Radiotherapy resistance: identifying universal biomarkers for various human cancers

Abstract

Radiotherapy (RT) is considered as a standard in the treatment of most solid cancers, including glioblastoma, lung, breast, rectal, prostate, colorectal, cervical, esophageal, and head and neck cancers. The main challenge in RT is tumor cell radioresistance associated with a high risk of locoregional relapse and distant metastasis. Despite significant progress in understanding mechanisms of radioresistance, its prediction and overcoming remain unresolved. This review presents the state-of-the-art for the potential universal biomarkers correlated to the radioresistance and poor outcome in different cancers. We describe radioresistance biomarkers functionally attributed to DNA repair, signal transduction, hypoxia, and angiogenesis. We also focus on high throughput genetic and proteomic studies, which revealed a set of molecular biomarkers related to radioresistance. In conclusion, we discuss biomarkers which are overlapped in most several cancers.

Keywords: Biomarker; Cancer; Radioresistance; Radiotherapy.

Fig. 1

Overlapping radioresistance biomarkers between different human cancers. Nine common biomarkers are shown in the seven most representative cancer types treated with RT. BC breast cancer, CC cervical cancer, ESCC esophageal squamous cell carcinoma, HNSCC head and neck squamous cell carcinoma, NSCLC non-small cell lung carcinoma, PC prostate cancer, RC rectal cancer

Fig. 2

Overlapping radioresistance biomarkers among the key processes related to radioresistance. Irradiation results in ROS generation and DNA damage. In response to irradiation, DNA repair is activated, accompanied by increased tyrosine kinase activity via multiple signal transduction pathways. The effects of ionizing radiation depend on the oxygenation/hypoxia metabolic balance in the tumor. Oxygenation induces ROS generation, which triggers DNA damage, but can activate the expression of pro-angiogenic genes. In contrast, hypoxia interferes with the effect of RT and can also stimulate the upregulation of angiogenic factors and immunosuppressive immune responses. The suppression of anti-tumor immune response is followed by the RT-induced metabolic and transcriptional changes in the pro-tumor phenotypes of tumor-associated macrophages (TAMs), cancer-associated fibroblasts (CAFs), and Tregs. TAMs and Tregs additionally promote angiogenesis. Boxes in blue reflect intracellular processes, boxes in grey demonstrate extracellular components, which trigger radioresistance in tumor cells. Common radioresistance biomarkers are given in the corresponding boxes and highlighted in red