Regulation of 18F-FDG accumulation in colorectal cancer cells with mutated KRAS

Masayoshi Iwamoto, Kenji Kawada, Yuji Nakamoto, Yoshiro Itatani, Susumu Inamoto, Kosuke Toda, Hiroyuki Kimura, Takehiko Sasazuki, Senji Shirasawa, Hiroaki Okuyama, Masahiro Inoue, Suguru Hasegawa, Kaori Togashi, Yoshiharu Sakai

Research output: Contribution to journalArticle

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Abstract

KRAS gene mutations occur in approximately 40% of colorectal cancers (CRCs) and are associated with resistance to anti-epidermal growth factor receptor antibody therapy. We previously demonstrated that 18F-FDG accumulation in PET was significantly higher in CRCs with mutated KRAS than in those with wild-type KRAS in a clinical setting. Here, we investigated the mechanisms by which mutated KRAS increased 18F-FDG accumulation. Methods: Using paired isogenic human CRC cell lines that differ only in the mutational status of the KRAS gene, we measured 18F-FDG accumulation in these cells in vitro and in vivo. We also investigated the roles of proteins that have a function in 18F-FDG accumulation. Finally, we examined the relationship among mutated KRAS, hypoxia-inducible factor 1α (HIF-1α), and maximum standardized uptake value with 51 clinical CRC samples. Results: In the in vitro experiments, 18F-FDG accumulation was significantly higher in KRAS-mutant cells than in wild-type controls under normoxic conditions. The expression levels of glucose transporter 1 (GLUT1) and hexokinase type 2 (HK2) were higher in KRAS-mutant cells, and 18F-FDG accumulation was decreased by knockdown of GLUT1. Hypoxic induction of HIF-1α was higher in KRAS-mutant cells than in wild-type controls; in turn, elevated HIF-1α resulted in higher GLUT1 expression and 18F-FDG accumulation. In addition, HIF-1α knockdown decreased 18F-FDG accumulation under hypoxic conditions only in the KRAS-mutant cells. Small-animal PET scans showed in vivo 18F-FDG accumulation to be significantly higher in xenografts with mutated KRAS than in those with wild-type KRAS. The immunohistochemistry of these xenograft tumors showed that staining of GLUT1 was consistent with that of HIF-1α and pimonidazole. In a retrospective analysis of clinical samples, KRAS mutation exhibited a significantly positive correlation with expressions of GLUT1 and HIF-1α and with maximum standardized uptake value. Conclusion: Mutated KRAS caused higher 18F-FDG accumulation possibly by upregulation of GLUT1; moreover, HIF-1α additively increased 18F-FDG accumulation in hypoxic lesions. 18F-FDG PET might be useful for predicting the KRAS status noninvasively.

Original languageEnglish
Pages (from-to)2038-2044
Number of pages7
JournalJournal of Nuclear Medicine
Volume55
Issue number12
DOIs
Publication statusPublished - Dec 1 2014

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Fluorodeoxyglucose F18
Colorectal Neoplasms
Hypoxia-Inducible Factor 1
Facilitative Glucose Transport Proteins
Heterografts
Glucose Transporter Type 1
Mutation
Hexokinase
Epidermal Growth Factor Receptor
Positron-Emission Tomography
Genes
Up-Regulation
Immunohistochemistry
Staining and Labeling

All Science Journal Classification (ASJC) codes

  • Radiology Nuclear Medicine and imaging

Cite this

Iwamoto, M., Kawada, K., Nakamoto, Y., Itatani, Y., Inamoto, S., Toda, K., ... Sakai, Y. (2014). Regulation of 18F-FDG accumulation in colorectal cancer cells with mutated KRAS. Journal of Nuclear Medicine, 55(12), 2038-2044. https://doi.org/10.2967/jnumed.114.142927

Regulation of 18F-FDG accumulation in colorectal cancer cells with mutated KRAS. / Iwamoto, Masayoshi; Kawada, Kenji; Nakamoto, Yuji; Itatani, Yoshiro; Inamoto, Susumu; Toda, Kosuke; Kimura, Hiroyuki; Sasazuki, Takehiko; Shirasawa, Senji; Okuyama, Hiroaki; Inoue, Masahiro; Hasegawa, Suguru; Togashi, Kaori; Sakai, Yoshiharu.

In: Journal of Nuclear Medicine, Vol. 55, No. 12, 01.12.2014, p. 2038-2044.

Research output: Contribution to journalArticle

Iwamoto, M, Kawada, K, Nakamoto, Y, Itatani, Y, Inamoto, S, Toda, K, Kimura, H, Sasazuki, T, Shirasawa, S, Okuyama, H, Inoue, M, Hasegawa, S, Togashi, K & Sakai, Y 2014, 'Regulation of 18F-FDG accumulation in colorectal cancer cells with mutated KRAS', Journal of Nuclear Medicine, vol. 55, no. 12, pp. 2038-2044. https://doi.org/10.2967/jnumed.114.142927
Iwamoto M, Kawada K, Nakamoto Y, Itatani Y, Inamoto S, Toda K et al. Regulation of 18F-FDG accumulation in colorectal cancer cells with mutated KRAS. Journal of Nuclear Medicine. 2014 Dec 1;55(12):2038-2044. https://doi.org/10.2967/jnumed.114.142927
Iwamoto, Masayoshi ; Kawada, Kenji ; Nakamoto, Yuji ; Itatani, Yoshiro ; Inamoto, Susumu ; Toda, Kosuke ; Kimura, Hiroyuki ; Sasazuki, Takehiko ; Shirasawa, Senji ; Okuyama, Hiroaki ; Inoue, Masahiro ; Hasegawa, Suguru ; Togashi, Kaori ; Sakai, Yoshiharu. / Regulation of 18F-FDG accumulation in colorectal cancer cells with mutated KRAS. In: Journal of Nuclear Medicine. 2014 ; Vol. 55, No. 12. pp. 2038-2044.
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author = "Masayoshi Iwamoto and Kenji Kawada and Yuji Nakamoto and Yoshiro Itatani and Susumu Inamoto and Kosuke Toda and Hiroyuki Kimura and Takehiko Sasazuki and Senji Shirasawa and Hiroaki Okuyama and Masahiro Inoue and Suguru Hasegawa and Kaori Togashi and Yoshiharu Sakai",
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AU - Iwamoto, Masayoshi

