Exosomes from the tumor microenvironment promote breast cancer progression and therapy resistance

Radiation is an important treatment modality for gastrointestinal tumors, but intestinal injury is a common side effect in cancer survivors. We wanted to develop a physiologically-relevant model for studying the molecular determinants of radiation-induced intestinal damage and testing novel intestinal radioprotectors. Using minimally invasive surgery, we implanted a radiopaque marker onto the surface of the mouse (C57BL/6) jejunum to serve as a fiducial marker for precise targeting of radiation. One-week post-surgery mice were imaged with ConeBeam CT (CBCT) to locate the marker and irradiated with 12 or 18 Gy to the marked area using the Small Animal Radiation Research Platform (SARRP). Cohorts of mice were sacrificed at time points ranging from 1h to 4 months post-RT and phosphorylation of H2AX, EdU immunofluorescence and TUNEL assays were used to assess radiation damage. Intestinal lysates and plasma were also collected to assess inflammatory cytokine levels. Our results indicate that the IR-induced damage is acute but reversible and largely restricted to the area of the marker, leaving the surrounding tissues intact. Intriguingly, although whole gut irradiation with these doses causes lethal GI syndrome, irradiation of a 5mm portion of the intestine did not cause any lethality or weight loss. However, fibrosis and collagen deposition 4 months postIR indicated chronic intestinal damage. A separate cohort of mice was treated daily with curcumin, a non-toxic radioprotector, three days prior and two weeks post-IR. Curcumintreated mice showed significant decreases in both local and systemic inflammatory cytokine levels as well as in fibrosis suggesting it is effective as a radioprotector of the intestine. Our results indicate that this model, which emulates closely clinically relevant intestinal radiationinduced injury, can be used to assess radioprotectors prior to testing in the clinic. Abstracts for RadOnc Research Retreat 10.14.2016 Page 4 of 36