Investigating the Contribution of Collagen to the Tumor Biomechanical Phenotype with Noninvasive Magnetic Resonance...

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 the tumor biomechanical phenotype and to evaluate its sensitivity to collagenase-induced stromal modulation. Elasticity (G _d) and viscosity (G _l) were significantly greater for orthotopic BT-474 (G _d = 5.9 ± 0.2 kPa, G _l = 4.7 ± 0.2 kPa, n = 7) and luc-MDA-MB-231-LM2-4 (G _d = 7.9 ± 0.4 kPa, G _l = 6.0 ± 0.2 kPa, n = 6) breast cancer xenografts, and luc-PANC1 (G _d = 6.9 ± 0.3 kPa, G _l = 6.2 ± 0.2 kPa, n = 7) pancreatic cancer xenografts, compared with tumors associated with the nervous system, including GTML/Trp53^KI/KI medulloblastoma (G _d = 3.5 ± 0.2 kPa, G _l = 2.3 ± 0.2 kPa, n = 7), orthotopic luc-D-212-MG (G _d = 3.5 ± 0.2 kPa, G _l = 2.3 ± 0.2 kPa, n = 7), luc-RG2 (G _d = 3.5 ± 0.2 kPa, G _l = 2.3 ± 0.2 kPa, n = 5), and luc-U-87-MG (G _d = 3.5 ± 0.2 kPa, G _l = 2.3 ± 0.2 kPa, n = 8) glioblastoma xenografts, intracranially propagated luc-MDA-MB-231-LM2-4 (G _d = 3.7 ± 0.2 kPa, G _l = 2.2 ± 0.1 kPa, n = 7) breast cancer xenografts, and Th-MYCN neuroblastomas (G _d = 3.5 ± 0.2 kPa, G _l = 2.3 ± 0.2 kPa, 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 G _d (P = 0.002) and G _l (P = 0.0006) in orthotopic breast tumors. Texture analysis of extracted images of picrosirius red staining revealed significant negative correlations of entropy with G _d (r = -0.69, P < 0.0001) and G _l (r = -0.76, P < 0.0001), and positive correlations of fractal dimension with G _d (r = 0.75, P < 0.0001) and G _l (r = 0.78, P < 0.0001). MR elastography can thus provide sensitive imaging biomarkers of tumor collagen deposition and its therapeutic modulation. SIGNIFICANCE: MR elastography enables noninvasive detection of tumor stiffness and will aid in the development of ECM-targeting therapies.