Research Progress of Heavy Ion Radiotherapy for Non-Small-Cell Lung Cancer
Abstract
:1. Non-Small-Cell Lung Cancer
2. Heavy Ion Radiotherapy
3. Heavy Ions and Their Biological Effects
4. Radiobiological Effects of Heavy Ions on Lung Cancer Cells and the Underlying Molecular Mechanisms
- Killing effects of heavy ions on NSCLC cells. Heavy ions cause apoptosis, necrosis, and senescence of cancer cells by causing complex DNA double-strand breaks (DSBs), which is also the main beneficial effect of heavy ions in cancer treatment. Low-LET radiation (photon) causes simple DNA damage within one or two circles of the DNA helix. In contrast, high-LET charged particle radiation mainly causes clustered DNA damage, which is characterized by multiple adjacent DNA lesions [18,19]. Using high resolution transmission electron microscopy (TEM) and gold-labeled DNA repair factors, it was found that the clustering of DSBs in heterochromatin following high-LET irradiation perturbed efficient DNA repair, leading to greater biological effectiveness versus that of low-LET irradiation [20]. This conclusion has also been confirmed in clinical CIRT. Using advanced high-resolution microscopy with deconvolution, Oike et al. observed the formation of complex DSBs in a human tumor clinically treated with CIRT, rather than X-ray radiotherapy [21]. DNA damage caused by heavy ions is more complex than that caused by X-rays, making it difficult for the DNA repair pathway to function effectively [22]. In other words, inhibition of DNA repair can enhance the effect of heavy ion therapy. Nakajima et al. investigated the involvement of the DNA damage signaling factors ataxia telangiectasia mutated (ATM), RING finger protein 8 (RNF8), and RNF168 in cells after high LET carbon ion irradiation; the results suggest that inhibition of RNF8 activity or its downstream pathway may enhance the efficacy of CIRT [23]. Yang et al. found that inhibition of DNA-PKcs enhanced radiosensitivity and increased the expression levels of ATM and ATR in NSCLC cells exposed to carbon ion irradiation, implying a role for DNA-PKcs in DNA damage repair signaling induced by carbon ions [24]. For photon radiation, they can indirectly damage DNA or other cellular structures by producing reactive oxygen species (ROS). This effect requires the participation of oxygen in the tumor microenvironment, so low-LET photons have poor killing effect on cancer cells under hypoxia conditions [25]. However, DNA damage induced by carbon ions does not depend on ROS production [26]. One explanation is the increased expression of hypoxia inducible factor 1α (HIF-1α) after photon irradiation [27], while heavy ions do not, so they work well in hypoxia conditions. Klein et al. irradiated A549 and H1437 cells with different doses of photons or carbon ions under hypoxic (1% O2) or normoxic (21% O2) conditions respectively. The inhibitors of DNA-PK and ATM were used in parallel. The results showed that DNA-PK inhibition combined with carbon irradiation was most effective in killing NSCLC cells under hypoxic conditions [28]. Carbon ions can cause clustered DNA damage, which is difficult to repair. This characteristic, which is superior to photons, endows carbon ions with stronger killing effect on NSCLC cells, even those that are hypoxic and radio-resistant. Further, many non-coding RNAs (ncRNAs) such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) play a regulatory role in the killing of lung cancer cells by heavy ions. Liu et al. found that circRNA ZNF208 significantly enhanced the resistance of NSCLC cells to X-rays, but the sensitivity to carbon ions did not change [29]. In addition to circRNA ZNF208, the down-regulation of lncRNA H19 also increases the sensitivity of NSCLC cells to heavy ions [30]. Therefore, these ncRNAs might function as a potential therapeutic target to enhance the efficacy of heavy ion radiotherapy for NSCLC. Despite high RBE and high tumor-killing ability of carbon ions, the tumor recurrence after CIRT is often observed, suggesting the presence of a subset of tumor cells resistant to CIRT. Darwis et al. identified a pivotal role for FGFR signaling in cancer cell survival through CIRT, and found that inhibition of FGFR using pan-FGFR inhibitor LY2874455 sensitized multiple NSCLC cell lines to carbon ions, which may be useful in the sensitization of CIRT-resistant cancers [31]. Besides, Amornwichet et al. found EGFR-mutant NSCLC cells, rather than KRAS-mutant NSCLC cells, showed low RBE of carbon ions over X-rays, indicating the potential of EGFR mutation status as a predictor of cellular response to CIRT [32]. These results suggest that clarification of the governing factors and signaling pathways in cellular response to carbon ion irradiation will help to further improve the treatment efficacy of CIRT.
- Effects of heavy ions on invasion and metastasis of lung cancer cells. Photon irradiation, rather than heavy ion irradiation, was found to significantly induce expression of matrix metalloproteinases (MMPs), stem cell factor (SCF), and β1-integrin, which promote angiogenesis and cancer cell metastasis [33,34,35]. Liu et al. irradiated A549 cells with carbon ions and X-rays. Carbon-ion irradiation at 1 Gy significantly reduced vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) levels and inhibited endothelial cell invasion and tube formation, suggesting inhibiting potential of angiogenesis by carbon ions [36]. Akino et al. irradiated A549 and EBC-1 lung cancer cells with 290 MeV/u carbon ion beams and 4 MeV X-rays. The results showed that carbon ion irradiation inhibited the migration and invasion of A549 and EBC-1 cells more effectively than X-rays. In addition, they found that carbon ion irradiation alone induced downregulation of ANLN expression in NSCLC cells, which is downstream of PI3K/Akt signaling and positively associated with tumor metastasis [37]. On this basis, Ogata et al. found that low dose carbon ion irradiation also reduced the level of phosphorylated Akt compared with untreated control group, while photon irradiation did not, suggesting that carbon ion irradiation can effectively inhibit the metastatic potential of A549 cells by suppressing the PI3K/Akt signaling pathway [38]. In addition, Kamlah et al. found that irradiation of A549 cells with X-rays (6 Gy) but not carbon ions (2 Gy) resulted in a significant increase in blood vessel density through increased expression of SCF and subsequently phosphorylation of c-Kit [35]. In summary, carbon ions have a distinct advantage over X-rays in preventing angiogenesis and the spread of tumors.
