Skip to main content
Top
Published in: Annals of Nuclear Medicine 4/2019

Open Access 01-04-2019 | Original Article

18F-FDG and 11C-choline uptake in proliferating tumor cells is dependent on the cell cycle in vitro

Authors: Motoi Roppongi, Mitsuru Izumisawa, Kazunori Terasaki, Yasushi Muraki, Masanori Shozushima

Published in: Annals of Nuclear Medicine | Issue 4/2019

Login to get access

Abstract

Objective

Among different PET tracers, 18F-fludeoxyglucose (FDG) and 11C-choline are known to have a high tumor uptake correlated with a high mitotic index of tumor cells. Thus, the uptake of 18F-FDG and 11C-choline may be dependent on the cell cycle. In the present study, we examined the uptake of 18F-FDG and 11C-choline in cancer cell lines by cell cycle synchronization to clarify the biological properties of cancer cells with respect to each tracer.

Methods

HeLa S3 Cells were synchronized by the double thymidine (TdR) block methods. 18F-FDG and 11C-choline were administered to synchronized cells, and the radioactivity per cell was measured to compare the cellular uptake of the tracers during S, G2/M, and G1 phases. Flow cytometry (FCM) was performed to measure the proportion of cells in G1, S, and G2/M phases. Furthermore, the levels of glucose transporter 1 (GLUT1) and choline transporter-like protein 1 (CTL1) in the cell were evaluated by FCM.

Results

The uptake of 18F-FDG was the highest in S to G2/M phases, and markedly decreased in G1 phase. The uptake of 11C-choline reached its peak in G2/M, and decreased in G1 phase. The level of GLUT1 expression was similar to that of 18F-FDG uptake during the cell cycle, and the level of CTL1 expression was similar to that of 11C-choline uptake throughout the cell cycle.

