The role of the microenvironment in regulation of CSPG-driven invasive and non-invasive tumor growth in glioblastoma

Abstract

Glioblastoma (GBM) is one of the most lethal type of brain cancer with poor survival time. GBM is characterized by infiltration of the cancer cells through the brain tissue while lower grade gliomas and other non-neural metastatic types form self-contained non-invasive lesions. Glycosylated chondroitin sulfate proteoglycans (CSPGs), acting as critical regulators of the tumor microenvironment, dramatically govern the spatiotemporal status of resident reactive astrocytes and activation of tumor-associated microglia. In this paper we develop a mathematical model to investigate the effect of the CSPG distribution on regulation of a fundamental switch between two distinct patterns: invasive and non-invasive tumors. We show that the model’s predictions agree with experimental results for a spherical glioma. The model specifically predicts that non-invasive tumor lesions are highly associated with a thick extracellular matrix (ECM) containing rich CSPGs, while the absence of glycosylated CSPGs results in diffusely infiltrative tumors. It is also shown that heavy CSPGs can drive the exodus of resident reactive astrocytes from the main tumor mass, and direct inhibition of tumor invasion by the astrogliotic capsule, leading to encapsulation of non-invasive lesions. However, stable residence of reactive astrocytes from GBM in the absence or low level of CSPGs presents a microenvironment favorable to diffuse infiltration due to loss of the primary (CSPG-induced cell-ECM bonding) and secondary (astrogliotic capsule) inhibitors. The mathematical model presents the clear role of the key tumor microenvironment in brain tumor invasion.