Cancer Associated Fibroblasts Mediate Cancer Progression and Remodel the Tumouroid Stroma
ObjectiveCancer associated fibroblasts (CAFs) are highly differentiated and heterogenous cancer stromal cells that promote tumour growth, angiogenesis and matrix remodelling. DesignWe utilised a novel 3D in vitro model of colorectal cancer, composed of a cancer mass and surrounding stromal compartment. We compared cancer invasion with an acellular stromal surround, a healthy or normal cellular stroma and a cancerous stroma. For the cancerous stroma we incorporated six patient-derived CAF samples to study their differential effects on cancer growth, vascular network formation, and remodelling. ResultsCAFs enhanced the distance and surface area of the invasive cancer mass whilst inhibiting vascular-like network formation. These processes were driven by the upregulation of hepatocyte growth factor (HFG), metallopeptidase inhibitor 1 (TIMP1) and fibulin 5 (FBLN5). Remodelling appeared to occur through the process of disruption of complex networks and was associated with the up upregulation of vascular endothelial growth factor (VEGFA) and down-regulation in vascular endothelial cadherin (VE-Cadherin). ConclusionThese results support, within a biomimetic 3D, in vitro framework, the direct role of CAFs in promoting cancer invasion and that CAFs are also key components in driving vasculogenesis and angiogenesis.