  14. Koukourakis MI, Giatromanolaki A, Sivridis E, Gatter KC, Harris AL (2006) Lactate dehydrogenase 5 expression in operable colorectal cancer: strong association with survival and activated vascular endothelial growth factor pathway—a report of the Tumour Angiogenesis Research Group. J Clin Oncol 24(26):4301–4308. doi:10.1200/JCO.2006.05.9501

    Article  PubMed  CAS  Google Scholar 

  15. Wigfield SM, Winter SC, Giatromanolaki A, Taylor J, Koukourakis ML, Harris AL (2008) PDK-1 regulates lactate production in hypoxia and is associated with poor prognosis in head and neck squamous cancer. Br J Cancer 98(12):1975–1984. doi:10.1038/sj.bjc.6604356

    Article  PubMed  CAS  Google Scholar 

  16. Macheda ML, Rogers S, Best JD (2005) Molecular and cellular regulation of glucose transporter (GLUT) proteins in cancer. J Cell Physiol 202(3):654–662. doi:10.1002/jcp. 20166

    Article  PubMed  CAS  Google Scholar 

  17. Tredan O, Galmarini CM, Patel K, Tannock IF (2007) Drug resistance and the solid tumor microenvironment. J Natl Cancer Inst 99(19):1441–1454. doi:djm13510.1093/jnci/djm135

    Article  PubMed  CAS  Google Scholar 

  18. Coleman CN (1996) Modulating the radiation response. Oncologist 1(4):227–231

    PubMed  CAS  Google Scholar 

  19. Janssen HL, Haustermans KM, Balm AJ, Begg AC (2005) Hypoxia in head and neck cancer: how much, how important? Head Neck 27(7):622–638. doi:10.1002/hed.20223

    Article  PubMed  CAS  Google Scholar 

  20. Nordsmark M, Alsner J, Keller J, Nielsen OS, Jensen OM, Horsman MR, Overgaard J (2001) Hypoxia in human soft tissue sarcomas: adverse impact on survival and no association with p53 mutations. Br J Cancer 84(8):1070–1075. doi:10.1054/bjoc.2001.1728S0007092001917288

    Article  PubMed  CAS  Google Scholar 

  21. Nordsmark M, Loncaster J, Chou SC, Havsteen H, Lindegaard JC, Davidson SE, Varia M, West C, Hunter R, Overgaard J, Raleigh JA (2001) Invasive oxygen measurements and pimonidazole labeling in human cervix carcinoma. Int J Radiat Oncol Biol Phys 49(2):581–586. doi:S0360-3016(00)01493-0

    Article  PubMed  CAS  Google Scholar 

  22. Nordsmark M, Overgaard J (2000) A confirmatory prognostic study on oxygenation status and loco-regional control in advanced head and neck squamous cell carcinoma treated by radiation therapy. Radiother Oncol 57(1):39–43

    Article  PubMed  CAS  Google Scholar 

  23. Hong SH, Roh SY, Ko YH, Won HS, Lee MA, Woo IS, Byun JH, Kang JH, Hong YS, Jung CK (2010) Prognostic significance of glycolytic metabolic change related to HIF-1α in oral squamous cell carcinomas. Korean J Pathol 44(4):360–369

    Article  Google Scholar 

  24. Chung FY, Huang MY, Yeh CS, Chang HJ, Cheng TL, Yen LC, Wang JY, Lin SR (2009) GLUT1 gene is a potential hypoxic marker in colorectal cancer patients. BMC Cancer 9:241. doi:1471-2407-9-24110.1186/1471-2407-9-241

    Article  PubMed  Google Scholar 

  25. Koukourakis MI, Giatromanolaki A, Simopoulos C, Polychronidis A, Sivridis E (2005) Lactate dehydrogenase 5 (LDH5) relates to up-regulated hypoxia inducible factor pathway and metastasis in colorectal cancer. Clin Exp Metastasis 22(1):25–30. doi:10.1007/s10585-005-2343-7

    Article  PubMed  CAS  Google Scholar 

  26. Brown JM (2000) Exploiting the hypoxic cancer cell: mechanisms and therapeutic strategies. Mol Med Today 6(4):157–162. doi:S1357-4310(00)01677-4