Conclusions

In this in vitro study, we demonstrated that 18F-FDG and 11C-choline had the highest uptake in S to G2/M phases and in G2/M phase, respectively, with a rapid decrease in G1 phase. These findings suggest that 18F-FDG and 11C-choline have a high accumulation in tumor cells with a high mitotic index. Furthermore, our study suggests that the expression of GLUT1 and CTL1 has cell cycle dependence, and the changes of 18F-FDG and 11C-choline accumulation seem to be caused by the above properties of these transporters.
Literature
1.
go back to reference Boellaard R, Delgado-Bolton R, Oyen WJ, Giammarile F, Tatsch K, Eschner W, et al. FDG PET/CT: EANM procedure guidelines for tumour imaging: version 2.0. Eur J Nucl Med Mol Imaging. 2015;42:328–54.CrossRefPubMed Boellaard R, Delgado-Bolton R, Oyen WJ, Giammarile F, Tatsch K, Eschner W, et al. FDG PET/CT: EANM procedure guidelines for tumour imaging: version 2.0. Eur J Nucl Med Mol Imaging. 2015;42:328–54.CrossRefPubMed
2.
go back to reference Kitajima K, Yamamoto S, Fukushima K, Minamimoto R, Kamai T, Jadvar H. Update on advances in molecular PET in urological oncology. Jpn J Radiol. 2016;34:470–85.CrossRefPubMedPubMedCentral Kitajima K, Yamamoto S, Fukushima K, Minamimoto R, Kamai T, Jadvar H. Update on advances in molecular PET in urological oncology. Jpn J Radiol. 2016;34:470–85.CrossRefPubMedPubMedCentral
3.
go back to reference Halfpenny W, Hain SF, Biassoni L, Maisey MN, Sherman JA, McGurk M. FDG-PET. A possible prognostic factor in head and neck cancer. Br J Cancer. 2002;86:512–6.CrossRefPubMedPubMedCentral Halfpenny W, Hain SF, Biassoni L, Maisey MN, Sherman JA, McGurk M. FDG-PET. A possible prognostic factor in head and neck cancer. Br J Cancer. 2002;86:512–6.CrossRefPubMedPubMedCentral
4.
go back to reference Minn H, Joensuu H, Ahonen A, Klemi P. Fluorodeoxyglucose imaging: a method to assess the proliferative activity of human cancer in vivo. Comparison with DNA flow cytometry in head and neck tumors. Cancer. 1988;61:1776–81.CrossRefPubMed Minn H, Joensuu H, Ahonen A, Klemi P. Fluorodeoxyglucose imaging: a method to assess the proliferative activity of human cancer in vivo. Comparison with DNA flow cytometry in head and neck tumors. Cancer. 1988;61:1776–81.CrossRefPubMed
5.
go back to reference Hara T, Inagaki K, Kosaka N, Morita T. Sensitive detection of mediastinal lymph node metastasis of lung cancer with 11C-choline PET. J Nucl Med. 2000;41:1507–13.PubMed Hara T, Inagaki K, Kosaka N, Morita T. Sensitive detection of mediastinal lymph node metastasis of lung cancer with 11C-choline PET. J Nucl Med. 2000;41:1507–13.PubMed
6.
go back to reference Glunde K, Penet MF, Jiang L, Jacobs MA, Bhujwalla ZM. Choline metabolism-based molecular diagnosis of cancer: an update. Expert Rev Mol Diagn. 2015;15:735–47.CrossRefPubMedPubMedCentral Glunde K, Penet MF, Jiang L, Jacobs MA, Bhujwalla ZM. Choline metabolism-based molecular diagnosis of cancer: an update. Expert Rev Mol Diagn. 2015;15:735–47.CrossRefPubMedPubMedCentral
7.
go back to reference Del Gobbo A, Pellegrinelli A, Gaudioso G, Castellani M, Zito Marino F, Franco R, et al. Analysis of NSCLC tumour heterogeneity, proliferative and 18F-FDG PET indices reveals Ki67 prognostic role in adenocarcinomas. Histopathology. 2016;68:746–51.CrossRefPubMed Del Gobbo A, Pellegrinelli A, Gaudioso G, Castellani M, Zito Marino F, Franco R, et al. Analysis of NSCLC tumour heterogeneity, proliferative and 18F-FDG PET indices reveals Ki67 prognostic role in adenocarcinomas. Histopathology. 2016;68:746–51.CrossRefPubMed
8.
go back to reference Hu SL, Yang ZY, Zhou ZR, Yu XJ, Ping B, Zhang YJ. Role of SUV(max) obtained by 18F-FDG PET/CT in patients with a solitary pancreatic lesion: predicting malignant potential and proliferation. Nucl Med Commun. 2013;34:533–9.CrossRefPubMed Hu SL, Yang ZY, Zhou ZR, Yu XJ, Ping B, Zhang YJ. Role of SUV(max) obtained by 18F-FDG PET/CT in patients with a solitary pancreatic lesion: predicting malignant potential and proliferation. Nucl Med Commun. 2013;34:533–9.CrossRefPubMed
9.
go back to reference Knehr M, Poppe M, Enulescu M, Eickelbaum W, Stoehr M, Schroeter D, et al. A critical appraisal of synchronization methods applied to achieve maximal enrichment of HeLa cells in specific cell cycle phases. Exp Cell Res. 1995;217:546–53.CrossRefPubMed Knehr M, Poppe M, Enulescu M, Eickelbaum W, Stoehr M, Schroeter D, et al. A critical appraisal of synchronization methods applied to achieve maximal enrichment of HeLa cells in specific cell cycle phases. Exp Cell Res. 1995;217:546–53.CrossRefPubMed
10.
