The TGF-β1 dynamics during radiation therapy and its correlation to symptomatic radiation pneumonitis in lung cancer patients

Abstract

BackgroudThe underlying molecular and cellular mechanisms of radiation pneumonitis (RP) are very complex. Several biological factors need to be considered together with the well known dosimetric parameters for understanding the molecular events in developing RP in lung cancer patients. The aim of this study was to correlate the variations of the cytokine levels in lung cancer patients during radiation therapy (RT) with the occurrence of symptomatic RP.MethodsThirty-four lung cancer patients who received three-dimensional conformal radiation therapy were evaluated prospectively. Serial blood samples before, at the beginning, in the middle of, at the end of RT and 2 and 4 weeks after RT were analyzed for IL-1α, IL-6, IL-10, TNF-α and TGF-β1 by performing enzyme-linked immunosorbent assay. The predictive values of dosimetric factors for RP were evaluated, too.ResultsOverall, 8 patients (23.5%) had grade ≥ 2 RP. By serial measurement of cytokines level, only the TGF-β1 level showed a correlation to the symptomatic RP. None of the other cytokines, IL-1α, IL-6, IL-10 and TNF-α level was correlated with the risk of RP. The mean pretreatment TGF-β1 level did not differ between RP and non-RP groups. However, during the period of radiation treatment, the TGF-β1 level began to increase at the end of RT in the RP group and became significantly higher 4 weeks after RT (p = 0.007). Using an ANOVA model for repeated-measures, we found significant associations between the changes of TGF-β1 during the time course of the RT and the risk of developing RP (p < 0.001). Most of the dosimetric factors showed a significant association with RP.ConclusionOur results show that the changes of TGF-β1 could be correlated with RP and the incorporation of the biological parameters into the dosimetric data could be useful for predicting symptomatic RP.

Inhibition of serine palmitoyltransferase delays the onset of radiation-induced pulmonary fibrosis through the negative regulation of sphingosine kinase-1 expression

“…Such a possibility can be inferred from the fact that synthetic ␣ -mannosyl ceramide analogs with myriocin instead of sphingosine as the backbone unit were shown to stimulate a particular V ␣ 19 subset of NKT cells ( 46 ). In view of the important role played by the immune system in the development of RIF and RILI ( 9,10,(47)(48)(49)(50)(51)(52)(53), it becomes critical to identify criteria for a timely switch from the enforcement of SphK1-S1P/DHS1P-S1PR signaling network at early stages of RILI progression to its inhibition in order to prevent the development of RIF. The ability of myriocin to defer radiation-induced SphK1 activation and RIF progression and to counteract TGF-␤ -induced signaling identifi es SPT as a novel therapeutic target for the management of RIF that can potentially lead to improvements in the outcomes in patients receiving radiotherapy for thoracic malignancies.…”

Loss of Nrf2 promotes alveolar type 2 cell loss in irradiated, fibrotic lung

“…Loss of Nrf2 expression can be a consequence of aging [9, 10], functional polymorphisms [11], and/or fibrotic TGF-β/pSmad3 signaling [12–15]. Preclinical models of pulmonary fibrosis indicate that Nrf2 is suppressed as the disease progresses [16, 17] and that haploinsufficiency is sufficient for enhanced susceptibility [8].…”

Radiation-induced pulmonary injury accelerated pulmonary metastasis in a mouse model of breast cancer

“…Radiation has previously been found to change the cell phenotype and tumor microenvironment, and as a result, an increased number of invasive residual tumor cells demonstrated higher rates of metastasis (8). However, the pathophysiology of radiation induced pneumonitis is complicated and remains unclear, although studies have indicated that inflammatory mediators affect genetic stability and cause persistent epigenetic alteration (9,10). This indicates that inflammatory components of the tumor microenvironment affect fundamental mechanisms responsible for the generation of metastatic variants (11).…”