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000305348 1001_ $$aJanas, Anastasia$$b0
000305348 245__ $$aRadiobiology and Radioresistance in High-Dose Radiosurgery for Brain Tumors: A Hypothesis-Generating Study Using an Intracranial Glioma Mouse Model.
000305348 260__ $$aAmsterdam [u.a.]$$bElsevier Science$$c2025
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000305348 520__ $$aStereotactic radiosurgery (SRS) is a precise, non-invasive treatment for brain tumors, yet underlying radiobiological mechanisms remain unclear. This study explored long-term dose-dependent tumor response to high-dose SRS in a murine glioma model, focusing on tumor-associated macrophages (TAMs) as key regulators of tumor microenvironment and immune modulation.Using the intracranial GL261-glioma mouse model, single-dose SRS was administered at either 20-Gy (clinically prescribed dose) or 40-Gy as a dose-escalation approach (n=24/dose). Tumor response was assessed longitudinally using 7T MRI at predefined intervals (d7, d30, d90, and d180) post-SRS or earlier upon symptom onset. Histological analyses performed at each timepoint evaluated cell proliferation, apoptosis, vascular morphology, blood-brain/tumor-barrier integrity, hypoxia, TAM recruitment, and polarization. Immune cell populations within tumor microenvironment were characterized using flow cytometry. Statistical analyses included a T-test and one-way ANOVA with Bonferroni or Dunnett correction.SRS efficacy was dose-dependent: 40-Gy suppressed tumor growth, while 20-Gy led to regrowth in 29% of cases between d30-51 post-SRS, necessitating stratification into responders and non-responders. Responders demonstrated reduced cell proliferation, sustained apoptosis, and vascular remodeling indicative of vessel normalization. Non-responders exhibited up to 94.5% increased hypoxia and up to 300-fold increased CXCR4 expression compared to responders. TAM recruitment inversely correlated with tumor volume (r=-0.8619, p=0.0056). The M1/M2 ratio in non-responders was similar to that of matched controls, but 3.8-fold and 4.8-fold lower than in responders at d30 and d90 post-SRS, respectively. FACS analysis confirmed an increased M1/M2 ratio by d30 in responders.This study offers key insights into longitudinal SRS radiobiology, highlighting the dynamic role of TAMs in sustaining long-term tumor control. Our findings support an association between hypoxia, CXCL12/CXCR4 signaling, and treatment resistance, and suggest a potential SRS-induced vascular normalization that may support improved therapeutic outcomes. While not designed to establish causality, the data provide a spatially and temporally resolved framework to guide future mechanistic studies and inform more effective SRS-based combination strategies.
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000305348 650_7 $$2Other$$aGlioblastoma (GBM)
000305348 650_7 $$2Other$$aImmunomodulation
000305348 650_7 $$2Other$$aMurine model
000305348 650_7 $$2Other$$aTumor-associated macrophages (TAMs)
000305348 650_7 $$2Other$$aradiobiology
000305348 650_7 $$2Other$$aradioresistance
000305348 650_7 $$2Other$$astereotactic radiosurgery (SRS)
000305348 7001_ $$aSenger, Carolin$$b1
000305348 7001_ $$aKrantchev, Kiril$$b2
000305348 7001_ $$aBrandenburg, Susan$$b3
000305348 7001_ $$aZhang, Wenying$$b4
000305348 7001_ $$aKluge, Anne$$b5
000305348 7001_ $$aAl-Rubaiey, Sanaria$$b6
000305348 7001_ $$aBukatz, Jan$$b7
000305348 7001_ $$aEitner, Chiara$$b8
000305348 7001_ $$aNieminen-Kelhä, Melina$$b9
000305348 7001_ $$aBoehm-Sturm, Philipp$$b10
000305348 7001_ $$0P:(DE-HGF)0$$aTinhofer, Ingeborg$$b11
000305348 7001_ $$aZips, Daniel$$b12
000305348 7001_ $$aVajkoczy, Peter$$b13
000305348 7001_ $$aAcker, Gueliz$$b14
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