Radiation-induced non-targeted response in vivo: role of the TGFβ-TGFBR1-COX-2 signalling pathway

Abstract

Background:Previous studies from our group and others have shown that cyclooxygenase-2 (COX-2) has an essential role in radiation-induced non-targeted responses and genomic instability in vivo. However, the signalling pathways involved in such effects remain unclear.Methods:A 1 cm2 area (1 cm × 1 cm) in the lower abdominal region of gpt delta transgenic mice was irradiated with 5 Gy of 300 keV X-rays. Nimesulide, a selective COX-2 inhibitor, was given to mice for five consecutive days before irradiation. Changes in transforming growth factor-beta (TGF-β) and TGF-β receptor type-1 (TGFBR1) mediated signalling pathways, in the out of radiation field lung and liver tissues were examined.Results:While the plasma level of cytokines remained unchanged, the expression of TGF-β and its receptors was elevated in non-targeted lung tissues after partial body irradiation. In contrast to the predominant expression of TGF-β in stromal and alveolar cells, but not in bronchial epithelial cells, TGF-β receptors, especially TGFBR1 were significantly elevated in non-targeted bronchial epithelial cells, which is consistent with the induction of COX-2. The different expression levels of TGFBR1 between liver and lung resulted in a tissue specific induction of COX-2 in these two non-targeted tissues. Multiple TGF-β induced signalling pathways were activated in the non-targeted lung tissues.Conclusion:The TGFβ-TGFBR1-COX-2 Signalling Pathway has a critical role in radiation-induced non-targeted response in vivo.

Successes and Failures of Combined Modality Therapies in Head and Neck Cancer

“…Relevant to our field, radiation activates TGF-β signaling pathway with cross-talk activation of COX-2 [70]. Well described are the subsequent increases in serum TGF-β associated with pulmonary injury and fibrosis within normal lung parenchyma [71].…”

“…ECOG 1308 assigned patients to neoadjuvant cisplatin, paclitaxel, and cetuximab with hopes of reducing macroscopic tumor volume. Patients with a complete response (CR) were treated with de-escalated radiation (54 Gy), whereas others received standard dose radiation (66)(67)(68)(69)(70). In patients obtaining a CR (71% of patients) followed by reduced RT, a 2-year PFS of 80% and 2-year OS of 93% was observed, compared to 65% and 87% in the non-CR group, respectively [31].…”

Gene Expression Analysis Reveals Inhibition of Radiation-Induced TGFβ-Signaling by Hyperbaric Oxygen Therapy in Mouse Salivary Glands

“…This pathway regulates the formation of extracellular matrix (ECM), and has been shown to be activated by RT (40)(41)(42)(43). The binding of TGFβ to its receptor can lead, via Smad dependent and independent pathways, to the expression of target genes such as Ctgf and Serpine1.…”

Key mechanisms involved in ionizing radiation-induced systemic effects. A current review

“…[63][64][65] The second proposed mechanism of RIBE lies in the ability of irradiated cells to excrete intracellularly-generated low-molecular-weight factors into the culture medium. The signal inducing bystander effects have been shown to include factors such as ROS, 66 cytokine(s), [67][68][69] interleukin(s), 66,70 cyclooxygenase-2 (COX-2), [71][72][73] tumor necrosis factor α (TNFα) 70,74 and transforming growth factor β1 (TGF-β1). 49,73,75 The interaction of that signal with the neighboring or a distant cell can lead to variable types of cellular and sub-cellular damage.…”