Extracellular matrix in glioblastoma: opportunities for emerging therapeutic approaches

Abstract

Extracellular matrix is a complex network of macromolecules that constitute a microenvironment of normal tissues and malignancies such as the primary brain tumor glioblastoma (GBM). The unique composition of the GBM ECM, compared with the brain, contributes to angiogenesis, invasion, and therapeutic resistance of GBM. On the other hand, components of tumor ECM and related aberrant signaling pathways offer opportunities for various therapeutic strategies that are under active investigations. Here we provide a comprehensive overview of emerging therapeutic approaches for GBM that target or utilize its unique ECM via antibodies or ligands, RNA interference, pharmacological agents and modification of ECM molecules. Furthermore, drug-loaded nanoparticles displaying ECM-directed antibodies or peptides enable tumor selective delivery of the payload. As an in vitro research platform, 3D tumor cell culture incorporating ECM can advance our understanding of tumor-ECM interactions.

Keywords: 3D culture; Extracellular matrix; antibodies; chemotherapy; glioblastoma; nanoparticles; oncolytic viruses; peptides; tumor microenvironment.

Figure 1

Extracellular matrix in brain and glioblastoma. Schematic presentation of relative abundance of a variety of extracellular matrix components in the brain (left) and glioblastoma (right).

Figure 2

Tumor extracellular matrix reduces efficacy of anti-cancer therapies. Illustration shows the roles of extracellular matrix in serving as barriers to drug diffusion, nutritional supply, and immune cell migration.

Figure 3

Drug or radioisotope-conjugated antibodies directed at extracellular matrix molecules. Illustration showing drug-conjugated antibody bi-specific to Extra domain B (EDB) of fibronectin and tanascin-C (TN-C) (left) and radio-labeled antibody against an extracellular matrix molecule (right), leading to damage of the tumor cell.

Figure 4

Hyaluronic acid targeted oncolytic virus therapy. Oncolytic adnovirus ICOVIR17 infects glioblastoma cells and induces expression of PH20 hyaluronidase. PH20 is secreted and degrades hyaluronic acid (HA) in the extracellular matrix. Immunogenic cell death triggered by ICOVIR17 and HA degradation result in activation of T cells and macrophages in the tumor microenvironment.