Title: The role of RAGE in the development of Endometrial Cancer
Funder: Tenovus Cancer Care

Abstract: Endometrial cancer is the most common gynaecological malignancy in western countries. The age-standardised incidence in Great Britain increased by 34% between 1993 and 2006. There are several established risk factors that are associated with exposure to excess estrogen in the absence of progesterone including hormone replacement therapy, treatment of breast cancer patients with Tamoxifen, polycystic ovary syndrome (PCOS), and obesity. In PCOS, metabolic aberrations including prolonged hyperglycemic exposure occur where advanced glycation end products (AGEs) are formed at an accelerated rate and accumulate in patients’ blood. A number of these associated risk factors also promote inflammation, a feature that is increasingly being shown to influence cancer, and may be involved in the initiation and progression of endometrial adenocarcinoma in a tissue that through the normal menstrual cycling process can be considered as a site of regular and repeated inflammation [1]. The Receptor for Advanced Glycation End products (RAGE) is a single-transmembrane member of the immunoglobulin protein family. RAGE activation, via AGEs, and other RAGE ligands, can result in activation of inflammatory signalling cascades in several cancers, and it is emerging as an important contributor to the constitutive inflammation process observed in a tumour microenvironment [2,3]. To date the role of RAGE in the endometrium, and any involvement in endometrial cancer development has not been reported. Recently we have made several key observations: 1) RAGE is expressed in the human endometrium, 2) AGE signals NF-κB activation in endometrial cells, 3) women with PCOS have significantly increased levels of RAGE, and separately 4) RAGE is drastically upregulated in endometrial cells treated with Tamoxifen. Given these initial observations, it seems possible that RAGE is involved in endometrial adenocarcinoma development. It is therefore imperative to extend our studies into patients with endometrial hyperplasia and endometrial cancer in order to determine whether RAGE plays a key role in cancer development through the establishment of an inflammatory environment. Through the examination of cellular models and samples obtained from cancer and ‘high risk’ groups of patients, the function of RAGE and downstream inflammatory markers will be determined using cell and molecular biology approaches. We propose to do this in two geographically distinct populations, Wales and Chile, through a strong collaboration with a RAGE expert in Chile, as this will give a more powerful understanding of the basis of the RAGE involvement in cancer development/progression due to the underlying genetic diversity of the two populations. The outcomes of the proposed research will provide a detailed understanding of the expression and function of RAGE and downstream inflammatory processes in endometrial adenocarcinoma development. If there is a clear involvement of RAGE, we will then begin considering the possibilities of targeting the RAGE pathway in pre-cancerous ‘at risk’ patient groups as a preventative therapy. Because of the systemic role of RAGE in the body, local delivery of RAGE pathway antagonists directly to the endometrium would make this a very appealing strategy for future drug delivery in patient care.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: CANCER AND NEOPLASMS