The function of REG1A - a gene induced by tumour-stroma interaction - in colon cancer development

Carcinomas are the most frequent malignant tumours in humans, accounting for the vast majority of cancer deaths. Carcinomas develop from epithelial cells by accumulation of mutations and are interwoven by genetically normal mesenchymal cells, which are known as the stromal part of the tumour. This so-called tumour stroma strongly influences the development of the tumour and is responsible for increased proliferation and invasive potential of the malignant cells. However, it is not exactly known how the stroma alters the malignant potential of the cancer cells and the molecular mechanisms behind remained rather unclear. We concentrate on fibroblasts, which are the main cellular constituents of the stroma in colon cancer. Recently, we developed a three-dimensional co-culture system, allowing us to identify genes, whose expression is induced upon the interaction of carcinoma cells with stromal fibroblasts. REG1A mRNA was one of the most significantly induced transcripts in the genome wide expression screen. The analysis of expression databases (BioExpress) revealed that REG1A mRNA is specifically elevated only in human colon cancer and eosophageal carcinomas, whereas other cancers as well as the vast majority of normal tissues were negative for REG1A transcript. This finding in combination with reports in the literature that REG1A is regulated by inflammatory signals, shows growth promoting activities and its presence is correlated with bad prognosis in gastrointestinal cancers, warrants closer examination. We will identify paracrine factors, which induce REG1A expression and would like to clarify its function in colon cancer. We will analyse the effects of REG1A protein on cell proliferation and survival, migration, invasion and stem cell properties in both, the epithelial as well as the fibroblast components. In addition we will determine, which major signalling pathways (e.g. MAPK, PI3K/Akt/mTOR, wnt pathway) are influenced by REG1A. Many of the cellular assays will be done using 3D cell culture models, which have been shown to be closer to the in vivo situation as conventional 2D cultures.