## 4 The Importance of Biomarkers in Monitoring RT Toxicity
### Secreted Soluble Protein Biomarkers  
Exposure to radiation initiates a programmed cellular response to promote tissue repair, involving the induction and regulation of several proinflammatory cytokines and growth factors [110]. While being beneficial for the rescue of normal cells exposed to RT, the RT-induced inflammatory response also sustains the survival of tumor cells and cancer progression [111], conferring to oncologic patients a poor prognostic outcome. Cell apoptosis and senescence after RT lead to increased TGF-\(\beta\) release. Their combination with hypoxia in the tumor may amplify this release to a higher degree. Transforming growth factor beta (especially in the isoform TGF-\(\beta\)1) plays a fundamental role in normal tissue injury after RT. This candidate biomarker is one of the most common cytokines released due to cell irradiation, its levels being closely connected to the RT dose, DNA damage, and toxicity due to radiation [112]. TGF-\(\beta\) is a regulator of the physiologic wound healing process, and its overproduction may lead to severe injuries in normal human tissues. Typically, a TGF-\(\beta\) increase in normal tissues may lead to fibrosis, being involved in toxicity related to chronic oxidative stress, genomic instability in tumors and in bystander cells, as well as secondary cancers [113; 114]. Additionally, TGF-\(\beta\) has been shown to be a critical suppressor of the anti-tumor immune defense, promoting the proliferation of cancer cells and angiogenesis and tumor metastasis [115; 116; 117; 118; 119]. Another promising biomarker belonging to the cytokine family is interleukin-6 (IL-6). This pleiotropic protein is involved in several inflammatory diseases since its axis is associated with immunity and metabolism. It also regulates hematopoiesis and acute-phase reactions. The evidence arising from the published literature shows a significant correlation between high levels of IL-6 in serum and a shorter survival/poor prognosis of cancer patients. [PERSON] et al., 1991 reported such a correlation for patients with multiple myeloma [120], together with [PERSON] et al., 1996, [121] while [PERSON] et al., 1989 reported IL-6 as a growth factor for renal cancer cells similar to the study of [PERSON] et al., 1992 [122; 123]. [PERSON] et al., 1990 concluded that high serum IL-6 is a prognostic factor in glioblastoma [124]. [PERSON] et al., 1989 suggested that IL-6 may promote in vivo tumor metastasis and invasiveness in breast cancer cases [125], while [PERSON] et al., 2023 indicated that IL-6 mediates the crosstalk between breast cancer cells and cancer-associated-fibroblasts in the tumor microenvironment [126]. [PERSON] et al., 1995 showed that elevated IL-6 serum levels in ovarian cancer patients correlate with poor prognosis [127], as did [PERSON] et al., 1991 [128]. In the same trend, [PERSON] et al., 2001 reported a general relationship between elevated IL-6 levels and metastatic cancer for prostate cancer patients [129], supporting similar conclusions by other researchers in previous publications [130; 131; 132; 133; 134]. The activation of the IL-6 axis has also been reported for patients with colorectal cancer or oesophageal squamous cell cancer [135; 136]. The IL-6 signaling pathway was shown to be involved in metastasis formation [137]. Moreover, the results presented by [PERSON] et al., 2011, indicate that increased levels of IL-6 enhance the radiosensitivity of CD4\({}^{+}\)CD25\({}^{+}\) T cells after low-dose gamma irradiation [106]. Experimental data presented by [PERSON] et al., 2012 demonstrate that IL-6 is crucial in shaping the radiation response of liver tumor cells, suggesting that concurrent treatment with IL-6 inhibitors (such as Tocilizumab) might be a promising therapeutic strategy for increasing the IR response of cancer cells [138].