Role of extracellular matrix and microenvironment in regulation of tumor growth and LAR-mediated invasion in glioblastoma

Abstract

The cellular dispersion and therapeutic control of glioblastoma, the most aggressive type of primary brain cancer, depends critically on the migration patterns after surgery and intracellular responses of the individual cancer cells in response to external biochemical cues in the microenvironment. Recent studies have shown that miR-451 regulates downstream molecules including AMPK/CAB39/MARK and mTOR to determine the balance between rapid proliferation and invasion in response to metabolic stress in the harsh tumor microenvironment. Surgical removal of the main tumor is inevitably followed by recurrence of the tumor due to inaccessibility of dispersed tumor cells in normal brain tissue. In order to address this complex process of cell proliferation and invasion and its response to conventional treatment, we propose a mathematical model that analyzes the intracellular dynamics of the miR-451-AMPK- mTOR-cell cycle signaling pathway within a cell. The model identifies a key mechanism underlying the molecular switches between proliferative phase and migratory phase in response to metabolic stress in response to fluctuating glucose levels. We show how up- or down-regulation of components in these pathways affects the key cellular decision to infiltrate or proliferate in a complex microenvironment in the absence and presence of time delays and stochastic noise. Glycosylated chondroitin sulfate proteoglycans (CSPGs), a major component of the extracellular matrix (ECM) in the brain, contribute to the physical structure of the local brain microenvironment but also induce or inhibit glioma invasion by regulating the dynamics of the CSPG receptor LAR as well as the spatiotemporal activation status of resident astrocytes and tumor-associated microglia. Using a multi-scale mathematical model, we investigate a CSPG-induced switch between invasive and non-invasive tumors through the coordination of ECM-cell adhesion and dynamic changes in stromal cells. We show that the CSPG-rich microenvironment is associated with non-invasive tumor lesions through LAR-CSGAG binding while the absence of glycosylated CSPGs induce the critical glioma invasion. We illustrate how high molecular weight CSPGs can regulate the exodus of local reactive astrocytes from the main tumor lesion, leading to encapsulation of non-invasive tumor and inhibition of tumor invasion. These different CSPG conditions also change the spatial profiles of ramified and activated microglia. The complex distribution of CSPGs in the tumor microenvironment can determine the nonlinear invasion behaviors of glioma cells, which suggests the need for careful therapeutic strategies.

LTBP1 plays a potential bridge between depressive disorder and glioblastoma

“…Additionally, glioma cells can secrete their own ECM components, including HA, brevikan, tenascin C and thrombospondin, as well as bronectin, which are actively expressed in the ECM of the developing nervous system along cell migration paths. [52,53]. This could partly explain that the in vitro GBM cell could also proliferate signi cantly different in our experiment.…”

miRNAs as Influencers of Cell–Cell Communication in Tumor Microenvironment

“…Both mathematical models and in vitro experiments showed an increase of miR-451 expression in glioblastoma cells in the presence of glucose. Mechanistically, miR-451 downregulates the AMPK (AMP-activate Protein Kinase) complex, promoting cellular proliferation and attenuating cellular migration [147,148]. On the contrary, the presence of lysophosphatidic acid (LPA) in the ECM promotes metastasis both in vitro and in vivo in models of human breast cancer.…”

Radiation Effects on Brain Extracellular Matrix

“…A major component of the brain ECM is chondroitin sulfate proteoglycans (CSPGs), which are actively involved in the organization of GBM TME and glioma invasion ( 27 ). The complex distribution of CSPGs in the tumor microenvironment can determine the invasion potential of glioma cells through the coordination of ECM-cell adhesion and dynamic changes in stromal cells ( 28 ). Among the main brain CSPGs are neurocan, brevican, CSPG4/NG2, CD44, aggrecan, versican, decorin, and biglycan.…”