Mechanical forces and enzymatic digestion act together to induce the remodeling of collagen fibrils in tumor microenvironment†

Abstract

Cancer is a serious disease in human beings, and its high lethality is mainly due to the invasion and metastasis of cancer cells. Clinically, the accumulation and high orientation of collagen fibrils were observed in cancerous tissue, which occurred not only at the location of invasion but also at 10–20 cm from the tumor. Studies indicated that the invasion of cancer cells could be guided by the oriented collagen fibrils, even in a dense matrix characterized by difficulty degradation. So, the orientation of collagen fibrils is closely related to invasion by cancer cells. However, the formation of the orientation of collagen fibrils remains insufficiently studied. A microfluidic chip-based collagen fibril tissue model was established to demonstrate its underlying mechanism. In this article, the dynamic mechanism of collagen fibril reconstruction from free orientation to high orientation was investigated at the mesoscopic dynamic level. In the experiment, the mechanical forces from interstitial flow and cell deformation were confirmed as significant factors for collagen fibril remodeling. Additionally, enzymes were confirmed as an another inducer to reconstruct the morphology of collagen fibrils, the mechanism of which was chemical degradation and recombination. Interstitial flow combined with an enzyme is an excellent combination for remodeling the distal collagen fibrils of a tumor, and this phenomenon was caught in a microfluidic platform with a micro-dose. This study to some extent answers the question of the kinetic mechanism of collagen fibril remodeling, and is expected to provide support for further proposed strategies to inhibit the orientation reconstruction of collagen fibrils and cancer treatment and prognosis.