AU - Kawada, Kenji

AU - Nakamoto, Yuji

AU - Itatani, Yoshiro

AU - Inamoto, Susumu

AU - Toda, Kosuke

AU - Kimura, Hiroyuki

AU - Sasazuki, Takehiko

AU - Shirasawa, Senji

AU - Okuyama, Hiroaki

AU - Inoue, Masahiro

AU - Hasegawa, Suguru

AU - Togashi, Kaori

AU - Sakai, Yoshiharu

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N2 - KRAS gene mutations occur in approximately 40% of colorectal cancers (CRCs) and are associated with resistance to anti-epidermal growth factor receptor antibody therapy. We previously demonstrated that 18F-FDG accumulation in PET was significantly higher in CRCs with mutated KRAS than in those with wild-type KRAS in a clinical setting. Here, we investigated the mechanisms by which mutated KRAS increased 18F-FDG accumulation. Methods: Using paired isogenic human CRC cell lines that differ only in the mutational status of the KRAS gene, we measured 18F-FDG accumulation in these cells in vitro and in vivo. We also investigated the roles of proteins that have a function in 18F-FDG accumulation. Finally, we examined the relationship among mutated KRAS, hypoxia-inducible factor 1α (HIF-1α), and maximum standardized uptake value with 51 clinical CRC samples. Results: In the in vitro experiments, 18F-FDG accumulation was significantly higher in KRAS-mutant cells than in wild-type controls under normoxic conditions. The expression levels of glucose transporter 1 (GLUT1) and hexokinase type 2 (HK2) were higher in KRAS-mutant cells, and 18F-FDG accumulation was decreased by knockdown of GLUT1. Hypoxic induction of HIF-1α was higher in KRAS-mutant cells than in wild-type controls; in turn, elevated HIF-1α resulted in higher GLUT1 expression and 18F-FDG accumulation. In addition, HIF-1α knockdown decreased 18F-FDG accumulation under hypoxic conditions only in the KRAS-mutant cells. Small-animal PET scans showed in vivo 18F-FDG accumulation to be significantly higher in xenografts with mutated KRAS than in those with wild-type KRAS. The immunohistochemistry of these xenograft tumors showed that staining of GLUT1 was consistent with that of HIF-1α and pimonidazole. In a retrospective analysis of clinical samples, KRAS mutation exhibited a significantly positive correlation with expressions of GLUT1 and HIF-1α and with maximum standardized uptake value. Conclusion: Mutated KRAS caused higher 18F-FDG accumulation possibly by upregulation of GLUT1; moreover, HIF-1α additively increased 18F-FDG accumulation in hypoxic lesions. 18F-FDG PET might be useful for predicting the KRAS status noninvasively.

AB - KRAS gene mutations occur in approximately 40% of colorectal cancers (CRCs) and are associated with resistance to anti-epidermal growth factor receptor antibody therapy. We previously demonstrated that 18F-FDG accumulation in PET was significantly higher in CRCs with mutated KRAS than in those with wild-type KRAS in a clinical setting. Here, we investigated the mechanisms by which mutated KRAS increased 18F-FDG accumulation. Methods: Using paired isogenic human CRC cell lines that differ only in the mutational status of the KRAS gene, we measured 18F-FDG accumulation in these cells in vitro and in vivo. We also investigated the roles of proteins that have a function in 18F-FDG accumulation. Finally, we examined the relationship among mutated KRAS, hypoxia-inducible factor 1α (HIF-1α), and maximum standardized uptake value with 51 clinical CRC samples. Results: In the in vitro experiments, 18F-FDG accumulation was significantly higher in KRAS-mutant cells than in wild-type controls under normoxic conditions. The expression levels of glucose transporter 1 (GLUT1) and hexokinase type 2 (HK2) were higher in KRAS-mutant cells, and 18F-FDG accumulation was decreased by knockdown of GLUT1. Hypoxic induction of HIF-1α was higher in KRAS-mutant cells than in wild-type controls; in turn, elevated HIF-1α resulted in higher GLUT1 expression and 18F-FDG accumulation. In addition, HIF-1α knockdown decreased 18F-FDG accumulation under hypoxic conditions only in the KRAS-mutant cells. Small-animal PET scans showed in vivo 18F-FDG accumulation to be significantly higher in xenografts with mutated KRAS than in those with wild-type KRAS. The immunohistochemistry of these xenograft tumors showed that staining of GLUT1 was consistent with that of HIF-1α and pimonidazole. In a retrospective analysis of clinical samples, KRAS mutation exhibited a significantly positive correlation with expressions of GLUT1 and HIF-1α and with maximum standardized uptake value. Conclusion: Mutated KRAS caused higher 18F-FDG accumulation possibly by upregulation of GLUT1; moreover, HIF-1α additively increased 18F-FDG accumulation in hypoxic lesions. 18F-FDG PET might be useful for predicting the KRAS status noninvasively.

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