Exploring Chemical Crosslinking of the Extracellular Matrix as a Potential Therapy for Recurrent Glioblastoma

Glioblastoma (GBM) is a type of cancer that originates from the glial cells of the brain and is difficult to treat due to the diffuse nature of the tumour. The recurrence of GBM at the surgical site is a significant problem after surgery. Filling the surgical cavity with saline and oedema occurring at the surgical site leads to dilution of the brain extracellular matrix (ECM) and, eventually, a less dense matrix around the tumour site, which could promote cancer cell migration and recurrence. The study initially investigated how brain matrix hyaluronic acid (HA) concentration and viscosity affect cancer cell migration. The results showed that higher concentrations of HA limited cell and spheroid migration in three different cell models of glioblastoma. Thus, we conclude that the brain ECM can be essential in facilitating cancer cell migration. Hence, we hypothesised that modifying brain ECM to inhibit cancer cell migration chemically is possible. The study then examined brain ECM crosslinking using oxidised hyaluronic acid (oxi HA) to prevent glioblastoma cell migration. The results showed that a low concentration of oxidised hyaluronic acid gel with adipic acid dihydrazide restricted glioblastoma cell movement and prevented the descent of spheroids through 3D mimics of brain ECM. The study then proposed a novel therapy using oxidised hyaluronic acid based crosslinking for stabilising the brain ECM to limit the migration of glioblastoma cells. The results showed that oxi HA effectively restricted cell migration in glioblastoma cell models in a dose-dependent manner. Animal studies demonstrated the efficacy of oxi HA in preventing tumour progression compared to nonoxi HA controls. The cross-linking of proteins in the ECM by oxi HA is expected to form a relatively thick gel/stiffer matrix that slows down or stops cell invasion by initialising a dormancy state in GBM cells. This study proposes a promising therapy for recurrent glioblastomas, which could be further explored in clinical studies.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2023

Author dc:creator

• Rajan, Rakesh

Advisor dc:contributor.advisor

• Duer, Melinda

• Extracellular matrix crosslinking
• Glioblastoma

Licence

• https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/571bc056-d1a8-4e9e-a2fc-dd7079ef7504/download
• https://www.rioxx.net/licenses/all-rights-reserved/

Language dc:language

eng

Author Identifier

0000-0002-3647-6233

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/370524