    Article  PubMed  CAS  Google Scholar 

  27. Hockel M, Schlenger K, Aral B, Mitze M, Schaffer U, Vaupel P (1996) Association between tumor hypoxia and malignant progression in advanced cancer of the uterine cervix. Cancer Res 56(19):4509–4515

    PubMed  CAS  Google Scholar 

  28. Knocke TH, Weitmann HD, Feldmann HJ, Selzer E, Potter R (1999) Intratumoral pO2-measurements as predictive assay in the treatment of carcinoma of the uterine cervix. Radiother Oncol 53(2):99–104

    Article  PubMed  CAS  Google Scholar 

  29. Yeung JM, Kalff V, Hicks RJ, Drummond E, Link E, Taouk Y, Michael M, Ngan S, Lynch AC, Heriot AG (2011) Metabolic response of rectal cancer assessed by 18-FDG PET following chemoradiotherapy is prognostic for patient outcome. Dis Colon Rectum 54(5):518–525. doi:10.1007/DCR.0b013e31820b36f000003453-201105000-00002

    Article  PubMed  CAS  Google Scholar 

  30. Martoni AA, Di Fabio F, Pinto C, Castellucci P, Pini S, Ceccarelli C, Cuicchi D, Iacopino B, Di Tullio P, Giaquinta S, Tardio L, Lombardi R, Fanti S, Cola B (2011) Prospective study on the FDG-PET/CT predictive and prognostic values in patients treated with neoadjuvant chemoradiation therapy and radical surgery for locally advanced rectal cancer. Ann Oncol 22(3):650–656. doi:mdq43310.1093/annonc/mdq433

    Article  PubMed  CAS  Google Scholar 

  31. Chapman JD, Engelhardt EL, Stobbe CC, Schneider RF, Hanks GE (1998) Measuring hypoxia and predicting tumor radioresistance with nuclear medicine assays. Radiother Oncol 46(3):229–237. doi:S0167814097001862

    Article  PubMed  CAS  Google Scholar 

  32. Jang NY, Kang SB, Kim DW, Kim JH, Lee KW, Kim IA, Kim JS (2011) The role of carcinoembryonic antigen after neoadjuvant chemoradiotherapy in patients with rectal cancer. Dis Colon Rectum 54(2):245–252. doi:10.1007/DCR.0b013e3181fcee6800003453-201102000-00020

    Article  PubMed  Google Scholar 

  33. Greijer AE, Delis-van Diemen PM, Fijneman RJ, Giles RH, Voest EE, van Hinsbergh VW, Meijer GA (2008) Presence of HIF-1 and related genes in normal mucosa, adenomas and carcinomas of the colorectum. Virchows Arch 452(5):535–544. doi:10.1007/s00428-008-0578-9

    Article  PubMed  CAS  Google Scholar 

  34. Koukourakis MI, Giatromanolaki A, Polychronidis A, Simopoulos C, Gatter KC, Harris AL, Sivridis E (2006) Endogenous markers of hypoxia/anaerobic metabolism and anemia in primary colorectal cancer. Cancer Sci 97(7):582–588. doi:CAS22010.1111/j.1349-7006.2006.00220.x

    Article  PubMed  CAS  Google Scholar 

  35. Kim JW, Tchernyshyov I, Semenza GL, Dang CV (2006) HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab 3(3):177–185. doi:S1550-4131(06)00062-310.1016/j.cmet.2006.02.002

    Article  PubMed  Google Scholar 

  36. Papandreou I, Cairns RA, Fontana L, Lim AL, Denko NC (2006) HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption. Cell Metab 3(3):187–197. doi:S1550-4131(06)00060-X10.1016/j.cmet.2006.01.012

    Article  PubMed  CAS  Google Scholar 

  37. Sakashita M, Aoyama N, Minami R, Maekawa S, Kuroda K, Shirasaka D, Ichihara T, Kuroda Y, Maeda S, Kasuga M (2001) Glut1 expression in T1 and T2 stage colorectal carcinomas: its relationship to clinicopathological features. Eur J Cancer 37(2):204–209. doi:S0959804900003713

