DNA damage response in peritumoral regions of oesophageal cancer microenvironment.

Oesophageal cancer is a highly aggressive disease, ranking among the 10 most common cancers in the world. Oesophageal cancer patients often suffer from multi-origin tumours, and therefore, it is important to improve our understanding of the complex biology, which underpins microenvironmental interactions in this disease. Extensive evidence indicates that the interaction of tumours with their microenvironment may play a crucial role in tumour initiation and progression. In this study, we analysed DNA damage response (DDR), immune cell invasion and cancer progression in 47 patients with oesophageal cancer from three different regions (tumour tissue, tumour-proximal non-malignant tissue and distant non-malignant tissue). Accumulated DDR (positive staining for γH2AX and phospho-ATM) was evident within tumour tissue and significantly increased in non-malignant tissue surrounding the tumour cells although activation of p53 by phosphorylation at serine 15 was observed only in tumour tissue. The level of DDR detected in cancer microenvironment depended largely on the distance from the tumour, as stronger DDR was observed in tumour-proximal areas compared with that in tumour-distant tissue. Induction of DDR in non-malignant tissues correlated with increased invasion of lymphocytes and macrophages and with precancerous progression. Our results support that DDR is induced in oesophageal cancer surrounding non-malignant epithelial cells, via activation of an inflammatory process, which in turn contributes to the progression of precancerous lesions. These findings provide novel pathological evidence for inflammation and DDR in influencing non-metastatic progression of cancer in its microenvironment.