Validation of Growth Differentiation Factor (GDF-15) as a Radiation Response Gene and Radiosensitizing Target in Mammary Adenocarcinoma Model

Abstract

In this chapter we summarize the role of cytokines in the radiation response, focusing in particular on growth differentiation factor-15 (GDF-15), and give a brief overview of our ongoing experiments in a mouse mammary carcinoma model. The principal function, receptor, and signaling pathway of GDF-15 remain uncertain, although several of its biological activities have already been described; the exact role of GDF-15 in cancer progression also remains poorly understood. Increased GDF-15 expression is a common feature of many cancers. Several studies have observed upregulation of GDF15 mRNA and protein in tumor biopsy. Serum GDF-15 levels are often markedly elevated in cases of metastatic cancer, and appear to occur in parallel with the stages and extent of disease, particularly in cases of prostate and melanoma [Senapati et al., 2010, Boyle et al., 2009]. Indeed, a number of studies have described an antitumorigenic function for GDF-15, by which it induces apoptosis and may negatively affect tumor growth [Cekanova et al., 2009, Jutooru et al., 2009]. Prevention by eliminating tumor promoters, early diagnosis and new target treatment are keys to reduce the numbers of deaths caused by breast cancer. In our present study, we propose that GDF-15 increases radioresistance. We demonstrate that down regulated mouse GDF-15 by RNA interference improves the radiosensitivity of the tumor in an LM2 mouse breast cancer model. In this regard, GDF-15 overexpression in breast cancer cell has been shown to supply important cytoprotective roles and resistance to radiation treatments. The paradoxical role of GDF-15 in breast cancer could be related to its pleiotropic effect on different signal pathway. Recent research has focused on molecular targets for radiation sensitization of cancer cells. It is of particular interest that several potential target proteins involved in radiation sensitization, which have been identified in growth related cellular signaling pathways.