Association of collagen architecture with glioblastoma patient survival

Abstract

Objective Glioblastoma (GBM) is the most malignant primary brain tumor. Collagen is present in low amounts in normal brain, but in GBMs, collagen gene expression is reportedly upregulated. However, to the authors’ knowledge, direct visualization of collagen architecture has not been reported. The authors sought to perform the first direct visualization of GBM collagen architecture, identify clinically relevant collagen signatures, and link them to differential patient survival. Methods Second-harmonic generation microscopy (SHG) was used to detect collagen in a GBM patient tissue microarray. Focal and invasive GBM mouse xenografts were stained with Picrosirius red. Quantitation of collagen fibers was performed using custom software. Multivariate survival analysis was done to determine if collagen is a survival marker for patients. Results In focal xenografts, collagen was observed at tumor brain boundaries. For invasive xenografts, collagen was intercalated with tumor cells. Quantitative analysis showed significant differences in collagen fibers for focal and invasive xenografts. The authors also found that GBM patients with more organized collagen had longer median survival than those with less organized collagen. Conclusions Collagen architecture can be directly visualized and is different in focal versus invasive GBMs. The authors also demonstrate that collagen signature is associated with patient survival. These findings suggest that there are collagen differences in focal versus invasive GBMs and that collagen is a survival marker for GBM.

Collective forces of tumor spheroids in three-dimensional biopolymer networks

“…Although collagen is present in only small amounts in the normal human brain, glioblastoma cells readily bind to collagen 20 . Moreover, recent studies have shown that fibrillar collagens are an integral part of the locally produced extracellular matrix in glioblastomas 21,22 , yet little is known about the traction forces exerted by GBM in order to facilitate movement through brain tissue. Furthermore, collagen is found in the basement membrane surrounding blood vessels, which are a major route of GBM invasion 20,23 .…”

The irradiated brain microenvironment supports glioma stemness and survival via astrocyte-derived Transglutaminase 2

“…4,5 Understanding which factors promote stemness and treatment resistance of glioma cells is of intense interest in developing new therapies in glioma. A large number of studies over the past decade have established that there is considerable plasticity in glioblastoma cell phenotypes, [6][7][8][9][10][11] that stem cell characteristics can be acquired by non-stem-like cells, 8,9,[12][13][14][15] and that microenvironmental cues such as hypoxia, 16 extracellular matrix proteins, [17][18][19][20][21][22][23][24][25] or growth factors secreted by stromal cells [26][27][28] may be sufficient to induce tumor cell stemness and therapeutic resistance. The role of the microenvironment in regulating tumor stemness is further supported by the finding that stem-like tumor cells are enriched in specific tumor niches; in GBM, primarily the perivascular niche (PVN) and hypoxic compartments.…”

Interaction of Discoidin Domain Receptor 1 with a 14-3-3-Beclin-1-Akt1 Complex Modulates Glioblastoma Therapy Sensitivity

“…In addition to integrins, the receptor tyrosine kinase discoidin domain receptor 1 (DDR1) binds to and is activated by collagens in the ECM (Xu et al, 2012), which are expressed in brain tumors and are associated with patient prognosis (Huijbers et al, 2010;Pointer et al, 2017). Type I collagen (Col I) was shown to populate microenvironmental niches where GBM GSCs reside, survive treatment, and propagate into recurrence (Motegi et al, 2014).…”