Elucidating the Role of Matrix Porosity and Rigidity in Glioblastoma Type IV Progression

Rui C Pereira,Luca Ceseracciu,Daniela P Boso,Raffaella Santagiuliana,Paolo Decuzzi,Bernhard A Schrefler

doi:10.3390/app10249076

Abstract

The highly infiltrating nature of glioma cells is the major cause for the poor prognosis of brain malignancies. Motility, proliferation, and gene expression of cells in natural and synthetic gels have been analyzed by several authors, yet quantitative studies elucidating the role of matrix porosity and rigidity in the development of whole malignant masses are missing. Here, an experimental-computational framework is introduced to analyze the behavior of U87-MG cells and spheroids in compact hyaluronic acid gels (HA), replicating the brain parenchyma; and fibrous collagen gels (COL), resembling the organized structures of the brain. Experimentally it was observed that individual U87-MG cells in COL assumed an elongated morphology within a few hours post inclusion (p.i.) and travelled longer distances than in HA. As spheroids, U87-MG cells rapidly dispersed into COL resulting in infiltrating regions as large as tumor cores (≈600 μm, at 8 days p.i.). Conversely, cells in HA originated smaller and denser infiltrating regions (≈300 μm, at 8 days p.i.). Notably, COL tumor core size was only 20% larger than in HA, at longer time points. Computationally, by introducing for the first time the effects of matrix heterogeneity in our numerical simulations, the results confirmed that matrix porosity and its spatial organization are key factors in priming the infiltrating potential of these malignant cells. The experimental-numerical synergy can be used to predict the behavior of neoplastic masses under diverse conditions and the efficacy of combination therapies simultaneously aiming at killing cancer cells and modulating the tumor microenvironment.

Highlights

Glioblastoma type IV (GBM) is the malignancy of the central nervous system with the poorest prognosis [1]
Cells of glioblastoma type IV transfected with green florescence protein—U87-MG GFP+ —were included into hydrogels of collagen hydrogels (COL) and hyaluronic acid gels (HA) either individually or as preformed spheroids (Figure 3)
Proliferation and motility of glioblastoma type IV cells were assessed in different extracellular matrices, namely made out of collagen type 1 and hyaluronic acid

Summary

Introduction

Glioblastoma type IV (GBM) is the malignancy of the central nervous system with the poorest prognosis [1]. Standard treatments for glioblastoma type IV currently consist of surgical resection followed by radiotherapy and chemotherapy [2]. The median survival for GBM patients is nearly. 14 months and the 5-year survival rate is only of 5%. A distinctive feature of GBM cells is their ability to infiltrate the host tissue forming multiple micro-metastases which cannot be surgically removed or efficiently killed by molecular anticancer therapies. Spreading of GBM cells is believed to occur through two major pathways: across the extracellular matrix (ECM), which is mainly composed of a dense.

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