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Published on: August 14, 2012
Radioresistant mouse pheochromocytoma cell lines
Sandy Lemm1,2, Marcel Gebhardt3, Thomas Groß4
1Institute of Radiopharmaceutical Cancer Research, Department of Radiopharmaceutical and Chemical Biology, Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany.
Objective:
Patients diagnosed with metastatic pheochromocytoma/paraganglioma (PCC/PGL) have limited treatment options. In some cases, peptide receptor radionuclide therapy (PRRT) is followed by an eruption of metastases, possibly originating from tumor cells with a radioresistant phenotype. However, the underlying mechanisms of radioresistance in PCC/PGL remain largely unknown and appropriate models are missing.
Methods:
Two genetically modified mouse pheochromocytoma (MPC) cell lines, one positive and one negative for hypoxia-inducible factor 2α expression (MPC+HIF-2α and MPC+EV [empty vector], respectively), were X-ray-conditioned through fractionated irradiation at sublethal doses. Two procedures were tested: one allowed for recovery between each irradiation step (recIR), while the other demanded daily irradiation (dayIR). Changes in cell morphology, growth rates, and DNA repair (γH2AX immunostaining) were characterized in response to irradiation.
Results:
We generated two MPC+HIF-2α- and two MPC+EV-derived cell lines that tolerate irradiations with X-rays at dose fractions of 2 Gy per day without significant growth inhibition. All recIR-and dayIR-conditioned cell lines showed increased DNA repair capacity. Morphological changes toward stronger clustering and slower growth were more pronounced in dayIR-conditioned than in recIR-conditioned cell lines. X-ray-conditioned MPC+HIF-2α cells showed the highest increase in resistance to X-ray-treatment with dose fractions up to 5 Gy per day.
Conclusion:
The herein established X-ray-conditioned MPC cell lines represent PCC/PGL models with a radioresistant phenotype. Further investigations on the radiation-induced genetic responses of these cell lines, their corresponding tumor spheroids, and tumor allografts in mice will help to elucidate the underlying mechanisms of acquired radioresistance and radionuclide therapy-induced metastatic eruption in PCC/PGL. Lastly, the suitability of advanced PRRT and complementary treatments can be tested to improve theranostic strategies.
Insights
New mouse models of metastatic pheochromocytoma/paraganglioma (PCC/PGL) were developed to study radioresistance. These models show increased DNA repair and resistance to X-ray treatment, aiding research into treatment failure.
Area of Science:
- Oncology
- Radiation Biology
- Genetics
Background:
- Metastatic pheochromocytoma/paraganglioma (PCC/PGL) presents limited therapeutic options.
- Peptide receptor radionuclide therapy (PRRT) can sometimes lead to metastatic eruption, suggesting radioresistant tumor cell phenotypes.
- The mechanisms of radioresistance in PCC/PGL are poorly understood, and suitable experimental models are lacking.
Purpose of the Study:
- To establish novel preclinical models of radioresistant pheochromocytoma/paraganglioma (PCC/PGL).
- To investigate the impact of hypoxia-inducible factor 2α (HIF-2α) on radioresistance development in PCC/PGL.
- To characterize DNA repair capacity and morphological changes in response to fractionated irradiation.
Main Methods:
- Two genetically modified mouse pheochromocytoma (MPC) cell lines, differing in HIF-2α expression (MPC+HIF-2α and MPC+EV), were subjected to fractionated X-ray irradiation.
- Two irradiation protocols were employed: recovery between fractions (recIR) and daily irradiation (dayIR).
- Changes in cell morphology, growth rate, and DNA repair marker (γH2AX) were assessed.
Main Results:
- MPC cell lines were conditioned to tolerate fractionated X-ray doses up to 2 Gy/day without significant growth inhibition.
- Conditioned cell lines exhibited enhanced DNA repair capacity.
- MPC+HIF-2α cells demonstrated the highest increase in radioresistance, tolerating up to 5 Gy/day.
- Daily irradiation (dayIR) induced more pronounced morphological changes (clustering, slower growth) compared to recovery irradiation (recIR).
Conclusions:
- Established X-ray-conditioned MPC cell lines serve as valuable models for studying radioresistant PCC/PGL.
- These models will facilitate further research into the mechanisms of acquired radioresistance and PRRT-induced metastasis.
- The models can be utilized to test advanced PRRT and complementary therapies for improved theranostic strategies.
