DUOX2, a New Biomarker for Disseminated Gastric Cancer’s Response to Low Dose Radiation in Mice

Abstract

Simple Summary The symptoms of early stomach cancer are often unremarkable, exhibiting only slight upper abdominal discomfort. By the time the symptoms become more obvious, the disease has usually progressed to an advanced stage resulting in more than 90% of inpatients presenting with locally advanced or metastatic cancer at the time of initial diagnosis. Disease that has spread into the abdomen is present in 10 to 30% of patients at the time of their initial surgery and is a frequent finding in patients who develop recurrent cancer. Treatment options are rather limited for these patients. Here, we designed a mouse model to evaluate the effect of very low dose of radiation to sensitize stomach cancer cells to conventional chemotherapy. Our data indicate that expression of DUOX2, an enzyme involved in the production of hydrogen peroxide, increases the odds of preventing cancer dissemination in response to low dose radiation and conventional chemotherapy. Abstract Treatment options are rather limited for gastrointestinal cancer patients whose disease has disseminated into the intra-abdominal cavity. Here, we designed pre-clinical studies to evaluate the potential application of chemopotentiation by Low Dose Fractionated Radiation Therapy (LDFRT) for disseminated gastric cancer and evaluate the role of a likely biomarker, Dual Oxidase 2 (DUOX2). Nude mice were injected orthotopically with human gastric cancer cells expressing endogenous or reduced levels of DUOX2 and randomly assigned to four treatment groups: 1; vehicle alone, 2; modified regimen of docetaxel, cisplatin and 5′-fluorouracil (mDCF) for three consecutive days, 3; Low Dose- Whole Abdomen Radiation Therapy (LD-WART) (5 fractions of 0.15 Gy in three days), 4; mDCF and LD-WART. The combined regimen increased the odds of preventing cancer dissemination (mDCF + LD-WART OR = 4.16; 80% CI = 1.0, 17.29) in the DUOX2 positive tumors, while tumors expressing lower DUOX2 levels were more responsive to mDCF alone with no added benefit from LD-WART. The molecular mechanisms underlying DUOX2 effects in response to the combined regimen include NF-κB upregulation. These data are particularly important since our study indicates that about 33% of human stomach adenocarcinoma do not express DUOX2. DUOX2 thus seems a likely biomarker for potential clinical application of chemopotentiation by LD-WART.