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TNF-α and IGF-1 differentially modulate ionizing radiation responses of lung cancer cell lines
Shyama Pal1, Poonam Yadav1, K B Sainis1
1Immunology Section, Radiation Biology & Health Sciences Division, Bio-Science Group, Bhabha Atomic Research Centre, Mumbai 400 085, India.
Abstract:
The mechanism by which tumor microenvironment derived cytokine network modulates therapy response is of great concern in lung cancer but is not completely understood. In this study, we evaluated the effects of tumor necrosis factor α (TNF-α) and insulin-like growth factor 1 (IGF-1) on response of lung cancer cell lines to ionizing radiation (IR). While TNF-α increased radio sensitivity and inhibited cell migration, treatment with IGF-1 promoted cell growth and increased migration. These effects of TNF- α were mediated by increased immediate activation of stress-activated protein kinases (SAPK)/jun amino-terminal kinases (JNK) and p38. IR induced DNA damage was increased by TNF- α and not altered by IGF-1. However, in IGF-1 treated cells, there was decreased γ- H2AX along with an increase in mitotic index, resulting in abnormal chromosomal segregation in the cells. Bio informatics analysis of 982 lung cancer patients revealed that higher expression of TNF- α was associated with low risk of cancer progression while overexpression of IGF-1 was correlated with high risk. Collectively, these results reveal that the cytokines in the tumor microenvironment differentially modulate radiation therapy through a variety of signaling mechanisms.
Insights
Tumor microenvironment cytokines like TNF-α and IGF-1 significantly impact lung cancer response to radiation therapy. Understanding these cytokine networks is crucial for improving cancer treatment outcomes.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- The tumor microenvironment's role in modulating cancer therapy response is critical but not fully understood.
- Cytokines within the tumor microenvironment are key players in cancer progression and treatment resistance.
Purpose of the Study:
- To investigate the effects of tumor necrosis factor-alpha (TNF-α) and insulin-like growth factor-1 (IGF-1) on lung cancer cell response to ionizing radiation (IR).
- To elucidate the signaling pathways involved in cytokine-mediated modulation of radio-sensitivity and cell behavior.
Main Methods:
- Exposure of lung cancer cell lines to TNF-α, IGF-1, and ionizing radiation (IR).
- Assessment of cell radiosensitivity, migration, DNA damage (γ-H2AX), and mitotic index.
- Analysis of stress-activated protein kinases (SAPK)/jun amino-terminal kinases (JNK) and p38 activation.
- Bioinformatic analysis of TNF-α and IGF-1 expression in 982 lung cancer patients.
Main Results:
- TNF-α enhanced radiosensitivity and inhibited cell migration, mediated by SAPK/JNK and p38 activation, and increased IR-induced DNA damage.
- IGF-1 promoted cell growth and migration, decreased γ-H2AX, and increased mitotic index, leading to abnormal chromosomal segregation.
- Higher TNF-α expression correlated with a lower risk of cancer progression, while IGF-1 overexpression correlated with a higher risk in patients.
Conclusions:
- Tumor microenvironment cytokines differentially modulate radiation therapy response in lung cancer.
- TNF-α and IGF-1 exert opposing effects on radiosensitivity and cellular behavior through distinct signaling pathways.
- These findings highlight the complex interplay of cytokines in determining lung cancer treatment outcomes.
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