Abstract

Special Delivery; The Peculiarities of Exosomal-TGFb in the Cancer Microenvironment

Jason Webber, Research Fellow, Cardiff University

The stroma surrounding carcinomas is aberrantly altered, consisting of alpha-smooth muscle actin (aSMA)-positive, myofibroblast-like, cells. The onset of such cells is regulated by TGFß. We have previously demonstrated that TGFß can be tethered to the surface of exosomes. Here we compare the relative importance of soluble and exosomal TGFß in stromal activation and investigate novel ways of targeting stroma-assisted tumour growth.

Prostate cancer exosomes, or soluble TGFß, were each capable of driving stromal fibroblast differentiation. Only the exosome-induced phenotype, however, was capable of supporting the formation of endothelial vessel-like structures in vitro and enhancing tumour growth in vivo. Knockdown of Rab27a attenuated exosome secretion, resulting in failure to induce a disease-associated stromal phenotype and subsequent loss of stromal-assisted tumour growth in vivo. The stromal precursor that gives rise to the disease-associated phenotype remains unclear with past evidence pointing to fibroblasts and mesenchymal stem cells (MSCs), among others. Interestingly, we observed the capacity of exosomes to also drive the differentiation of MSCs to a disease-like stromal phenotype. Finally, whilst we do not yet fully understand why the stroma responses to exosomal versus soluble TGFß differ, our data suggests a role of heparan sulphate proteoglycans which we have shown to be involved in the tethering of TGFß to the exosome surface.

Overall, these findings suggest a role for exosomal, not soluble, TGFß as the physiological modulator of the tumour stroma, driving multiple changes that support disease progression.