Project Grant of £150,000 - 2008-2011

Research Institution - University of Liverpool

Principal Applicant - Eithne Costello PhD, Senior Lecturer

Project Title - Crosstalk between pancreatic cancer cells and tumour infiltrating monocytes: role in invasion and potential for therapeutic exploitation?

Summary of proposed study - We recently reported the presence of two small calcium binding proteins, S100A8 and S100A9, in inflammatory cells known as monocytes (cells of myeloid origin), present in pancreatic tumours.

S100A8 and S100A9 are known to attract inflammatory cells to sites of inflammation. Their role in cancer is not well established. However, a recent study (Hiratsuka et al., Nature Cell Biology 2006 Dec;8; 1369-75) provided evidence that lung cancer cells transplanted into a primary site in mice (the back) released factors that stimulated the production of S100A8 and S100A9 in monocytes at a secondary site (the lungs). The S100 proteins then attracted the cancer cells to the secondary site. The phenomenon was prevented by treating the mice with blocking antibodies specific for these proteins.

We have observed that factors secreted from pancreatic cancer cells can increase the expression of S100A8 and S100A9 in monocytes in culture. We wish to determine whether these S100 proteins can also promote the spread of pancreatic cancer cells.

We additionally observed that the numbers of monocytes expressing S100A8 relative to those expressing S100A9 was curiously much lower in tumours that had lost Smad4 expression (p<0.004). Thus the ‘type’ of monocyte in the vicinity of Smad-ve tumours differed from those in Smad4+ve tumours. Smad4 normally suppresses tumour formation. However 50% of pancreatic cancers lose Smad4 function, coinciding with a gain in the ability to invade. While the biological significance of our observation is not yet clear, a recent study in mice (Kitamura et al. Nat Genet. 2007 Apr;39(4):467-75) showed that Smad4-ve colon cancers recruited a form of immature myeloid cell (similar to our S100 expressing cells) which promoted the invasion of the cancer cells.

Here we aim to:

1. Assess the role of S100A8/S100A9 in pancreatic cancer cell invasion.
2. Study Smad4+ve and Smad4–ve pancreatic tumour-associated monocytes to determine how they may influence the invasion process.

Our ultimate goal is to use this information for therapeutic intervention.