Lysyl Oxidase as a Potential Target for Infiltrative Growth in Glioblastoma

Glioblastoma (GBM) is the most common primary brain cancer. It is highly aggressive and unlike many other cancers types, the median survival for patients after treatment (14.6 months) has barely improved in the last 20 years. Infiltrative growth into the surrounding brain parenchyma is thought to be responsible for tumour recurrence and ultimately the death of the patient. Novel therapies are desperately needed to prevent this infiltrative growth and the subsequent recurrence.

GBM infiltrative cells invade by migrating along the region immediately adjacent to blood vessels, known as the perivascular niche. The perivascular niche is composed of a specialised laminin-rich basement membrane, and is a known chemoattractant for GBM cells. Here, we investigated a role for the enzyme Lysyl Oxidase (LOX) in GBM infiltration. LOX is a tumour-secreted hypoxia regulated enzyme previously shown to promote invasion of other solid tumour cancers.

Analysis of publicly available gene expression data from GBM patient samples revealed a strong association between LOX expression and poor survival, specifically in the more hypoxic and invasive mesenchymal GBM subtype. We have demonstrated that invasive phenotype in patient-derived GBM stem cell lines is associated with high LOX expression, and invasion is dependent on LOX activity through blocking experiments. Furthermore, over expression of LOX in non-invasive lines drives infiltrative growth in vivo and ex vivo, and exhibits increased chemotaxis towards extracellular laminin. We have shown that a MMP-7 is associated with the over expression of LOX to drive invasive growth in GBM.

Our findings suggest that LOX up regulates MMP-7 that fragments laminin creating a chemotactic gradient, which attracts GBM cells enabling infiltration of the perivascular niche. Targeting LOX may represent an effective therapy against infiltrative GBM.