Radionuclides in radiation-induced bystander effect; may it share in radionuclide therapy?

Abstract

For many years in radiobiology and radiotherapy predominated the conviction that cellular DNA is the main target for ionizing radiation, however, the view has changed in the past 20 years. Nowadays, it is assumed that not only directed (targeted) radiation effect, but also an indirect (non-targeted) effect may contribute to the result of radiation treatment. Non-targeted effect is relatively well recognized after external beam irradiation in vitro and in vivo, and comprises such phenomena like radiation-induced bystander effect (RIBE), genomic instability, adaptive response and abscopal (out of field) effect. These stress-induced and molecular signaling mediated phenomena appear in non-targeted cells as variety responses resembling that observed in directly hit cells. Bystander effects can be both detrimental and beneficial in dependence on dose, dose-rate, cell type, genetic status and experimental condition. Less is known about radionuclide-induced non-targeted effects in radionuclide therapy, although, based on characteristics of the radionuclide radiation, on experiments in vitro utilizing classical and 3-D cell cultures, and preclinical study on animals it seems obvious that exposure to radionuclide is accompanied by various bystander effects, mostly damaging, less often protective. This review summarizes existing data on radionuclide induced bystander effects comprising radionuclides emitting beta- and alpha-particles and Auger electrons used in tumor radiotherapy and diagnostics. So far, separation of the direct effect of radionuclide decay from crossfire and bystander effects in clinical targeted radionuclide therapy is impossible because of the lack of methods to assess whether, and to what extent bystander effect is involved in human organism. Considerations on this topic are also included.

TNF-α May Exert Different Antitumor Effects in Response to Radioactive Iodine Therapy in Papillary Thyroid Cancer with/without Autoimmune Thyroiditis

“…When 131 I accumulates in the remnant thyroid tissue, its decay results in thyroid cancer cells’ high energy deposition and minimal irradiation of the surrounding normal tissues. The expression of TNF-α and TIMP-1 is increased after irradiation [ 12 , 13 , 28 ] and can be involved in the 131 I-induced bystander effect. Similar to the previously mentioned studies [ 12 , 13 , 28 ], our results showed that 131 I intake led to a 3.55-fold increase in TNF-α and a 1.19-fold in TIMP-1 in patients without AIT.…”

“…The expression of TNF-α and TIMP-1 is increased after irradiation [ 12 , 13 , 28 ] and can be involved in the 131 I-induced bystander effect. Similar to the previously mentioned studies [ 12 , 13 , 28 ], our results showed that 131 I intake led to a 3.55-fold increase in TNF-α and a 1.19-fold in TIMP-1 in patients without AIT. Moreover, the involvement of TNF-α and the MMP-9/TIMP-1 complex in the radiation-induced non-targeted effects has been demonstrated by the highly statistically significant correlations measured between TNF-α and TIMP-1 (r = 0.68, p < 0.001) and TNF-α and the MMP-9/TIMP-1 ratio (r = −0.66, p < 0.001).…”

“…Recent data have suggested that radiation therapy may modulate antitumor immune responses [ 9 ] and induce changes in the local microenvironment, affecting tumor development [ 10 ] and not only through “danger” signals that propagate from irradiated to non-irradiated cells [ 11 , 12 ]. The expression of TNF-α is increased after irradiation and may be involved in non-targeted effects, especially in bystander signaling in non-irradiated cells within or in the vicinity of the irradiated area, either via intercellular gap junctions or medium transfer mechanisms along with matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) [ 13 ]. It is well known that the tumor necrosis factor-alpha (TNF-α) precursor is cleaved to release soluble TNF-α to increase apoptosis in response to high-dose radiation of tumors [ 14 ].…”

Cell surface sphingomyelin: key role in cancer initiation, progression, and immune evasion

“…These inflammatory molecules provide the necessary signals for the recruitment and stimulation of dendritic cells (DC) and macrophages (M) to properly present TAA to helper (CD4+) and cytotoxic T (CTL) lymphocytes, which may target and kill residual and metastatic tumor cells bearing TAA on their surface membrane. The figure is uploaded on the net by Maria Widel and was reproduced with her permission [ 18 ] …”

To go where no one has gone before: the necessity of radiobiology studies for exploration beyond the limits of the “Holy Gray” in radionuclide therapy

“…Lastly, also not to be forgotten are the so-called abscopal and bystander effects, which describe effects only indirectly related to radiation exposure such as an activation of the immune system to non-irradiated foci in response to damage incurred by irradiated foci. These effects show both a high degree of heterogeneity and still are poorly understood [17].…”