Östman and Augsten, Curr Opin Genet Dev. 2009 19: 67–73. Augsten et al., Proc Natl Acad Sci U S A. 2009 106: 3414–3419 Poster No. 142 Radiation Induces Invasiveness of Pancreatic Cancer via Upregulation of Heparanase Esther Bensoussan 1 , Amichay Meirovitz1, Irit Cohen1, Immanuel Lerner1, Benito Casu2, Israel Vlodavsky3, Michael Elkin1 1 Department Of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel, 2 Ronzoni selleck chemicals llc Institute,
Milan, Italy, 3 Technion-Israel Institute of Technology, Haifa, Israel Pancreatic cancer is one of the most aggressive neoplasms with an extremely low survival rate. Because most pancreatic carcinoma patients miss the opportunity for complete surgical resection at the time of diagnosis, radiotherapy remains a major component of treatment modalities. However, pancreatic cancer often shows resistance to radiation therapy. Ionizing radiation (IR)-induced aggressiveness is emerging as one of the important mechanisms responsible for limited benefit of radiation therapy in pancreatic cancer, but the identity of downstream effectors responsible for this effect remains poorly investigated. Here we report that IR promotes pancreatic
SYN-117 clinical trial cancer aggressiveness through up-regulation of the PtdIns(3,4)P2 heparanase. Heparanase is a predominant mammalian enzyme capable of degrading heparan sulfate (HS), the main polysaccharide component of the basement membrane and other types
of extracellular matrix (ECM). Cleavage of HS by heparanase leads to disassembly of ECM, enables cell invasion, releases HS–bound angiogenic and growth factors from the ECM depots, and generates bioactive HS fragments. We found that clinically relevant doses of IR augment invasive ability of pancreatic cells in vitro and in vivo via induction of heparanase. Our results indicate that effect of IR on heparanase expression is mediated by Egr1 transcription factor. Moreover, specific inhibitor of heparanase enzymatic activity abolished IR-induced invasiveness of pancreatic carcinoma cells in vitro, while combined treatment with IR and the heparanase inhibitor, but not IR alone, attenuated orthotopic pancreatic tumor progression in vivo. The proposed up-regulation of heparanase by IR represents a new molecular pathway through which IR may promote pancreatic tumor aggressiveness, providing explanation for the limited benefit from radiation therapy in pancreatic cancer. Our research is expected to offer a new approach to improve the efficacy of radiation therapy and better define target patient population in which such approach could be particularly beneficial. Poster No.