go back to reference Pascali C, Bogni A, Iwata R, Decise D, Crippa F, Bombardieri E. High efficiency preparation of l-[S-methyl-C-11]methionine by on-column [C-11]methylation on C18 Sep-Pak. J Label Compd Rad. 1999;42:715–24.CrossRef Pascali C, Bogni A, Iwata R, Decise D, Crippa F, Bombardieri E. High efficiency preparation of l-[S-methyl-C-11]methionine by on-column [C-11]methylation on C18 Sep-Pak. J Label Compd Rad. 1999;42:715–24.CrossRef
11.
go back to reference Cao G, Liu LM, Cleary SF. Modified method of mammalian cell synchronization improves yield and degree of synchronization. Exp Cell Res. 1991;193:405–10.CrossRefPubMed Cao G, Liu LM, Cleary SF. Modified method of mammalian cell synchronization improves yield and degree of synchronization. Exp Cell Res. 1991;193:405–10.CrossRefPubMed
12.
go back to reference Meistrich ML, Meyn RE, Barlogie B. Synchronization of mouse L-P59 cells by centrifugal elutriation separation. Exp Cell Res. 1977;105:169–77.CrossRefPubMed Meistrich ML, Meyn RE, Barlogie B. Synchronization of mouse L-P59 cells by centrifugal elutriation separation. Exp Cell Res. 1977;105:169–77.CrossRefPubMed
13.
go back to reference Kubota R, Kubota K, Yamada S, Tada M, Ido T, Tamahashi N. Microautoradiographic study for the differentiation of intratumoral macrophages, granulation tissues and cancer cells by the dynamics of fluorine-18-fluorodeoxyglucose uptake. J Nucl Med. 1994;35:104–12.PubMed Kubota R, Kubota K, Yamada S, Tada M, Ido T, Tamahashi N. Microautoradiographic study for the differentiation of intratumoral macrophages, granulation tissues and cancer cells by the dynamics of fluorine-18-fluorodeoxyglucose uptake. J Nucl Med. 1994;35:104–12.PubMed
14.
go back to reference Kubota R, Kubota K, Yamada S, Tada M, Takahashi T, Iwata R, et al. Methionine uptake by tumor tissue: a microautoradiographic comparison with FDG. J Nucl Med. 1995;36:484–92.PubMed Kubota R, Kubota K, Yamada S, Tada M, Takahashi T, Iwata R, et al. Methionine uptake by tumor tissue: a microautoradiographic comparison with FDG. J Nucl Med. 1995;36:484–92.PubMed
15.
go back to reference Ohira H, Kubota K, Ohuchi N, Harada Y, Fukuda H, Satomi S. Comparison of intratumoral distribution of 99mTc-MIBI and deoxyglucose in mouse breast cancer models. J Nucl Med. 2000;41:1561–8.PubMed Ohira H, Kubota K, Ohuchi N, Harada Y, Fukuda H, Satomi S. Comparison of intratumoral distribution of 99mTc-MIBI and deoxyglucose in mouse breast cancer models. J Nucl Med. 2000;41:1561–8.PubMed
16.
go back to reference Sugawara Y, Fisher SJ, Zasadny KR, Kison PV, Baker LH, Wahl RL. Preclinical and clinical studies of bone marrow uptake of fluorine-1-fluorodeoxyglucose with or without granulocyte colony-stimulating factor during chemotherapy. J Clin Oncol. 1998;16:173–80.CrossRefPubMed Sugawara Y, Fisher SJ, Zasadny KR, Kison PV, Baker LH, Wahl RL. Preclinical and clinical studies of bone marrow uptake of fluorine-1-fluorodeoxyglucose with or without granulocyte colony-stimulating factor during chemotherapy. J Clin Oncol. 1998;16:173–80.CrossRefPubMed
17.
go back to reference Shozushima M, Tsutsumi R, Terasaki K, Sato S, Nakamura R, Sakamaki K. Augmentation effects of lymphocyte activation by antigen-presenting macrophages on FDG uptake. Ann Nucl Med. 2003;17:555–60.CrossRefPubMed Shozushima M, Tsutsumi R, Terasaki K, Sato S, Nakamura R, Sakamaki K. Augmentation effects of lymphocyte activation by antigen-presenting macrophages on FDG uptake. Ann Nucl Med. 2003;17:555–60.CrossRefPubMed
18.
go back to reference Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009;324:1029–33.CrossRefPubMedPubMedCentral Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009;324:1029–33.CrossRefPubMedPubMedCentral
19.
go back to reference Vander Heiden MG, Locasale JW, Swanson KD, Sharfi H, Heffron GJ, Amador-Noguez D, et al. Evidence for an alternative glycolytic pathway in rapidly proliferating cells. Science. 2010;329:1492–9.CrossRefPubMed Vander Heiden MG, Locasale JW, Swanson KD, Sharfi H, Heffron GJ, Amador-Noguez D, et al. Evidence for an alternative glycolytic pathway in rapidly proliferating cells. Science. 2010;329:1492–9.CrossRefPubMed
20.
go back to reference Macheda ML, Rogers S, Best JD. Molecular and cellular regulation of glucose transporter (GLUT) proteins in cancer. J Cell Physiol. 2005;202:654–62.CrossRefPubMed Macheda ML, Rogers S, Best JD. Molecular and cellular regulation of glucose transporter (GLUT) proteins in cancer. J Cell Physiol. 2005;202:654–62.CrossRefPubMed
21.
go back to reference Kunkel M, Reichert TE, Benz P, Lehr HA, Jeong JH, Wieand S, et al. Overexpression of Glut-1 and increased glucose metabolism in tumors are associated with a poor prognosis in patients with oral squamous cell carcinoma. Cancer. 2003;97:1015–24.CrossRefPubMed Kunkel M, Reichert TE, Benz P, Lehr HA, Jeong JH, Wieand S, et al. Overexpression of Glut-1 and increased glucose metabolism in tumors are associated with a poor prognosis in patients with oral squamous cell carcinoma. Cancer. 2003;97:1015–24.CrossRefPubMed