    Article  PubMed  CAS  Google Scholar 

  38. Haber RS, Rathan A, Weiser KR, Pritsker A, Itzkowitz SH, Bodian C, Slater G, Weiss A, Burstein DE (1998) GLUT1 glucose transporter expression in colorectal carcinoma: a marker for poor prognosis. Cancer 83(1):34–40. doi:10.1002/(SICI)1097-0142(19980701)83:1<34::AID-CNCR5>3.0.CO;2-E

    Article  PubMed  CAS  Google Scholar 

  39. Chang HJ, Jung KH, Kim DY, Jeong SY, Choi HS, Kim YH, Sohn DK, Yoo BC, Lim SB, Kim DH, Ahn JB, Kim IJ, Kim JM, Yoon WH, Park JG (2005) Bax, a predictive marker for therapeutic response to preoperative chemoradiotherapy in patients with rectal carcinoma. Hum Pathol 36(4):364–371. doi:S004681770500046810.1016/j.humpath.2005.01.018

    Article  PubMed  CAS  Google Scholar 

  40. Bengala C, Bettelli S, Bertolini F, Sartori G, Fontana A, Malavasi N, Depenni R, Zironi S, Del Giovane C, Luppi G, Conte PF (2010) Prognostic role of EGFR gene copy number and KRAS mutation in patients with locally advanced rectal cancer treated with preoperative chemoradiotherapy. Br J Cancer 103(7):1019–1024. doi:660585310.1038/sj.bjc.6605853

    Article  PubMed  CAS  Google Scholar 

  41. Toiyama Y, Inoue Y, Saigusa S, Okugawa Y, Yokoe T, Tanaka K, Miki C, Kusunoki M (2010) Gene expression profiles of epidermal growth factor receptor, vascular endothelial growth factor and hypoxia-inducible factor-1 with special reference to local responsiveness to neoadjuvant chemoradiotherapy and disease recurrence after rectal cancer surgery. Clin Oncol (R Coll Radiol) 22(4):272–280. doi:S0936-6555(10)00002-610.1016/j.clon.2010.01.001

    Article  CAS  Google Scholar 

  42. Saigusa S, Toiyama Y, Tanaka K, Okugawa Y, Fujikawa H, Matsushita K, Uchida K, Inoue Y, Kusunoki M (2012) Prognostic significance of glucose transporter-1 (GLUT1) gene expression in rectal cancer after preoperative chemoradiotherapy. Surg Today 42(5):460–469. doi:10.1007/s00595-011-0027-2

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

The present work has been supported by grants from the clinical research fund of St. Vincent’s Hospital.

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Authors and Affiliations

  1. Department of Medical Oncology, Medical School, The Catholic University of Korea, St. Vincent’s Hospital, Suwon, South Korea

    Byoung Yong Shim & Der Sheng Sun

  2. Department of Hospital Pathology, Medical School, The Catholic University of Korea, St. Vincent’s Hospital, Suwon, South Korea

    Ji-Han Jung

  3. Department of Gastroenterology, Medical School, The Catholic University of Korea, St. Vincent’s Hospital, Suwon, South Korea

    Kang-Moon Lee

  4. Department of Surgery, Medical School, The Catholic University of Korea, St. Vincent’s Hospital, 93 Ji-dong, Paldal-gu, 442-723, Suwon, South Korea

    Hyung-Jin Kim & Hyeon-Min Cho

  5. Department of Medical Oncology, Medical School, The Catholic University of Korea, Seoul St. Mary’s Hospital, Seoul, South Korea

    Sook Hee Hong

  6. Department of Radiation Oncology, Medical School, The Catholic University of Korea, St. Vincent’s Hospital, Suwon, South Korea

    Sung Hwan Kim

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  1. Byoung Yong Shim
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Correspondence to Hyeon-Min Cho.

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Shim, B.Y., Jung, JH., Lee, KM. et al. Glucose transporter 1 (GLUT1) of anaerobic glycolysis as predictive and prognostic values in neoadjuvant chemoradiotherapy and laparoscopic surgery for locally advanced rectal cancer. Int J Colorectal Dis 28, 375–383 (2013). https://doi.org/10.1007/s00384-012-1542-3

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