Annals of Surgical Oncology

, Volume 25, Issue 5, pp 1432–1439 | Cite as

Significance of Glucose Transporter Type 1 (GLUT-1) Expression in the Therapeutic Strategy for Pancreatic Ductal Adenocarcinoma

  • Hiroshi Kurahara
  • Kosei Maemura
  • Yuko Mataki
  • Masahiko Sakoda
  • Satoshi Iino
  • Yota Kawasaki
  • Takaaki Arigami
  • Shinichiro Mori
  • Yuko Kijima
  • Shinichi Ueno
  • Hiroyuki Shinchi
  • Shoji Natsugoe
Pancreatic Tumors
First Online:
Received:

Abstract

Background

This study aimed to examine the prognostic relevance of glucose transporter type 1 (GLUT-1), which is a key regulator of the glucose metabolism. In particular, the study aimed to examine the association between GLUT-1 expression and the therapeutic effect of chemoradiotherapy (CRT) in pancreatic ductal adenocarcinoma (PDAC).

Methods

Patients with PDAC were enrolled in the study. Patients with distant metastases and those who received only chemotherapy as treatment were excluded from the study. Specimens for immunohistochemical evaluations were obtained through surgical resection and endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) of the primary tumor before any treatment.

Results

This study included 197 patients. Of these 197 patients, 100 underwent upfront surgery, and 97 received neoadjuvant CRT (NACRT), which was performed mainly for patients with locally advanced tumors. Of the 97 patients who received NACRT, 21 later underwent surgical resection. For the patients who underwent upfront surgery, low GLUT-1 expression was an independent factor for a better prognosis. For the patients who underwent NACRT, low GLUT-1 expression was significantly associated with greater tumor size reduction, a higher resection rate, and a better prognosis. Additionally, GLUT-1 expression was significantly increased after NACRT treatment.

Conclusions

Among the patients with PDAC, those with low GLUT-1 expression in the primary tumor had a better prognosis those with high GLUT-1 expression. Moreover, the patients with low GLUT-1 expression displayed a better therapeutic response to NACRT.

This is a preview of subscription content, log in to check access

Notes

Acknowledgment

This study was funded by Grants-in-Aid for Scientific Research (26462067) from the Japan Society for the Promotion of Science, Ministry of Health, Labour and Welfare, Japan.

Disclosure

There are no conflicts of interest.

Supplementary material

10434_2018_6357_MOESM1_ESM.docx (16 kb)
Supplementary material 1 (DOCX 15 kb)
10434_2018_6357_MOESM2_ESM.docx (16 kb)
Supplementary material 2 (DOCX 16 kb)
10434_2018_6357_MOESM3_ESM.docx (15 kb)
Supplementary material 3 (DOCX 14 kb)
10434_2018_6357_MOESM4_ESM.docx (16 kb)
Supplementary material 4 (DOCX 16 kb)
10434_2018_6357_MOESM5_ESM.jpg (690 kb)
Fig. S1 Kaplan–Meier survival curves from the initial treatment (surgery) for patients who underwent upfront surgery.. Supplementary material 5 (JPEG 690 kb)
10434_2018_6357_MOESM6_ESM.jpg (1 mb)
Fig. S2 Kaplan–Meier survival curves from the initial treatment for patients who underwent neoadjuvant chemoradiotherapy (NACRT). a Overall survival (OS) of patients who underwent surgical resection after NACRT. b Recurrence-free survival of patients who underwent surgical resection after NACRT. c OS of patients who did not undergo surgical resection after NACRT. d Progression-free survival of patients who did not undergo surgical resection after NACRT. Supplementary material 6 (JPEG 1027 kb)
10434_2018_6357_MOESM7_ESM.jpg (713 kb)
Fig. S3 Kaplan–Meier survival curves from the initial treatment for patients who underwent neoadjuvant chemoradiotherapy (NACRT). Eight patients experienced a low-to-high change in glucose transporter type 1 (GLUT-1) expression due to NACRT. Supplementary material 7 (JPEG 712 kb)

