Degradation and Remodeling of Epitaxially Grown Collagen Fibrils

Abstract

Introduction— The extracellular matrix (ECM) in the tumor microenvironment contains high densities of collagen that are highly aligned, resulting in directional migration called contact guidance that facilitates efficient migration out of the tumor. Cancer cells can remodel the ECM through traction force controlled by myosin contractility or proteolytic activity controlled by matrix metalloproteinase (MMP) activity, leading to either enhanced or diminished contact guidance. Methods— Recently, we have leveraged the ability of mica to epitaxially grow aligned collagen fibrils in order to assess contact guidance. In this article, we probe the mechanisms of remodeling of aligned collagen fibrils on mica by breast cancer cells. Results— We show that cells that contact guide with high fidelity (MDA-MB-231 cells) exert more force on the underlying collagen fibrils than do cells that contact guide with low fidelity (MTLn3 cells). These high traction cells (MDA-MB-231 cells) remodel collagen fibrils over hours, pulling so hard that the collagen fibrils detach from the surface, effectively delaminating the entire contact guidance cue. Myosin or MMP inhibition decreases this effect. Interestingly, blocking MMP appears to increase the alignment of cells on these substrates, potentially allowing the alignment through myosin contractility to be uninhibited. Finally, amplification or dampening of contact guidance with respect to a particular collagen fibril organization is seen under different conditions. Conclusions— Both myosin II contractility and MMP activity allow MDA-MB-231 cells to remodel and eventually destroy epitaxially grown aligned collagen fibrils.

Prognostic significance of abnormal matrix collagen remodeling in colorectal cancer based on histologic and bioinformatics analysis

“…Therefore, in patients with CRC, changes in the remodeling and expression of different collagens should be comprehensively analyzed at different stages of tumor progression. Matrix collagen remodeling is largely regulated by the LOX and MMP family (50). The present study revealed that the expression of LOXL2, MMP-1, MMP-2, MMP-7 and MMP-9 at the tumor invasion front was significantly higher in the metastatic group than in the non-metastatic and normal groups.…”

“…Matrix collagen remodeling is largely regulated by the LOX and MMP family ( 50 ). The present study revealed that the expression of LOXL2, MMP-1, MMP-2, MMP-7 and MMP-9 at the tumor invasion front was significantly higher in the metastatic group than in the non-metastatic and normal groups.…”

Matrix Metalloproteinases Shape the Tumor Microenvironment in Cancer Progression

“…By adhering to them, myofibroblastic CAFs set this meshwork under strong tension and cause an increased interstitial pressure typical of solid tumors [ 434 , 435 ]. Conversely, ECM-cleaving MMPs, typically found during wound healing and in fibrotic processes, determine the turnover of the tumor stroma and reduce contact guidance by fibrillar matrix structures [ 436 ]. They are needed by the motile tumor cells to penetrate the dense and tensed collagen network of the TME and tumor collagenous capsule.…”

Effect of surface morphologies and chemistry of paper on deposited collagen

“…Cells attached to the substrate could also participate in collagenase activity leading to collagen signal loss, however, such influence requisite significant cell contractility, which is highly unlikely given their limited adhesion with cellulose. [41,42] We subsequently treated the paper substrates with fluorinated alkyl silanes to improve stability during cell culture, which has been shown to delay biodegradation, in part, due to restricted permeation of moisture. [10] As expected, the dependence of collagen intensity with time diminished on treated paper (Figure 3c).…”