The transcription factor Stat3 plays essential roles in biological processes involving development, immunity and inflammation. Stat3 is known to regulate the expression of a large repertoire of genes which when deregulated, as in the context of tumorigenesis, can lead to the development of some of the well-known hallmarks of cancer, such as resistance to cell death and sustained proliferation, therefore Stat3 and its signalling pathway presents promising therapeutic targets. Although the aberrant intrinsic Stat3 signalling in tumour cells is well characterised, the effect(s) of Stat3 signalling among the infiltrating cells of the tumour microenvironment is still poorly understood. With this project we aim to elucidate the role of Stat3 in the non-tumoural compartment, and explore the therapeutic value of Stat3 inhibition for gastric and colon cancer.
We generated the CAGsrtTA3;STAT3.1348 (shStat3) mouse that utilises short-hairpin RNAi technology allowing for conditional and reversible Stat3 reduction. To study the effects of systemic Stat3 inhibition, the shStat3 was crossed with the gp130F/F mutant mouse that spontaneously develops gastric cancer. To assess the effects of Stat3 suppression in the non-tumoural compartment alone, the shStat3 mice were sub-cutaneously injected with MC38 murine colon cancer cells. Tumours and other tissues of these mice were excised and analysed.
We found that shStat3-mediated systemic Stat3 suppression resulted in significant tumour reduction in the gp130F/F gastric cancer mice. Similarly, isolated Stat3 reduction in the non-tumoural compartment of the shStat3 mice, restricted the growth of Stat3-proficient MC38 tumour allografts. Immunophenotyping of excised tumours highlighted an increase of a monocytic Ly6C+Ly6G- myeloid population.
Our data provides evidence for the therapeutic value of specific Stat3 targeting in gastrointestinal cancers. Interestingly, we have shown that Stat3 suppression in the non-tumoural compartment alone was enough to result in significant tumour reduction, indicating a prominent role of Stat3 in creating a pro-tumourigenic microenvironment. We have also identified a monocytic population as candidate cell type that drives this Stat3 suppression mediated anti-tumour effect.