Abstract
BackgroundCancer-associated fibroblasts (CAFs) are highly differentiated and heterogeneous cancer-stromal cells that promote tumour growth, angiogenesis and matrix remodelling.MethodsWe utilised an adapted version of a previously developed 3D in vitro model of colorectal cancer, composed of a cancer mass and the 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 correlated with the upregulation of hepatocyte growth factor (HGF), metallopeptidase inhibitor 1 (TIMP1) and fibulin-5 (FBLN5). Vascular remodelling of previously formed endothelial structures occurred through the disruption of complex networks, and was associated with the upregulation of vascular endothelial growth factor (VEGFA) and downregulation in vascular endothelial cadherin (VE-Cadherin).ConclusionsThese results support, within a biomimetic 3D, in vitro framework, the direct role of CAFs in promoting cancer invasion, and their key function in driving vasculogenesis and angiogenesis.
Highlights
Vimentin staining was done in Cancer associated fibroblasts (CAFs) tumouroids grown to confluency and the morphology was compared to normal human dermal fibroblasts (HDFs) within tumouroids (Figure 1 C&D)
The presence of a cancerous CAF stroma increased the distance and surface area of invasion of colorectal cancer (CRC) into the stromal compartment whilst, at the same time, inhibiting vasculogenesis. These processes were driven by the up-regulation of hepatocyte growth factor (HFG), metallopeptidase inhibitor 1 (TIMP1) and fibulin 5 (FBLN5)
The remodelling appeared to occur through the process of disruption of complex endothelial networks and was associated with up-regulation of vascular endothelial growth factor (VEGFA) and a down-regulation in vascular endothelial cadherin (VECadherin)
Summary
Cancer associated fibroblasts (CAFs) are highly differentiated and heterogenous cancer stromal cells that promote tumour growth, angiogenesis and matrix remodelling. Our approach to engineering a 3D in vitro colorectal cancer model incorporates patient-derived CAFs in the stromal compartment and allows us to study the patient-specific effect on vasculature formation during cancer growth and progression. This novel approach of modelling cancer-CAF interplay allows us to directly demonstrate the cellular cross-talk between the cancer and stromal cells within a stable and stiff ECM. We studied how the presence of CAFs, and the release of growth factors and cytokines, altered the formation of vascular networks and remodelled pre-existing vascular networks
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