Proinvasive extracellular matrix remodeling in tumor microenvironment in response to radiation

Abstract

Ionizing radiation is widely used for patient with glioblastoma (GBM). However, the effect of radiation on patient survival is marginal and upon recurrence tumors frequently shift toward mesenchymal subtype adopting invasiveness. Here, we show that ionizing radiation affects biomechanical tension in GBM microenvironment and provides proinvasive extracellular signaling cue, hyaluronic acid (HA)-rich condition. In response to radiation, HA production was increased in GBM cells by HA synthase-2 (HAS2) that was transcriptionally upregulated by NF-ĸB. Notably, NF-ĸB was persistently activated by IL-1α-feedback loop, making HA abundance in tumor microenvironment after radiation. Radiation-induced HA abundance causally has been linked to invasiveness of GBM cells by generating movement track as an extracellular matrix, and by acting as a signaling ligand for CD44 receptor, leading to SRC activation, which is sufficient for mesenchymal shift of GBM cells. Collectively, our findings provide an explanation for the frequent brain tumor relapse after radiotherapy, and potential therapeutic targets to block mesenchymal shift upon relapse.

Radiation Effects on Brain Extracellular Matrix

“…The increase of HA content in tumor tissue affects the biomechanical tension in the GBM microenvironment and provides pro-invasive extracellular signaling cue due to binding with CD44 receptor and SRC activation sufficient for a mesenchymal shift of GBM cells. These findings suggest an explanation for the frequent brain tumor relapse after radiotherapy ( 37 ).…”

“…The U251 cells with activated NG2 expression (U251–NG2) were significantly more resistant to 5 Gy irradiation compared to the NG2-negative U251 cells suggesting NG2 as an important prognostic factor for radiotherapy resistance ( 35 ). X-ray irradiation of U87MG GBM cells ( 137 Cs τ-rays source, 2 Gy/day for 3 days) activates the expression of CD44 in these cells ( 37 ), and CD44 protein content was elevated in primary human GBM tumors that were developed in nude rat brain and undergone irradiation at a dose of 50 Gy, by 4 weeks after irradiation ( 38 ). At the same time, expression levels of brevican, neurocan, aggrecan, and versican in irradiated U87MG cells was not changed ( 37 ).…”

“…X-ray irradiation of U87MG GBM cells ( 137 Cs τ-rays source, 2 Gy/day for 3 days) activates the expression of CD44 in these cells ( 37 ), and CD44 protein content was elevated in primary human GBM tumors that were developed in nude rat brain and undergone irradiation at a dose of 50 Gy, by 4 weeks after irradiation ( 38 ). At the same time, expression levels of brevican, neurocan, aggrecan, and versican in irradiated U87MG cells was not changed ( 37 ). Although a significant decrease in the expression of circular noncoding RNA from versican (circ_VCAN, hsa_circ_0073237) in irradiated U87 and U251 cells by 13 h post-irradiation was demonstrated (4–5- and 8–9-fold, respectively), it was significantly up-regulated in radioresistant glioma tissues compared with the radiosensitive tissues.…”

Hyaluronic acid synthase 2 promotes malignant phenotypes of colorectal cancer cells through transforming growth factor beta signaling

“…[26][27][28] Among these factors, HAS2, the rate-limiting enzyme for HA synthesis, is often elevated in various cancers. However, although its importance is well documented in many cancers, including glioma, breast cancer and squamous cell carcinoma, 18,29,30 its oncogenic role in CRC remains obscure. HA is a major component of the extracellular matrix and regulator of many cell processes such as cell migration, proliferation and differentiation.…”

A human co‐culture cell model incorporating microglia supports glioblastoma growth and migration, and confers resistance to cytotoxics

“…[16][17][18] Comprising ~20% of the tissue volume, brain extracellular matrix contains few fibrous proteins and high amounts of proteoglycans, glycosaminoglycans (GAGs), and glycoproteins. [16][17][18] Comprising ~20% of the tissue volume, brain extracellular matrix contains few fibrous proteins and high amounts of proteoglycans, glycosaminoglycans (GAGs), and glycoproteins.…”