Proinvasive extracellular matrix remodeling in tumor microenvironment in response to radiation.
Ki-Chun YooYongjoon SuhYoojeong AnHae-June LeeYe Ji JeongNizam UddinYan-Hong CuiTae-Hoon RohJin-Kyoung ShimJong Hee ChangJong Bae ParkMin-Jung KimIn-Gyu KimSeok-Gu KangSu-Jae LeePublished in: Oncogene (2018)
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.
Keyphrases
- radiation induced
- extracellular matrix
- induced apoptosis
- stem cells
- cell cycle arrest
- signaling pathway
- bone marrow
- radiation therapy
- free survival
- oxidative stress
- pi k akt
- endoplasmic reticulum stress
- squamous cell carcinoma
- lps induced
- early stage
- cell death
- risk assessment
- tyrosine kinase
- antibiotic resistance genes
- rectal cancer
- inflammatory response
- human health
- locally advanced