Poster Presentation 25th Lorne Cancer Conference 2013

Haematopoietic Cell Kinase Promotes the Development and Progression of Colorectal Cancer in Mice. (#316)

Ashleigh Poh 1 , Adele Preaudet 1 , Emma C Stuart 1 , Matthias Ernst 1 , Tracy L Putoczki 1 , Robert JJ O'Donoghue 1
  1. Olivia Newton John Cancer Research Institute, Heidelberg, Victoria

Macrophages are a major component of the tumour micro-environment in colorectal cancer and may be broadly classified into two groups: M1 (classically activated) and M2 (alternatively activated) macrophages. Haematopoietic Cell Kinase (Hck) is expressed within macrophages and aberrant activation has been shown to correlate with a poor prognosis in human colorectal cancer. To investigate the role of Hck in colorectal carcinogenesis, Hck knock-in mutant mice (HckF/F) were subjected to the azoxymethane/dextran sodium sulphate (AOM/DSS) model of colitis-associated cancer. Following AOM/DSS challenge, HckF/F mice exhibited more severe colitis and tumours compared to wild-type (WT) animals. Furthermore, mucosal invasion and metastases were observed HckF/F mice while completely absent in WT controls. Immunohistochemistry and flow cytometry showed an equivalent number of macrophages between AOM/DSS challenged WT and HckF/F mice, while gene expression analysis of M1/M2 phenotypic markers showed a significant upregulation of M2 genes (Arg1, Il10) in HckF/F polyps and colons compared to WT controls. Bone-marrow chimeras were generated and HckF/F hosts with WT bone-marrow (WT→HckF/F) exhibited fewer tumours and increased survival compared to syngeneic chimeras (HckF/F→HckF/F). The expression of M2 genes (Arg1, Il10) was decreased in WT→HckF/F mice compared to HckF/F→HckF/F controls. However, no increase in tumour burden or change in M2 gene expression was observed in HckF/F→WT mice. To assess the contribution of lymphocytes in Hck-mediated tumourigenesis, lymphocyte deficient HckF/F;Rag1-/- compound mutants underwent AOM/DSS challenge. HckF/F;Rag1-/- animals exhibited milder colitis and an absence of tumours compared to HckF/F mice, suggesting that lymphocytes may enhance tumour development in HckF/F mice. In conclusion, Hck activity promotes the development and progression of AOM/DSS-induced cancer via upregulation of M2-associated genes. These findings suggest that the targeting of parallel non-oncogenic pathways, such as Hck signalling, could be used in conjunction with current anti-cancer therapies to improve patient survival.