Poster Presentation 26th Lorne Cancer Conference 2014

Haematopoietic Cell Kinase Promotes Macrophage Polarisation and the Progression of Gastrointestinal Cancer in Mice. (#233)

Ashleigh Poh 1 , Adele Preaudet 1 , Simon Monard 1 , Matthias Ernst 1 , Robert O'Donoghue 1
  1. Olivia Newton John Cancer Research Institute, Heidelberg, Victoria

Macrophages are a major component of the tumour micro-environment in gastrointestinal cancers and may be broadly classified into two groups: M1 (classically-activated) and M2 (alternatively-activated) macrophages. Haematopoietic Cell Kinase (Hck) is a Src family kinase expressed within macrophages that is involved in macrophage polarisation and aberrant activation has been shown to correlate with a poor prognosis in human gastrointestinal cancers. We investigated the role of Hck in tumourigenesis using two mouse models of inflammation-associated cancer. Firstly, Hck mutant mice that express a constitutively active form of Hck (HckF/F) were crossed with gp130 knock-in mutant mice (gp130F/F)that develop spontaneous gastric tumours as a result of constitutive Stat3/mTORC activation (gp130F/F;HckF/F). HckF/F;gp130F/F mutants exhibited enhanced tumour development at 12 weeks of age compared to gp130F/F mice and submucosal tumour invasion was also observed in HckF/F;gp130F/+ mutants at 9 months while absent in gp130F/F controls. Secondly, HckF/F mice were subjected to the azoxymethane/dextran sodium sulphate (AOM/DSS) model of colon cancer. Following treatment, HckF/F mice exhibited an increased incidence and size of tumours compared to wild-type (WT) animals, in addition to mucosal invasion which was absent in WT mice. Given previous studies have shown AOM/DSS-induced tumours are dependent on lymphocytes we assessed the contribution of these cells in lymphocyte deficient HckF/F;Rag1-/- compound mutants following AOM/DSS challenge. Consistent with published studies, Rag1-/- animals were protected from tumourigenesis, however tumour development was observed in HckF/F;Rag1-/- mice. Gene expression and immunohistochemical analysis showed the HckF/F mutation significantly upregulated tumour proliferation and the expression of M2 markers Arg1 and Ym1. Flow cytometry identified increased numbers of Arg1+/Ym1+ positive macrophages in HckF/F tumours compared to WT mice with no difference in the total macrophage component between both genotypes. These results demonstrate that Hck activation promotes M2 polarisation and is sufficient to promote tumourigenesis independently of lymphocytes. These findings suggest that the therapeutic inhibition of parallel non-oncogenic pathways, such as Hck signalling, could improve prognosis and/or survival for cancer patients.