Establishment of patient-derived lung tumorspheres and their response to internal irradiation by Auger electrons

The high recurrence rate of lung cancer is a major clinical challenge associated with therapy-resistant cancer stem cells (CSCs), which are rare subpopulations. Future successful treatment is required to also eradicate these subpopulations. Furthermore, the majority of anti-cancer treatments are being tested in adherent monolayer cultures with the limitations this entails in the translation of results into clinical practice. The present study aimed to establish and characterize patient-derived long-term primary lung cancer tumorspheres enriched in CSCs and evaluate the effects of Auger electrons on them. These electrons are emitted from radionuclides that decay by electron capture or internal conversion and have demonstrated promising therapeutic potential. Their low energy (<1 keV) is sufficiently potent to induce DNA double-strand breaks and eventually cell death while minimizing irradiation of non-targeted surrounding cells. Labeling a thymidine analog (deoxyuridine) with the Auger electron-emitting radionuclide [I-125], which is exclusively incorporated into the DNA of proliferating cells during the S-phase, ensures a close distance to the DNA. Primary cell cultures grown as tumorspheres were established and characterized. The tumorspheres were morphologically distinct and differed concerning their proliferation rate and fraction of CSCs. Surface markers associated with CSCs were upregulated and 5-[I-125]iodo-2 '-deoxyuridine was incorporated in the tumorspheres. The Auger electrons induced DNA double-strand breaks, G2/M arrest and apoptosis in the tumorspheres; however, the tumorspheres derived from different patients exhibited heterogeneities in their sensitivity to Auger electron irradiation.

Automated summary

The high recurrence rate of lung cancer is a major challenge in clinical practice, which is associated with therapy-resistant cancer stem cells (CSCs). This study aimed to evaluate the effects of Auger electrons on patient-derived lung cancer tumorspheres enriched in CSCs. The results showed that Auger electrons induced DNA double-strand breaks, cell cycle arrest, and apoptosis in tumorspheres, but the sensitivity to Auger electron irradiation varied among tumorspheres derived from different patients.