Role of the inflammatory microenvironment in development of colon cancer
We are examining the role of pro-inflammatory signalling in colon cancer progression using a mouse model of colitis-associated cancer. By selective deletion of the integrin-linked kinase (ILK) gene in myeloid cells we observe a significant reduction in colonic inflammation, as evidenced by reduced macrophage infiltration and improved disease index. Importantly, reduced colonic inflammation in the ILK knockout mice significantly reduces tumour incidence, indicating that pro-inflammatory ILK signalling in the monocytic compartment promotes tumourigenesis. A key event in pro-inflammatory ILK signalling is activation of the nuclear transcription factor, NF-kappaB, which regulates production of pro-inflammatory cytokines such as TNF-alpha. We are studying unique regulation of intracellular NF-kappaB signalling by ILK, as well as profiling cytokine and cancer-related protein signatures in colon tumours and in tumour-associated macrophages (+/- ILK) in order to understand the role of ILK in pro-tumourigenic regulation by the innate immune system. Accordingly, we are developing and testing small molecule ILK inhibitors in vivo as potential therapeutics to block pro-inflammatory signalling within the tumour microenvironment, and thereby suppress tumour growth.