Current insights into matrix metalloproteinases and glioma progression: transcending the degradation boundary

Nicholas A Pullen,¹ Andrew R Pickford,² Mark M Perry,³ Diane M Jaworski,⁴ Katie F Loveson,³ Daniel J Arthur,³ Jonathan R Holliday,³ Timothy E Van Meter,⁵ Ritchie Peckham,³ Waqar Younas,³ Sophie EJ Briggs,⁶ Sophie MacDonald,³ Thomas Butterfield,³ Myrianni Constantinou,³ Helen L Fillmore<sup>3

1</sup>School of Biological Sciences, University of Northern Colorado, Greeley, CO, USA; ²Biophysics Laboratories, School of Biological Sciences, Institute of Biological and Biomedical Sciences, University of Portsmouth, ³School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth, UK; ⁴Department of Neurological Sciences, Robert Larner College of Medicine, University of Vermont, Burlington, VT, ⁵Department of Pediatrics, Pediatric Hematology–Oncology, VCU School of Medicine, Richmond, VA, USA; ⁶Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, AB, Canada

Abstract: Glioblastoma multiforme (GBM) remains one of the most deadly cancers, with modest advances in overall survival despite significant improvements in imaging, surgery, and molecular genomic understanding. The highest-grade glioma, GBM is a primary brain cancer that is molecularly heterogeneous among patients and even within the same patient. Key hallmarks include glioma-cell invasion, angiogenesis, and therapeutic resistance. While once considered a major player in glioma invasion, members of the MMP family are also associated with other key pathological hallmarks of glioma. Investigations into understanding MMP function in GBM were slowed due to the failed MMP-inhibitor trials for GBM in the 2000s. In contrast, the field of MMPs in other brain pathologies has flourished in such areas as traumatic brain injury, multiple sclerosis, and stroke. In the past decade, the increase in publicly available data sets documenting patient-biopsy molecular information has empowered laboratory investigations into the spectrum of genomic, transcriptomic, and proteomic changes associated with glioma, including MMPs. In this review, we selected one of these data sets to illustrate a small sample of information that can be obtained from such analyses. Combined with recent reports on the use of MMP-cleavable peptides for imaging and the multifunctionality of MMPs, including intracellular nonproteolytic actions in various cell types, this paves the way for new avenues of MMP research. Understanding the function of MMPs in host–tumor interactions both spatially and temporally during tumor progression and in response to treatment will be crucial for the advancement of targeting specific MMPs in GBM. The opportunities to explore MMP regulation, expression, and function further in GBM have never been so great with progress in modern bioinformatics and molecular techniques, and it is hoped that advancements will translate in some way to patients diagnosed with GBM.

Keywords: glioblastoma, matrix metalloproteinase, glioma, brain