References

  1. 1.
    Gillen S, Schuster T, Meyer Zum Buschenfelde C, Friess H, Kleeff J. Preoperative/neoadjuvant therapy in pancreatic cancer: a systematic review and meta-analysis of response and resection percentages. PLoS Med. 2010;7:e1000267.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Ying JE, Zhu LM, Liu BX. Developments in metastatic pancreatic cancer: is gemcitabine still the standard? World J Gastroenterol. 2012;18:736–45.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014;64:9–29.CrossRefPubMedGoogle Scholar
  4. 4.
    Small W Jr, Berlin J, Freedman GM, et al. Full-dose gemcitabine with concurrent radiation therapy in patients with nonmetastatic pancreatic cancer: a multicenter phase II trial. J Clin Oncol. 2008; 26:942–47.CrossRefPubMedGoogle Scholar
  5. 5.
    Shinchi H, Maemura K, Mataki Y, et al. A phase II study of oral S-1 with concurrent radiotherapy followed by chemotherapy with S-1 alone for locally advanced pancreatic cancer. J Hepatobiliary Pancreat Sci. 2012;19:152–58.CrossRefPubMedGoogle Scholar
  6. 6.
    Takahashi H, Akita H, Tomokuni A, et al. Preoperative gemcitabine-based chemoradiation therapy for borderline resectable pancreatic cancer: impact of venous and arterial involvement status on surgical outcome and pattern of recurrence. Ann Surg. 2016;264:1091–97.CrossRefPubMedGoogle Scholar
  7. 7.
    Levine AJ, Puzio-Kuter AM. The control of the metabolic switch in cancers by oncogenes and tumor suppressor genes. Science. 2010;330:1340–44.CrossRefPubMedGoogle Scholar
  8. 8.
    Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74.CrossRefPubMedGoogle Scholar
  9. 9.
    Warburg O. On the origin of cancer cells. Science. 1956;123:309–14.CrossRefPubMedGoogle Scholar
  10. 10.
    Meijer TW, Kaanders JH, Span PN, Bussink J. Targeting hypoxia, HIF-1, and tumor glucose metabolism to improve radiotherapy efficacy. Clin Cancer Res. 2012;18:5585–94.CrossRefPubMedGoogle Scholar
  11. 11.
    Luo XM, Xu B, Zhou ML, Bao YY, Zhou SH, Fan J, Lu ZJ. Co-inhibition of GLUT-1 expression and the PI3K/Akt signaling pathway to enhance the radiosensitivity of laryngeal carcinoma xenografts in vivo. PloS One. 2015;10:e0143306.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Macheda ML, Rogers S, Best JD. Molecular and cellular regulation of glucose transporter (GLUT) proteins in cancer. J Cell Physiol. 2005;202:654–62.CrossRefPubMedGoogle Scholar
  13. 13.
    Zhang C, Liu J, Liang Y, et al. Tumour-associated mutant p53 drives the Warburg effect. Nat Commun. 2013;4:2935.PubMedPubMedCentralGoogle Scholar
  14. 14.
    Vaupel P, Mayer A, Hockel M. Tumor hypoxia and malignant progression. Methods Enzymol. 2004;381:335–54.CrossRefPubMedGoogle Scholar
  15. 15.
    Shin SH, Kim SC, Hong SM, Kim YH, Song KB, Park KM, Lee YJ. Genetic alterations of K-ras, p53, c-erbB-2, and DPC4 in pancreatic ductal adenocarcinoma and their correlation with patient survival. Pancreas. 2013;42:216–22.CrossRefPubMedGoogle Scholar
  16. 16.
    Kim H, Saka B, Knight S, et al. Having pancreatic cancer with tumoral loss of ATM and normal TP53 protein expression is associated with a poorer prognosis. Clin Cancer Res, 2014;20:1865–72.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Younes M, Brown RW, Mody DR, Fernandez L, Laucirica R. GLUT1 expression in human breast carcinoma: correlation with known prognostic markers. Anticancer Res. 1995;15:2895–8.PubMedGoogle Scholar
  18. 18.
