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Editorial

The Potential Roles of Radiation-Induced Bystander Effects in Radiation Therapy

Hongying Yang1,2 *

1School of Radiation Medicine and Protection, Medical College of Soochow University/School for Radiological and Interdisciplinary
Sciences (RAD-X), Soochow University
2Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions R2306, Bldg.402, 199 Renai Road,
Suzhou Industrial Park, Suzhou, Jiangsu Province, P. R. China 215123

*Corresponding author: Dr. Hongying Yang, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions R2306, Bldg.402, 199 Renai Road, Suzhou Industrial Park, Suzhou, Jiangsu Province, P. R. China 215123, Tel: +86- 512-65882637; Fax: +86-512-65884830; Email: yanghongying@suda.edu.cn

Submitted: 07-26-2014 Accepted: 07-27-2014 Published: 09-04-2014

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Article

 
Radiation-induced bystander effects (RIBEs) refer to the biological changes in unirradiated cells or tissues when the neighboring cells or tissues are traversed by ionizing radiation, such as changes in gene expression, DNA damage, cell killing, malignant transformation, epigenetic alterations et al. In spite of the reports on RIBEs in earlier time [1-4], this phenomenon did not attract much interest until 1992, when Nagasawa and Little provided the direct evidence for the occurrence of RIBE [5]. Since then, RIBEs have been demonstrated in a variety of cell types (including normal and cancer cells), tissue models and in vivo [6-9]. So far, the concept of bystander effects has been broadened, containing not only bystander responses in cell culture, but also long-range effects occurring within or between tissues or organs called abscopal, out-of-field or distant bystander response [10]. Along with other non-targeted effects such as adaptive response, genetic instability, et al., RIBEs challenge conventional radiation dogmas such as the DNA targeted theory and linear no-threshold (LNT) model so that they may have an impact on estimation of radiation cancer risk, particular at low doses [11], and outcomes of radiation therapy (RT) as well [10].

RIBE was once thought a low dose effect, meaning that it makes an important contribution to the overall effects at low doses, but plays little role in the biological responses at high doses [12]. However, more and more studies suggest that RIBE is one of the important factors that should be taken into consideration in the evaluation of protocols for cancer radiotherapy. RIBEs have been found to occur in the scenarios of intensity-modulated radiotherapy (IMRT) and spatially fractionated radiation (GRID) treatment [13-16]. They can take place from irradiated to unirradiated cells and other way around [13]. And cellular communication between differentially irradiated cell populations plays an important role [15]. The maximum cell death produced by the bystander effect could be calculated through a biophysical model, suggesting that it should not be ignored [17]. As a matter of fact, it is suggested that bystander effects may be essential in producing a robust decrease in cancer cell survival in directly irradiated populations [18]. And the abscopal effect induced by RT that sterilized nonirradiated tumor cells was through bystander signals in xenograft mouse mode [19]. In addition, acquired tumorcell radiation resistance at the treatment site was found to be strongly related to radiation-orchestrated intercellular communication [20]. Moreover, since irradiation can promote the invasiveness of both irradiated and bystander cancer cells [21], RIBEs may play an important role in cancer metastasis. A novel concept [22] has been proposed that RT-caused damage in various organs can upregualte some factors such as chemokines, growth factors, alarmines, and bioactive phosphosphingolipids in “bystander” tissues, which provide chemotactic signals to cancer cells that survived the initial treatment resulting to metastasis. All of these studies indicate that RIBEs can not only play an important role in low dose effects, but also affect the overall biological effects in the scenario of RT where high doses apply, thus affecting the efficacy of RT.

