Abstract
BACKGROUND: Glioblastoma (GBM) is the most malignant brain cancer. Collagen is minimally expressed in normal brain parenchyma; however, previous reports show upregulated collagen gene expression in GBM. We perform the first direct GBM collagen visualization, identify clinically relevant collagen signatures in focal and invasive GBMs and link them to differential patient survival. METHODS: Customized second harmonic generation (SHG) multiphoton workstation with excitation wavelength tuned to 890nm and a 445± 25nm bandpass emission filter was used to detect collagen in a clinically-annotated human GBM tissue microarray (TMA) for 111 patients. Human GBM cancer stem cell lines that form focal or invasive xenografts were implanted into mice brains. Symptomatic mice with verified xenografts were euthanized, brains excised, and stained with picrosirius red. Quantitative characterization of collagen fibers in xenografts and TMA images was performed with custom software. RESULTS: Collagen was directly visualized in GBMs with SHG and picrosirius red. In focal GBM xenografts, collagen was observed at tumor-brain boundaries, appearing to encapsulate the tumors. For invasive GBM xenografts, collagen was intercalated with tumor cells. Quantitative collagen analysis showed significant differences for mean angle between fibers for focal (60.3856 ± 2.2113) and invasive (70.2529 ± 1.6211) GBM xenografts. GBM TMA specimens were segregated into two collagen groups: fibrillar and immature. Patients with fibrillar GBM collagen had a statistically significantly better median survival (69.6 weeks) compared to immature GBM collagen patients (30.4 weeks). The mean angle between fibers was significantly different for GBMs with fibrillar (84.37 ± 7.298) versus immature (113.2 ± 11.60) collagen. CONCLUSIONS: We demonstrate that collagen can be directly visualized in GBMs, and is different in focal vs. invasive tumors. Our data suggest collagen is a potential survival marker: patients with fibrillar collagen have improved survival. Therefore, we hypothesize that collagen may influence tumor cell invasion by acting as a barrier, and collagen disruption may promote tumor invasion.
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