    Haber RS, Rathan A, Weiser KR, et al. GLUT1 glucose transporter expression in colorectal carcinoma: a marker for poor prognosis. Cancer. 1998;83:34–40.CrossRefPubMedGoogle Scholar
  19. 19.
    Kawamura T, Kusakabe T, Sugino T, et al. Expression of glucose transporter-1 in human gastric carcinoma: association with tumor aggressiveness, metastasis, and patient survival. Cancer. 2001;92:634–41.CrossRefPubMedGoogle Scholar
  20. 20.
    Melstrom LG, Salabat MR, Ding XZ, et al. Apigenin down-regulates the hypoxia response genes: HIF-1alpha, GLUT-1, and VEGF in human pancreatic cancer cells. J Surg Res. 2011;167:173–81.CrossRefPubMedGoogle Scholar
  21. 21.
    Basturk O, Singh R, Kaygusuz E, Kaygusuz E, Balci S, Dursun N, Adsay NV. GLUT-1 expression in pancreatic neoplasia: implications in pathogenesis, diagnosis, and prognosis. Pancreas. 2011;40:187–92.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Sharen G, Peng Y, Cheng H, Liu Y, Shi Y, Zhao J. Prognostic value of GLUT-1 expression in pancreatic cancer: results from 538 patients. Oncotarget. 2017;8:19760–7.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Sobin LH, Gospodarowicz MK, Wittekind C, International Union against Cancer (2010) TNM Classification of Malignant Tumours. 7th ed.Wiley-Blackwell, Chichester.Google Scholar
  24. 24.
    Maemura K, Shinchi H, Noma H, et al. Comparison of hyper-fractionated accelerated and standard fractionated radiotherapy with concomitant low-dose gemcitabine for unresectable pancreatic cancer. Anticancer Res. 2008;28:2369–72.PubMedGoogle Scholar
  25. 25.
    Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228–47.CrossRefPubMedGoogle Scholar
  26. 26.
    Chikamoto A, Inoue R, Komohara Y, et al. Preoperative high maximum standardized uptake value in association with glucose transporter 1 predicts poor prognosis in pancreatic cancer. Ann Surg Concol. 2017;24:2040–6.CrossRefGoogle Scholar
  27. 27.
    Erickson RA. EUS-guided FNA. Gastrointest Endosc. 2004;60:267–79.CrossRefPubMedGoogle Scholar
  28. 28.
    Higashi M, Yokoyama S, Yamamoto T, et al. Mucin expression in endoscopic ultrasound-guided fine-needle aspiration specimens is a useful prognostic factor in pancreatic ductal adenocarcinoma. Pancreas. 2015;44:728–34.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Kurahara H, Maemura K, Mataki Y, Sakoda M, Shinchi H, Natsugoe S. Impact of p53 and PDGFR-beta expression on metastasis and prognosis of patients with pancreatic cancer. World J Surg. 2016;40:1977–84.CrossRefPubMedGoogle Scholar
  30. 30.
    Yamada R, Mizuno S, Uchida K, et al. Human equilibrative nucleoside transporter 1 expression in endoscopic ultrasonography-guided fine-needle aspiration biopsy samples is a strong predictor of clinical response and survival in the patients with pancreatic ductal adenocarcinoma undergoing gemcitabine-based chemoradiotherapy. Pancreas. 2016;45:761–71.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Society of Surgical Oncology 2018

Authors and Affiliations

  • Hiroshi Kurahara
    • 1
  • Kosei Maemura
    • 1
  • Yuko Mataki
    • 1
  • Masahiko Sakoda
    • 1
  • Satoshi Iino
    • 1
  • Yota Kawasaki
    • 1
  • Takaaki Arigami
    • 1
  • Shinichiro Mori
    • 1
  • Yuko Kijima
    • 1
  • Shinichi Ueno
    • 2
  • Hiroyuki Shinchi
    • 3
  • Shoji Natsugoe
    • 1
  1. 1.Department of Digestive Surgery, Breast and Thyroid SurgeryKagoshima UniversityKagoshimaJapan
  2. 2.Department of Clinical OncologyKagoshima UniversityKagoshimaJapan
  3. 3.Department of Health SciencesKagoshima UniversityKagoshimaJapan

Personalised recommendations