Investigating the Contribution of Collagen to the Tumor Biomechanical Phenotype with Non-invasive Magnetic Resonance Elastography.
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Increased stiffness in the extracellular matrix (ECM) contributes to tumor progression and metastasis. Therefore, stromal modulating therapies and accompanying biomarkers are being developed to target ECM stiffness. Magnetic resonance (MR) elastography can noninvasively and quantitatively map the viscoelastic properties of tumors in vivo and thus has clear clinical applications. Herein, we used MR elastography, coupled with computational histopathology, to interrogate the contribution of collagen to tumor biomechanical phenotype and evaluate its sensitivity to collagenase-induced stromal modulation. Elasticity (Gd) and viscosity (Gl) were significantly greater for orthotopic BT-474 (Gd=5.9±0.2kPa, Gl=4.7±0.2kPa, n=7) and luc-MDA-MB-231-LM2-4 (Gd=7.9±0.4kPa, Gl=6.0±0.2kPa, n=6) breast cancer xenografts, and luc-PANC1 (Gd=6.9±0.3kPa, Gl=6.2±0.2kPa, n=7) pancreatic cancer xenografts, compared to tumors associated with the nervous system, including GTML/Trp53KI/KI medulloblastoma (Gd=3.5±0.2kPa, Gl=2.3±0.2kPa, n=7), orthotopic luc-D-212-MG (Gd=3.5±0.2kPa, Gl=2.3±0.2kPa, n=7), luc-RG2 (Gd=3.5±0.2kPa, Gl=2.3±0.2kPa n=5) and luc-U-87-MG (Gd=3.5±0.2kPa, Gl=2.3±0.2kPa n=8) glioblastoma xenografts, intracranially propagated luc-MDA-MB-231-LM2-4 (Gd=3.7±0.2kPa, Gl=2.2±0.1kPa, n=7) breast cancer xenografts, and Th-MYCN neuroblastomas (Gd=3.5±0.2kPa, Gl=2.3±0.2kPa, n=5). Positive correlations between both elasticity (r=0.72, p<0.0001) and viscosity (r=0.78, p<0.0001) were determined with collagen fraction, but not with cellular or vascular density. Treatment with collagenase significantly reduced Gd (p=0.002) and Gl (p=0.0006) in orthotopic breast tumors. Texture analysis of extracted images of picrosirius red staining revealed significant negative correlations of entropy with Gd (r=-0.69, p<0.0001) and Gl (r=-0.76, p<0.0001), and positive correlations of fractal dimension with Gd (r=0.75, p<0.0001) and Gl (r=0.78, p<0.0001). MR elastography can thus provide sensitive imaging biomarkers of tumor collagen deposition and its therapeutic modulation.
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Computational Pathology & Integrated Genomics
Paediatric Solid Tumour Biology and Therapeutics
Ultrasound & Optical Imaging
License start date
Cancer Res, 2019