Collagen fibers mediate MRI-detected water diffusion and anisotropy in breast cancers

Abstract

Collagen 1 (Col1) fibers play an important role in tumor interstitial macromolecular transport and cancer cell dissemination. Our goal was to understand the influence of Col1 fibers on water diffusion, and to examine the potential of using noninvasive diffusion tensor imaging (DTI) to indirectly detect Col1 fibers in breast lesions. We previously observed, in human MDA-MB-231 breast cancer xenografts engineered to fluoresce under hypoxia, relatively low amounts of Col1 fibers in fluorescent hypoxic regions. These xenograft tumors together with human breast cancer samples were used here to investigate the relationship between Col1 fibers, water diffusion and anisotropy, and hypoxia. Hypoxic low Col1 fiber containing regions showed decreased apparent diffusion coefficient (ADC) and fractional anisotropy (FA) compared to normoxic high Col1 fiber containing regions. Necrotic high Col1 fiber containing regions showed increased ADC with decreased FA values compared to normoxic viable high Col1 fiber regions that had increased ADC with increased FA values. A good agreement of ADC and FA patterns was observed between in vivo and ex vivo images. In human breast cancer specimens, ADC and FA decreased in low Col1 containing regions. Our data suggest that a decrease in ADC and FA values observed within a lesion could predict hypoxia, and a pattern of high ADC with low FA values could predict necrosis. Collectively the data identify the role of Col1 fibers in directed water movement and support expanding the evaluation of DTI parameters as surrogates for Col1 fiber patterns associated with specific tumor microenvironments as companion diagnostics and for staging.

Application of in vivo MR methods in the study of breast cancer metabolism

“…In addition to ADC, DTI provides a measure of diffusion anisotropy, namely fractional anisotropy (FA), which has been used to detect blockage of ducts and lobules in the breast. Blocked ducts increase the extracellular tortuosity and restriction of the movement of water, leading to reduced ADC in all directions and hence decreased FA . A correlation of FA with the prognostic factors such as ER, Ki67 labeling index, nuclear grade and intrinsic subtype of invasive breast cancer compared with ADC has also been reported .…”

Characterisation of fibrosis in chemically-induced rat mammary carcinomas using multi-modal endogenous contrast MRI on a 1.5T clinical platform

“…The data for the pseudo-diffusion volume fraction f, often considered related to perfusion, showed no correlation with the endothelial marker CD31, which is likely reflective of the inherent difficulty in reliably fitting IVIM data, but also the complexity of tumour perfusion [ 30 , 38 ]. In contrast, the non-significant correlation of f with necrosis (r=-0.607, p=0.0165) may suggest that f does not solely capture vascular fraction [ 23 ] and may be related to the degree of non-Gaussian diffusion introduced by the presence of collagen fibres [ 14 ]. The high CoV values associated with the pseudo-diffusion parameters, however, indicate that caution is required in interpreting these results.…”

“…Several MRI biomarkers have the potential to detect breast cancer fibrosis. The fibrous nature of collagen may increase the non-monoexponential contribution to the diffusion-weighted MRI (DWI) signal, arising from the propensity of water molecules to diffuse along the fibres, combined with reduced diffusivity from encountering more barriers to random diffusion, compared to surrounding tissue [ 12 – 14 ]. Increased macromolecular collagen fibre content may also yield a greater destruction of signal arising from MT MRI from off-resonance saturation [ 15 ], and the short-lived signal of collagen (T 2 *~500μs) may be detectable with ultrashort-echo time (UTE) sequences [ 16 ].…”

Cancer Metabolism and Tumor Heterogeneity: Imaging Perspectives Using MR Imaging and Spectroscopy

“…Diffusion tensor imaging (DTI) assesses changes in microstructural anisotropy from water diffusion by applying several directional diffusion gradients. Measuring fractional anisotropy (FA) from DTI can detect blockage of the ducts and lobules by cancer cells in the breast, which increases the extracellular tortuosity and restriction of the water movement, causing a reduction of the diffusion coefficients in all directions and consequently also decreasing the diffusion anisotropy [ 51 ]. DTI also predicts tumor infiltration and anisotropic pathways of cancer invasion [ 52 , 53 ], and FA maps are associated with the diagnostic utility in glioma [ 54 ], pancreatic cancer [ 55 ], breast cancer [ 56 ], prostate cancer [ 57 ], and hepatocellular carcinoma [ 58 ].…”