Besides to the benefits of RT for cancer patients, RT often causes side effects. It has been found that the side effects of RT and bystander cell signaling may have a larger impact than previously acknowledged [23]. Additionally, ionizing radiation is a well-known carcinogen. Almost 1 in 10 cancer diagnoses are second malignancies. It is critical to understand the contribution of RT to second cancer induction [24]. Although most of second cancers occur within the irradiation field of original tumor, some second cancers develop in the organs relatively far from the radiation field [25,26]. The results from these clinical studies not only indicate that radiation is an important cause of the incidence of second cancer, but also suggest that RIBEs may contribute to this. The finding that radiation can induce genomic instability through bystander effects or increased mutation rates in the progeny of surviving irradiated cells in vitro suggests that RT-induced second primary cancer can arise from radiation-induced somatic genomic instability [24,27]. However, direct evidence for the involvement of RIBEs in the occurrence of second cancer post-RT is still limited. This warrants further studies on the roles of RIBEs in the process of second cancer incidence.

RIBE is a manifestation of intercellular signal transduction in nature. The majority of studies on RIBEs have been carried out in normal cells. Although the mechanisms underlying RIBEs are still poorly understood, gap junction intercellular communication (GJIC) [6], reactive oxygen species (ROS) [28] and soluble signaling molecules such as inflammatory cytokines [29] have been demonstrated to be involved in bystander signaling of normal cells. So far,it appears that normal or cancer cells share some common bystander signaling. For example, Transformation Growth Factor β1 (TGF-β1) has been demonstrated to be an important signaling of RIBEs in normal [30] and cancer cells [31,32]. Similarly, nitric oxide plays an important mediating role in RIBEs in both normal [33] and cancer cells [34]. Very recently, exosomes, specialized membranous nanosized vesicles secreted by a variety of cells such as cancer cells, has been shown to be one kind of signal carriers between irradiated and bystander cancer cells [35] and human kerotinocytes [36]. Besides the signalings between irradiated and bystander cells, ATM, cyclooxygenase-2, ERK, JNK, MAPK, NF-κB, TGF-β1 pathways in irradiated and bystander cells have been found to mediate bystander effects in cancer cells [29]. Recent studies have also found that radiation promotes the invasion of the non-irradiated, surrounding breast cancer cells through metabolic alterations [37], and autophagy plays a negative role in RIBEs in breast cancer cells involving the activation of the CSF2-JAK2 pathway [38]. Additionally, the data on RIBEs also suggest the
possible cell type dependence of bystander signaling pathways. While Dickey et al. [39] reported that miRNAs did not seem to be the primary signaling factor associated with bystander DNA damage in human colon carcinoma cell lines; we found that miR-21 acted as an important mediator of RIBEs in H1299 non-small-cell lung cancer cells [31].

The occurrence of RIBEs is out of question by now, but their potential importance in RT still needs to be determined. In addition to acquiring more data on RIBEs in animal systems and humans, sophisticated theoretical models taking non-targeted effects into consideration should be developed with the cooperation of radiation biologists, physicists and system biologists. With this kind of models, it is possible that the efficacy, side effects and the risk ofsecond cancer of RT may be predetermined more accurately. Moreover, the underlying mechanisms of RIBEs in vivo need to be elucidated. With clear understanding of the mechanisms involving some specific signaling pathways, it may be doable to develop novel radiosensitizers to amplify deleterious RIBEs in cancer cells or protective agents to decrease side effects and second cancer risk in normal tissues or organs, thus increasing the therapeutic gains.

Acknowledgements

Research in the author’s laboratory is supported by the National Natural Science Foundation of China (grant No. 31270898 and 11335011), the Key programs of Natural Science Foundation of Jiangsu Educational Committee (12KJA310005), and the Priority Academic Program Development of Jiangsu Higher Education Institution (PARD).


 

References

References

1.Murphy JB, Liu HJ, Sturm E.Studies on X-ray effects : IX. The action of serum from X-rayed animals on lymphoid cells in vitro. J Exp Med 1922 35: 373-384.

2.Parsons WB, Watkins CH, Pease GL et al. Changes in sternal marrow following roentgen-ray therapy to the spleen in chronic granulocytic leukemia. Cancer 1954 7: 179-189.

3.Souto J. Tumour development in the rat induced by blood of irradiated animals. Nature. 1962 195: 1317-1318.

