TY - JOUR
T1 - Tumor microenvironment affects exogenous sodium/iodide symporter expression
AU - Castillo-Rivera, Fabio
AU - Ondo-Méndez, Alejandro
AU - Guglielmi, Julien
AU - Guigonis, Jean Marie
AU - Jing, Lun
AU - Lindenthal, Sabine
AU - Gonzalez, Andrea
AU - López, Diana
AU - Cambien, Béatrice
AU - Pourcher, Thierry
N1 - Funding Information:
This work was supported by the program ECOS-Nord/Colciencias/Icetex. Lun Jing was funded by a grant from the Recherche en matières de Sûreté Nucléaire et Radioprotection program from the French National Research Agency. The authors thank Dr Philippe Trochet from VisualSonics for ultrasound experiments. Equipment for this study was purchased through grants from the Recherche en matières de Sûreté Nucléaire et Radioprotection program from the French National Research Agency and the Conseil Départemental 06. The authors wish to thank Robert Barthel for critical reading of the manuscript.
Publisher Copyright:
© 2020
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2021/1/30
Y1 - 2021/1/30
N2 - For decades, sodium/iodide symporter NIS-mediated iodide uptake has played a crucial role in the radioactive ablation of thyroid cancer cells. NIS-based gene therapy has also become a promising tool for the treatment of tumors of extrathyroidal origin. But its applicability has been hampered by reduced expression of NIS, resulting in a moderated capacity to accumulate 131I and in inefficient ablation. Despite numerous preclinical enhancement strategies, the understanding of NIS expression within tumors remains limited. This study aims at a better understanding of the functional behavior of exogenous NIS expression in the context of malignant solid tumors that are characterized by rapid growth with an insufficient vasculature, leading to hypoxia and quiescence. Using subcutaneous HT29NIS and K7M2NIS tumors, we show that NIS-mediated uptake and NIS expression at the plasma membrane of cancer cells are impaired in the intratumoral regions. For a better understanding of the underlying molecular mechanisms induced by hypoxia and quiescence (separately and in combination), we performed experiments on HT29NIS cancer cells. Hypoxia and quiescence were both found to impair NIS-mediated uptake through mechanisms including NIS mis-localization. Modifications in the expression of proteins and metabolites involved in plasma membrane localization and in energy metabolism were found using untargeted proteomics and metabolomics approaches. In conclusion, our results provide evidence that hypoxia and quiescence impair NIS expression at the plasma membrane, and iodide uptake. Our study also shows that the tumor microenvironment is an important parameter for successful NIS-based cancer treatment.
AB - For decades, sodium/iodide symporter NIS-mediated iodide uptake has played a crucial role in the radioactive ablation of thyroid cancer cells. NIS-based gene therapy has also become a promising tool for the treatment of tumors of extrathyroidal origin. But its applicability has been hampered by reduced expression of NIS, resulting in a moderated capacity to accumulate 131I and in inefficient ablation. Despite numerous preclinical enhancement strategies, the understanding of NIS expression within tumors remains limited. This study aims at a better understanding of the functional behavior of exogenous NIS expression in the context of malignant solid tumors that are characterized by rapid growth with an insufficient vasculature, leading to hypoxia and quiescence. Using subcutaneous HT29NIS and K7M2NIS tumors, we show that NIS-mediated uptake and NIS expression at the plasma membrane of cancer cells are impaired in the intratumoral regions. For a better understanding of the underlying molecular mechanisms induced by hypoxia and quiescence (separately and in combination), we performed experiments on HT29NIS cancer cells. Hypoxia and quiescence were both found to impair NIS-mediated uptake through mechanisms including NIS mis-localization. Modifications in the expression of proteins and metabolites involved in plasma membrane localization and in energy metabolism were found using untargeted proteomics and metabolomics approaches. In conclusion, our results provide evidence that hypoxia and quiescence impair NIS expression at the plasma membrane, and iodide uptake. Our study also shows that the tumor microenvironment is an important parameter for successful NIS-based cancer treatment.
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U2 - 10.1016/j.tranon.2020.100937
DO - 10.1016/j.tranon.2020.100937
M3 - Research Article
C2 - 33217645
AN - SCOPUS:85096201676
SN - 1936-5233
VL - 14
JO - Translational Oncology
JF - Translational Oncology
IS - 1
M1 - 100937
ER -