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Abstract
As a new class of cancer therapeutic agents, oncolytic viruses (OVs) have gained much attention not only due to their ability to selectively replicate in and lyse tumor cells, but also for their potential to stimulate antitumor immune responses. As a result, there is an increasing need for in vitro modeling systems capable of recapitulating the 3D physiological tumor microenvironment. Here, we investigated the potential of our recently developed microphysiological system (MPS), featuring a vessel-like channel to reflect the in vivo tumor microenvironment and serving as culture spaces for 3D multicellular tumor spheroids (MCTSs). The MCTSs consist of cancer A549 cells, stromal MRC5 cells, endothelial HUVECs, as well as the extracellular matrix. 3D MCTSs residing in the MPS were infected with oncolytic VSV expressing GFP (oVSV-GFP). Post-infection, GFP signal intensity increased only in A549 cells of the MPS. On the other hand, HUVECs were susceptible to virus infection under 2D culture and IFN-β secretion was quite delayed in HUVECs. These results thus demonstrate that OV antitumoral characteristics can be readily monitored in the MPS and that its behavior therein somewhat differs compared to its activity in 2D system. In conclusion, we present the first application of the MPS, an in vitro model that was developed to better reflect in vivo conditions. Its various advantages suggest the 3D MCTS-integrated MPS can serve as a first line monitoring system to validate oncolytic virus efficacy.
Highlights
Oncolytic viruses (OVs) selectively infect and destroy tumor cells, sparing the normal cells and minimizing normal tissue damage [1]
The internal components forming the TME-like environment in the microphysiological system (MPS) were ECM and 29 3D multicellular tumor spheroids (MCTSs) located in 29 wells (Fig 1B)
3D MCTS consisting of human cancer A549 cells and human fibroblast MRC5 cells mimic the structure of in vivo tumor tissues
Summary
Oncolytic viruses (OVs) selectively infect and destroy tumor cells, sparing the normal cells and minimizing normal tissue damage [1]. Among several types of 3D-cultured spheroid models [11], 3D multicellular tumor spheroids (3D MCTSs) show suitable in vivo environments for evaluating the properties of onco-selective infection of OVs [12]. Another approach is applying a microphysiological system (MPS) to simulate blood vessel-like structures [13,14]. If the MPS and 3D MCTSs are properly combined, it would serve as a much better in vitro tumor model for evaluating the efficacy of OVs because it mimics the actual physiological conditions of the tumor tissue, including the fluid dynamics and cell-to-cell interactions in the TME.
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