It is well known that growth and survival of cancer stem cells (CSCs) is highly influenced by tumour microenvironmental factors and molecular signalling, initiated by cytokines and growth factors. IL-6 is a key regulator of a number of cellular processes including proliferation, survival, differentiation, migration and invasion and it is also commonly overexpressed in many cancers. Recent evidence shows that IL-6 is not only secreted by tumour cells, but is produced at even higher levels by endothelial cells (ECs). Research shows that high intratumoural levels of IL-6 enhance the survival, self-renewal and tumour initiation potential of cancer stem cells. These studies of the impact of IL-6 on CSCs provide strong motivation for the development of anti-IL-6 therapies for the targeted treatment of stem cell driven cancers.
In this talk, a multi-scale mathematical model that operates at the intracellular, molecular, and tissue level is developed in order to investigate the impacts of endothelial cell-secreted IL-6 signalling on the crosstalk between tumour cells and ECs during tumour growth. This endothelial cell-tumour cell (EC-TC) model is used to study the therapeutic impact of Tocilizumab (TCZ), a competitive IL-6R inhibitor, on tumour growth and cancer stem cell (CSC) fraction, alone and in combination with the traditional chemotherapeutic agent, Cisplatin. The approach used here is novel in that it includes full receptor occupancy dynamics between endothelial-cell produced IL-6, IL-6R, and TCZ. Validation is achieved by directly comparing model predictions to data generated by a series of in vivo experiments. This multiscale approach provided excellent predictive agreement with the decrease in tumour volumes, as well as a decrease in CSC fraction.
Targeting key regulators of the cancer stem cell phenotype to overcome their critical influence on tumour growth is a promising new strategy for cancer treatment. This predictive modelling framework can serve to rapidly evaluate dosing strategies for IL-6 pathway modulation, as well as providing the basis for proposing combination treatments with IL-6 blockade and cytotoxic or other targeted therapies.