4.Hollowell JG Jr, Littlefield LG. Chromosome damage induced by plasma of x-rayed patients: an indirect effect of x-ray. Proc Soc Exp Biol Med. 1968 129: 240-244.

5.Nagasawa H, Little JB. Induction of sister chromatid exchanges by extremely low doses of alpha-particles. Cancer Res. 1992 52: 6394-6396.

6.Azzam EI, de Toledo SM, Little JB. Direct evidence for the participation of gap junction-mediated intercellular communication in the transmission of damage signals from alpha -particle irradiated to nonirradiated cells. Proc Natl Acad Sci U S A. 2001 98: 473-478.

7.Burdak-Rothkamm S, Short SC, Folkard M et al. ATR-dependent radiation-induced gamma H2AX foci in bystander primary human astrocytes and glioma cells. Oncogene 2007 26: 993-1002.

8.Acheva A, Ghita M, Patel G et al. Mechanisms of DNA damage response to targeted irradiation in organotypic 3D skin cultures. PLoS One. 2014, 9: e86092.

9.Koturbash I, Rugo RE, Hendricks CA et al. Irradiation induces DNA damage and modulates epigenetic effectors in distant bystander tissue in vivo. Oncogene. 2006, 25: 4267- 4275.

10.Prise KM, O’Sullivan JM. Radiation-induced bystander signalling in cancer therapy. Nat Rev Cancer. 2009, 9: 351- 360.

11.Prise KM. New advances in radiation biology. Occup Med (Lond). 2006, 56: 156-161.

12.Yang H., Held KD. Reviews in Cancer Biology & Therapeutics 2007 Chapter 4: 73-88.

13.Mackonis EC, Suchowerska N, Zhang M et al. Cellular response to modulated radiation fields. Phys Med Biol. 2007, 52: 5469-5482.

14.Butterworth KT, McGarry CK, O’Sullivan JM, Hounsell AR, Prise KM. A study of the biological effects of modulated 6 MV radiation fields. Phys Med Biol. 2010, 55: 1607-1618.

15.Trainor C, Butterworth KT, McGarry CK, Liberante F, O’Sullivan JM et al. Cell survival responses after exposure to modulated radiation fields. Radiat Res. 2012, 177: 44-51.

16.Asur RS, Sharma S, Chang CW, Penagaricano J, Kommuru IM et al. Spatially fractionated radiation induces cytotoxicity and changes in gene expression in bystander and radiation adjacent murine carcinoma cells. Radiat Res. 2012, 177: 751-765.

17.Gómez-Millán J, Katz IS, Farias Vde A, Linares-Fernández JL, López-Peñalver J et al. The importance of bystander effects in radiation therapy in melanoma skin-cancer cells and umbilical-cord stromal stem cells. Radiother Oncol. 2012, 102: 450-458.

18.McMahon SJ, Butterworth KT, Trainor C, McGarry CK, O’Sullivan JM et al. A kinetic-based model of radiation-induced intercellular signalling. PLoS One 2013 8: e54526.

19.Strigari L, Mancuso M, Ubertini V, Soriani A, Giardullo P et al. Abscopal effect of radiation therapy: Interplay between radiation dose and p53 status. Int J Radiat Biol. 2014, 90: 248-255.

20.Aravindan N, Aravindan S, Pandian V, Khan FH, Ramraj SK et al. Acquired tumor cell radiation resistance at the treatment site is mediated through radiation-orchestrated intercellular communication. Int J Radiat Oncol Biol Phys 2014 88: 677-685.

21.He M, Dong C, Ren R, Yuan D, Xie Y et al. Radiation enhances the invasiveness of irradiated and nonirradiated bystander hepatoma cells through a VEGF-MMP2 pathway initiated by p53. Radiat Res. 2013, 180: 389-397.

22.Ratajczak MZ, Jadczyk T, Schneider G, Kakar SS, Kucia M. Induction of a tumor-metastasis-receptive microenvironment as an unwanted and underestimated side effect of treatment by chemotherapy or radiotherapy. J Ovarian Res. 2013, 6: 95.

