Abstract
Radiation-induced bystander effects (RIBE) may have potential implications for radiotherapy, yet the radiobiological impact and underlying mechanisms in hypoxic tumor cells remain to be determined. Using two human tumor cell lines, hepatoma HepG2 cells and glioblastoma T98G cells, the present study found that under both normoxic and hypoxic conditions, increased micronucleus formation and decreased cell survival were observed in non-irradiated bystander cells which had been co-cultured with X-irradiated cells or treated with conditioned-medium harvested from X-irradiated cells. Although the radiosensitivity of hypoxic tumor cells was lower than that of aerobic cells, the yield of micronucleus induced in bystander cells under hypoxia was similar to that measured under normoxia indicating that RIBE is a more significant factor in overall radiation damage of hypoxic cells. When hypoxic cells were treated with dimethyl sulfoxide (DMSO), a scavenger of reactive oxygen species (ROS), or aminoguanidine (AG), an inhibitor of nitric oxide synthase (NOS), before and during irradiation, the bystander response was partly diminished. Furthermore, when only hypoxic bystander cells were pretreated with siRNA hypoxia-inducible factor-1α (HIF-1α), RIBE were decreased slightly but if irradiated cells were treated with siRNA HIF-1α, hypoxic RIBE decreased significantly. In addition, the expression of HIF-1α could be increased in association with other downstream effector molecules such as glucose transporter 1 (GLUT-1), vascular endothelial growth factor (VEGF), and carbonic anhydrase (CA9) in irradiated hypoxic cells. However, the expression of HIF-1α expression in bystander cells was decreased by a conditioned medium from isogenic irradiated cells. The current results showed that under hypoxic conditions, irradiated HepG2 and T98G cells showed reduced radiosensitivity by increasing the expression of HIF-1α and induced a syngeneic bystander effect by decreasing the expression of HIF-1α and regulating its downstream target genes in both the irradiated or bystander cells.
Highlights
Hypoxic regions are a common feature of most solid tumors, have radioresistant biological effects, and represent the most aggressive fraction of a tumor (Horsman et al, 2012; Peitzsch et al, 2017; Busk et al, 2020)
We found that when a small fraction of glioblastoma cells T98G were targeted with localized ions from a microbeam, additional micronucleus could be induced in the neighboring cells of either T98G or normal human fibroblasts (Mayer et al, 2012), which suggests that bystander response may have two potential impacts on radiotherapy by increasing the efficacy of tumor cell killing but simultaneously increasing the secondary cancer risk via the production of genetic damage occurs in normal bystander cells
We report that the increased expression of hypoxia-inducible factor-1α (HIF-1α) and its downstream proteins in hypoxic-irradiated cells leads to an increase of radioresistance but induces a bystander effect via downregulating HIF-1α expression in hypoxic nonirradiated bystander cells
Summary
Hypoxic regions are a common feature of most solid tumors, have radioresistant biological effects, and represent the most aggressive fraction of a tumor (Horsman et al, 2012; Peitzsch et al, 2017; Busk et al, 2020). Recent experimental evidence has shown that cells may respond directly to radiation exposure or through communicated transmissible factors capable of inducing cellular responses in non-irradiated cells, which is referred to as the radiation-induced bystander effect (RIBE) (Shao et al, 2003; Kamochi et al, 2008; Lorimore et al, 2008; Shao et al, 2008a; Zhu et al, 2008; Heeran et al, 2019). There may be a close interrelationship between cellular bystander responses and systemic tissue responses to radiation exposure including abscopal effects and the involvement of immune signaling (Formenti and Demaria, 2009; Prise and O’Sullivan, 2009; Griffin et al, 2020a,b). The impact of factors within the tumor microenvironment including hypoxia has not yet been determined
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