22.
go back to reference Zhou S, Wang S, Wu Q, Fan J, Wang Q. Expression of glucose transporter-1 and -3 in the head and neck carcinoma—the correlation of the expression with the biological behaviors. ORL J Otorhinolaryngol Relat Spec. 2008;70:189–94.CrossRefPubMed Zhou S, Wang S, Wu Q, Fan J, Wang Q. Expression of glucose transporter-1 and -3 in the head and neck carcinoma—the correlation of the expression with the biological behaviors. ORL J Otorhinolaryngol Relat Spec. 2008;70:189–94.CrossRefPubMed
23.
go back to reference Waki A, Fujibayashi Y, Yokoyama A. Recent advances in the analyses of the characteristics of tumors on FDG uptake. Nucl Med Biol. 1998;25:589–92.CrossRefPubMed Waki A, Fujibayashi Y, Yokoyama A. Recent advances in the analyses of the characteristics of tumors on FDG uptake. Nucl Med Biol. 1998;25:589–92.CrossRefPubMed
24.
go back to reference Waki A, Kato H, Yano R, Sadato N, Yokoyama A, Ishii Y, et al. The importance of glucose transport activity as the rate-limiting step of 2-deoxyglucose uptake in tumor cells in vitro. Nucl Med Biol. 1998;25:593–7.CrossRefPubMed Waki A, Kato H, Yano R, Sadato N, Yokoyama A, Ishii Y, et al. The importance of glucose transport activity as the rate-limiting step of 2-deoxyglucose uptake in tumor cells in vitro. Nucl Med Biol. 1998;25:593–7.CrossRefPubMed
25.
go back to reference Hara T, Kosaka N, Kishi H. PET imaging of prostate cancer using carbon-11-choline. J Nucl Med. 1998;39:990–5.PubMed Hara T, Kosaka N, Kishi H. PET imaging of prostate cancer using carbon-11-choline. J Nucl Med. 1998;39:990–5.PubMed
26.
go back to reference Kwee SA, DeGrado TR, Talbot JN, Gutman F, Coel MN. Cancer imaging with fluorine-18-labeled choline derivatives. Semin Nucl Med. 2007;37:420–8.CrossRefPubMed Kwee SA, DeGrado TR, Talbot JN, Gutman F, Coel MN. Cancer imaging with fluorine-18-labeled choline derivatives. Semin Nucl Med. 2007;37:420–8.CrossRefPubMed
27.
go back to reference Tian M, Zhang H, Oriuchi N, Higuchi T, Endo K. Comparison of 11C-choline PET and FDG PET for the differential diagnosis of malignant tumors. Eur J Nucl Med Mol Imaging. 2004;31:1064–72.PubMed Tian M, Zhang H, Oriuchi N, Higuchi T, Endo K. Comparison of 11C-choline PET and FDG PET for the differential diagnosis of malignant tumors. Eur J Nucl Med Mol Imaging. 2004;31:1064–72.PubMed
28.
go back to reference Kouji H, Inazu M, Yamada T, Tajima H, Aoki T, Matsumiya T. Molecular and functional characterization of choline transporter in human colon carcinoma HT-29 cells. Arch Biochem Biophys. 2009;483:90–8.CrossRefPubMed Kouji H, Inazu M, Yamada T, Tajima H, Aoki T, Matsumiya T. Molecular and functional characterization of choline transporter in human colon carcinoma HT-29 cells. Arch Biochem Biophys. 2009;483:90–8.CrossRefPubMed
29.
go back to reference Nagashima F, Nishiyama R, Iwao B, Kawai Y, Ishii C, Yamanaka T, et al. Molecular and functional characterization of choline transporter-like proteins in esophageal cancer cells and potential therapeutic targets. Biomol Ther (Seoul). 2018;26:399–408.CrossRef Nagashima F, Nishiyama R, Iwao B, Kawai Y, Ishii C, Yamanaka T, et al. Molecular and functional characterization of choline transporter-like proteins in esophageal cancer cells and potential therapeutic targets. Biomol Ther (Seoul). 2018;26:399–408.CrossRef
30.
go back to reference Wang T, Li J, Chen F, Zhao Y, He X, Wan D, et al. Choline transporters in human lung adenocarcinoma: expression and functional implications. Acta Biochim Biophys Sin (Shanghai). 2007;39:668–74.CrossRef Wang T, Li J, Chen F, Zhao Y, He X, Wan D, et al. Choline transporters in human lung adenocarcinoma: expression and functional implications. Acta Biochim Biophys Sin (Shanghai). 2007;39:668–74.CrossRef
31.
go back to reference Izumisawa M, Shozushima M, Sato H. The relationship between histopathological findings in oral squamous cell carcinoma and FDG uptake on PET. Oral Radiol. 2003;19:149–57.CrossRef Izumisawa M, Shozushima M, Sato H. The relationship between histopathological findings in oral squamous cell carcinoma and FDG uptake on PET. Oral Radiol. 2003;19:149–57.CrossRef
Metadata
Title
18F-FDG and 11C-choline uptake in proliferating tumor cells is dependent on the cell cycle in vitro
Authors
Motoi Roppongi
Mitsuru Izumisawa
Kazunori Terasaki
Yasushi Muraki
Masanori Shozushima
Publication date
01-04-2019
Publisher
Springer Singapore
Published in
Annals of Nuclear Medicine / Issue 4/2019
Print ISSN: 0914-7187
Electronic ISSN: 1864-6433
DOI
https://doi.org/10.1007/s12149-018-01325-6

Other articles of this Issue 4/2019

Annals of Nuclear Medicine 4/2019 Go to the issue