23.Hubenak JR, Zhang Q, Branch CD, Kronowitz SJ. Mechanisms of injury to normal tissue after radiotherapy: a review. Plast Reconstr Surg. 2014, 133: 49e-56e.

24.Sigurdson AJ, Jones IM. Oncogene. Second cancers after radiotherapy: any evidence for radiation-induced genomic instability? 2003, 22: 7018-7027.

25.Brenner DJ, Curtis RE, Hall EJ, Ron E. Second malignancies in prostate carcinoma patients after radiotherapy compared with surgery. Cancer. 2000, 88: 398-406.

26.Kleinerman RA, Boice JD Jr, Storm HH, Sparen P, Andersen A et al. Second primary cancer after treatment for cervical cancer. An international cancer registries study. Cancer. 1995, 76: 442-452.

27.Chinnadurai M, Paul SF, Venkatachalam P. The effect of growth architecture on the induction and decay of bleomycin and X-ray-induced bystander response and genomic instability in lung adenocarcinoma cells and blood lymphocytes. Int J Radiat Biol. 2013, 89: 69-78.

28.Yang H, Asaad N, Held KD. Medium-mediated intercellular communication is involved in bystander responses of Xray- irradiated normal human fibroblasts. Oncogene. 2005, 24: 2096-2103.

29.Hei TK, Zhou H, Chai Y, Ponnaiya B, Ivanov VN. Radiation induced non-targeted response: mechanism and potential clinical implications. Curr Mol Pharmacol. 2011, 4: 96-105.

30.Iyer R, Lehnert BE, Svensson R. Factors underlying the cell growth-related bystander responses to alpha particles. Cancer Res. 2000, 60: 1290-1298.

31.Jiang Y, Chen X, Tian W et al. The role of TGF-β1-miR-21- ROS pathway in bystander responses induced by irradiated non-small-cell lung cancer cells. Br J Cancer. 2014, 111(4): 772-780.

32.Gow MD, Seymour CB, Ryan LA, Mothersill CE. Induction of bystander response in human glioma cells using high-energy electrons: a role for TGF-beta1. Radiat Res.2010, 173: 769-778.

33.Han W, Chen S, Yu KN, Wu L. Nitric oxide mediated DNA double strand breaks induced in proliferating bystander cells after alpha-particle irradiation. Mutat Res. 2010, 684: 81-89.

34.Shao C, Folkard M, Prise KM. Role of TGF-beta1 and nitric oxide in the bystander response of irradiated glioma cells. Oncogene. 2008, 27: 434-440.

35.Al-Mayah AH, Irons SL, Pink RC, Carter DR, Kadhim MA. Possible role of exosomes containing RNA in mediating nontargeted effect of ionizing radiation. Radiat Res. 2012, 177: 539-545.

36.Jella KK, Rani S, O’Driscoll L, McClean B, Byrne HJ et al. Exosomes are involved in mediating radiation induced bystander signaling in human keratinocyte cells. Radiat Res. 2014, 181: 138-145.

37.Liao EC, Hsu YT, Chuah QY, Lee YJ, Hu JY et al. Radiation induces senescence and a bystander effect through metabolic alterations. Cell Death Dis. 2014, 5: e1255.

38.Huang YH, Yang PM, Chuah QY, Lee YJ, Hsieh YF et al. Autophagy promotes radiation-induced senescence but inhibits bystander effects in human breast cancer cells. Autophagy. 2014, 10: 1212-1228.

39.Dickey JS, Zemp FJ, Altamirano A, Sedelnikova OA, Bonner WM et al. H2AX phosphorylation in response to DNA double-strand break formation during bystander signalling: effect of microRNA knockdown. Radiat Prot Dosimetry. 2011, 143: 264-269.

Cite this article: Yang H. The Potential Roles of Radiation-Induced Bystander Effects in Radiation Therapy. J J Rad Oncol. 2014, 1(2): 008.

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