The extracellular matrix proteoglycan versican has long been associated with a poor outcome for a range of cancers. Additionally, there is growing evidence for versicans involvement in altering macrophage infiltration and signalling in a variety of inflammatory diseases, particularly during tumour progression. However, the mechanisms involved are poorly characterised.
Our research focuses on understanding the interaction between Adamts1 (the predominate versican protease) and versican; and how they influence immune cell infiltration, and further deviate the immune response within tumours. Utilising the MMTV-PyMT mouse mammary tumour model, we have demonstrated that Adamts1(-/-)/PyMT tumours, display a reduced tumour burden with an associated decrease in cleaved versican and increased CD45(+) leukocyte infiltration. Further characterisation of immune cell gene expression has indicated that cytotoxic (anti-tumourigenic) cell activation is increased in Adamts1(-/-) tumours, compared with Adamts1(+/+) tumours.
To explore whether this increased prevalence of intact versican in Adamts1(-/-) tumours is responsible for regulating this tumour associated immune profile, we purified endotoxin free full-length recombinant V1-versican, and explored its role in regulating the physiological behaviours of macrophages in vitro .
By treating RAW 264.7 and bone marrow derived macrophages with intact V1-versican, we demonstrated that V1-versican is able to significantly induce the gene expression of several pro-inflammatory type-1 cytokines and chemokines (P<0.001), whilst disregarding the expression of type-2 genes. Versican was also able to induced a decrease in macrophage adhesion to fibronectin (P<0.0001), with 3D-confocal imaging demonstrating a notable change in cell morphology and associated cell spread (P<0.001). V1-versican also induced a significant increase in cell migration (P<0.001) with live-cell imaging suggesting a change in migratory rate. Interestingly, these changes were independent of versican’s immune activating ability.
Ongoing studies continue to investigate molecular pathways by which intact V1-versican is able to induce these changes in macrophage physiology, and how myeloid cells may utilise versican during tumour infiltration.