Duox2, A Key Player For Chemopotentiation By Low-Dose Fractionated Radiation Therapy In Gastric Cancer Cells

One of the most conventional therapy for solid tumors is radiotherapy. Still, this modality presents a challenge when it comes to managing highly disseminated gastrointestinal cancers due to increased toxicity to surrounding tissues. Recent laboratory and clinical data indicate that Low Dose Fractionated Radiation Therapy (LDFRT) can potentiate systemic chemotherapy and presents the possibility to revisit the concept of Whole Abdominal Radiotherapy (WART) for disseminated intra-abdominal gastric cancers. Earlier work considered LDFRT ineffective for tumor removal but we now know that LDFRT induces hyper-radiosensitivity (HRS) in a number of proliferating cells. We have recently shown that dual oxidase (DUOX2) is a major contributor to induce HRS at radiation doses as low as 0.15 Gy and sensitize human gastric cancer cells to chemotherapy. The aim of our study is to determine the utility of DUOX2 as a potential biomarker for the clinical application of chemopotentiation by LDFRT. First, we performed immunohistochemistry (IHC) on 48 human gastric samples with progressive grades. Our data indicate that only about 50% of human gastric cancers are positive for DUOX2. The reason for DUOX2 variability of expression is not clear but may be linked to inflammation since six of the seven (86%) gastritis samples we examined expressed strong levels of DUOX2 in the surface of epithelial cells. Our data also indicate that expression of DUOX2 significantly increases the levels of macrophages infiltration in tissue expressing DUOX2 as well as in the stroma surrounded by cells expressing DUOX2. This suggests that expression of DUOX2 could impact on the dynamic of the tumor microenvironment. Expression of DUOX2 in response to LDFRT is conserved since we also observed this in mice primary gastric cancer cells as well as cancer stem cells. Furthermore, as a first step to develop DUOX2 as an accessible biomarker, we studied DUOX2 activity by measuring the accumulation of oxidative serum proteins in gastric cancer cells media. Our data indicate that down regulation of DUOX2 significantly reduces the levels of serum protein oxidation. Taken together these data suggest that DUOX2 could potentially be used as a biomarker to stratify patients and follow the efficiency of clinical application of chemopotentiation by LDFRT. Citation Format: Palak R. Parekh, Elizabeth Chang, Navesh K. Sharma, France Carrier. DUOX2, a key player for chemopotentiation by low-dose fractionated radiation therapy in gastric cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5852. doi:10.1158/1538-7445.AM2017-5852