Abstract
Radiotherapy is an important therapeutic approach to treating malignant tumors of different localization, including brain cancer. Glioblastoma multiforme (GBM) represents the most aggressive brain tumor, which develops relapsed disease during the 1st year after the surgical removal of the primary node, in spite of active adjuvant radiochemotherapy. More and more evidence suggests that the treatment's success might be determined by the balance of expected antitumor effects of the treatment and its non-targeted side effects on the surrounding brain tissue. Radiation-induced damage of the GBM microenvironment might create tumor-susceptible niche facilitating proliferation and invasion of the residual glioma cells and the disease relapse. Understanding of molecular mechanisms of radiation-induced changes in brain ECM might help to reconsider and improve conventional anti-glioblastoma radiotherapy, taking into account the balance between its antitumor and ECM-destructing activities. Although little is currently known about the radiation-induced changes in brain ECM, this review summarizes current knowledge about irradiation effects onto the main components of brain ECM such as proteoglycans, glycosaminoglycans, glycoproteins, and the enzymes responsible for their modification and degradation.
Highlights
Adjuvant chemoradiotherapy with temozolomide is a conventional protocol for the standard treatment for newly diagnosed glioblastoma multiforme (GBM) [1]
Irradiation affects normal brain microenvironment, resulting in changes in hippocampal neurogenesis and attenuates tolerance of normal brain after cranial irradiation [20]. These results are supported by the fact that after complete resection of the tumor mass and chemoradiotherapy, GBM commonly recurs around the tumor removal site, suggesting that the microenvironment at the tumor border provides therapeutic resistance to GBM cells [21]
According to the presented data, X-ray radiation affects all key components of normal brain extracellular matrix (ECM) (PGs, collagens, matrix metalloproteinases (MMPs), and heparanase) in different extent and directions (Figure 1)
Summary
Adjuvant chemoradiotherapy with temozolomide is a conventional protocol for the standard treatment for newly diagnosed glioblastoma multiforme (GBM) [1]. Irradiation affects normal brain microenvironment, resulting in changes in hippocampal neurogenesis and attenuates tolerance of normal brain after cranial irradiation [20] These results are supported by the fact that after complete resection of the tumor mass and chemoradiotherapy, GBM commonly recurs around the tumor removal site, suggesting that the microenvironment at the tumor border provides therapeutic resistance to GBM cells [21]. The presented data demonstrate that different components of the GBM TME (including oxidative stress and inflammation, immune response, and angiogenesis) actively respond to X-ray irradiation, whereas the contribution of extracellular matrix (ECM) to radiation-induced changes in both GBM tumor and normal brain tissue remain much less investigated. X-ray irradiation of U87MG GBM cells (137Cs 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
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