The transcription factor Stat3 regulates the expression of a large repertoire of genes which when deregulated, can lead to the development of some of the well-known hallmarks of cancer, such as resistance to cell death and sustained proliferation. Aberrant Stat3 activation has been characterised across a number of different cancers including gastrointestinal cancers, presenting Stat3 and its signalling pathway as a promising therapeutic target. Although 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. This project aims 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 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 selective Stat3 suppression in the non-tumoural compartment, the shStat3 mice were subcutaneously injected with syngeneic MC38 murine colon cancer cells.
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 expressing less immunosuppressive markers.
Our data provides evidence for the therapeutic value of Stat3 specific targeting in gastrointestinal cancers. Interestingly, we have shown that isolated Stat3 suppression in the non-tumoural compartment can also 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 to drive this Stat3 suppression mediated anti-tumour effect.