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Tumor microenvironment affects exogenous sodium/iodide symporter expression.

Fabio Castillo-Rivera1, Alejandro Ondo-Méndez1, Julien Guglielmi2

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Sodium/iodide symporter (NIS) expression and iodide uptake are reduced in tumors due to hypoxia and quiescence. This impairs NIS-based cancer gene therapy, highlighting the tumor microenvironment

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HypoxiaProtein traffickingQuiescenceSodium/Iodide symporter (NIS)Tumor microenvironment

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Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Sodium/iodide symporter (NIS) is crucial for radioactive ablation of thyroid cancer.
  • NIS-based gene therapy shows promise for extrathyroidal tumors but is limited by reduced NIS expression.
  • Understanding NIS expression in tumors is critical for enhancing therapeutic efficacy.

Purpose of the Study:

  • To investigate the functional behavior of exogenous NIS expression in solid tumors.
  • To elucidate the impact of tumor microenvironment factors like hypoxia and quiescence on NIS expression and function.
  • To identify molecular mechanisms underlying impaired NIS activity in tumors.

Main Methods:

  • Subcutaneous tumor models (HT29NIS and K7M2NIS) were used to assess NIS-mediated iodide uptake.
  • Experiments were conducted on HT29NIS cells to study the effects of hypoxia and quiescence.
  • Untargeted proteomics and metabolomics were employed to analyze molecular changes.

Main Results:

  • NIS-mediated uptake and plasma membrane expression of NIS were impaired in intratumoral regions.
  • Hypoxia and quiescence, individually and combined, reduced NIS-mediated uptake.
  • NIS mis-localization and alterations in proteins/metabolites involved in plasma membrane localization and energy metabolism were observed.

Conclusions:

  • Hypoxia and quiescence negatively impact NIS expression at the plasma membrane and subsequent iodide uptake.
  • The tumor microenvironment significantly influences the success of NIS-based cancer therapies.
  • Further research into modulating the tumor microenvironment is warranted for improved NIS-based treatments.