- Effects of heavy ions on immunogenicity of lung cancer cells. Radiation not only has an immunostimulatory effect, but also shows an immunosuppressive effect. Therefore, it is important to understand the immunomodulatory properties of radiation to enhance the curative effect of radiotherapy [39,40,41]. The change of immunogenicity induced by heavy ions is key in the regulation of tumor immunity. Heavy ions cause tumor cells to die in different ways and release pro-inflammatory cytokines; chemokines; tumor antigens; and other danger signals, called damage-associated molecular patterns (DAMPs). DAMPs can activate the immune system, and immune cells are attracted to the area where the tumor is located [42]. Some progress has been made in the study of heavy ion-induced DAMPs. Ran et al. used ELISA to detect the levels of HMGB1, IL-10, and TGF-β in A549, H520, and Lewis Lung Carcinoma (LLC) cell lines under different “time windows” and “dose windows” after X-ray or carbon ion irradiation. The results showed that both X-rays and carbon ions promoted HMGB1, IL-10, and TGF-β levels in a time-dependent manner, and only X-rays increased the HMGB1 level in a dose-dependent manner. In addition, carbon ions increased higher HMGB1 levels compared with X-rays, while the levels of immunosuppressive factors IL-10 and TGF-β were relatively reduced. These results suggest that carbon ions may be superior to conventional X-rays in inducing immune-enhancing effects [43]. Huang et al. found that carbon ions promoted the cell surface translocation of calreticulin more strongly than protons and photons at 2 and 4 Gy, which plays a pivotal role in activating anti-tumor immunity [15]. In addition, Wang et al. found that carbon ions noticeably induced Klrk1 gene expression and activated the NKG2D/NKG2D-Ls pathway in a murine Lewis lung cancer model, which were tightly related to the functional status of NK cells. CIRT combined with Treg inhibition significantly increased the infiltration and function of NK cells and prolonged the survival of cancer-bearing mice [44]. Compared with photons, heavy ions can play a better role in induction of tumor immunity, rendering the combination of heavy ion radiotherapy and immunotherapy a promising therapy.
5. Research Progress on Heavy Ion Therapy for Non-Small-Cell Lung Cancer
6. Discussion
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Tumor Staging | Sample Size | Dose/Fractions | Overall Survival | Local Control | Toxicity | Reference |
---|---|---|---|---|---|---|
I | 50 | 72 Gy/9 fr | 5-year, 50% | 5-year, 94.7% | Grade ≥ 3: 0 (0%) | [70] |
I | 79 | 52.8 Gy/4 fr for stage IA 60.0 Gy/4 fr for stage IB | 5-year, 45% | 5-year, 90% | Grade ≥ 3: 0 (0%) | [48] |
I | 218 | 28–50 Gy/1 fr | 3-year, 68.3% 5-year, 49.4% | 3-year, 77.9% 5-year, 72.7% | Grade ≥ 3: 1 (0.46%), Grade 3 chest wall pain: 1 (0.46%) | [57] |
I | 57 | 50 Gy/1 fr | 3-year, 91.2% 5-year, 81.7% | 3-year, 96.4% 5-year, 91.8% | Grade ≥3: 0 (0%) | [58] |
I/II | 47 | 59.4–95.4 Gy/18 fr | 5-year, 42% | 5-year, 64% | Grade ≥ 3: 3 (3.7%), Grade 3 radiation pneumonitis: 3 (3.7%) | [71] |
I/II | 34 | 68.4–79.2 Gy/9 fr | 5-year, 84% | |||
II/III | 32 | 68.0–76.0 Gy/12–16 fr | 2-year, 68.0% 3-year, 54.3% | 2-year, 83.5% 3-year, 77.1% | Grade ≥ 3: 1 (3.1%), Grade 3 radiation pneumonitis: 1 (3.1%) | [62] |
II/III | 64 | 52.8–72.0 Gy/4–16 fr | 2-year, 62.2% | 2-year, 81.8% | Grade ≥ 3: 0 (0%) | [4] |
III | 65 | 64.0–76.0 Gy/16 fr | 2-year, 54.9% 3-year, 42.0% | 2-year, 73.9% 3-year, 70.2% | Grade ≥ 3: 6 (9.2%), Grade 3 radiation pneumonitis: 4 (6.2%), Grade 3 bronchial fistula: 1 (1.5%), Grade 4 mediastinal haemorrhage: 1 (1.5%) | [54] |
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Liang, S.; Zhou, G.; Hu, W. Research Progress of Heavy Ion Radiotherapy for Non-Small-Cell Lung Cancer. Int. J. Mol. Sci. 2022, 23, 2316. https://doi.org/10.3390/ijms23042316
Liang S, Zhou G, Hu W. Research Progress of Heavy Ion Radiotherapy for Non-Small-Cell Lung Cancer. International Journal of Molecular Sciences. 2022; 23(4):2316. https://doi.org/10.3390/ijms23042316
Chicago/Turabian StyleLiang, Siqi, Guangming Zhou, and Wentao Hu. 2022. "Research Progress of Heavy Ion Radiotherapy for Non-Small-Cell Lung Cancer" International Journal of Molecular Sciences 23, no. 4: 2316. https://doi.org/10.3390/ijms23042316