Elastographic Assessment of Xenograft Pancreatic Tumors

Abstract

High tissue pressures prevent chemotherapeutics from reaching the parenchyma of pancreatic ductal adenocarcinoma, which makes it difficult to treat this aggressive disease. Researchers currently use invasive probes to monitor the effectiveness of pressure-reducing therapies, but this practice introduces additional complications. Here, we hypothesize that Young’s modulus is a good surrogate for tissue pressure because collagen density and hyaluoronic acid, the key features of the tumor microenvironment responsible for high tissue pressures, also affect modulus elastograms. To corroborate this hypothesis, we used model-based quasi-static elastography to assess how the Young’s modulus of naturally occurring AsPc-1 pancreatic tumors varies with collagen density and hyaluoronic acid concentration. We observed that Young’s moduli of orthotopically grown xenograft tumors were 6 kPa (p < 0.05) higher than that of their subcutaneously grown counterparts. We also observed a strong correlation between Young’s modulus and regions within the tumors with high collagen (R2 ≈ 0.8) and hyaluoronic acid (R2 ≈ 0.6) densities. These preliminary results indicate that hyaluronic acid and collagen density, features of the pancreatic ductal adenocarcinoma tumor microenvironment responsible for high tissue pressure, influence Young’s modulus.

Elastography Can Map the Local Inverse Relationship between Shear Modulus and Drug Delivery within the Pancreatic Ductal Adenocarcinoma Microenvironment

“…Figure 4A-D shows representative shear modulus elastograms and verteporfin uptake maps obtained from AsPC-1 and BxPC-3 tumors. For both tumor groups, shear modulus was heterogeneously distributed, which is consistent with our previous reported results (33). Fluorescence intensity was also heterogeneously distributed, which suggests that drug uptake in the tumors varied spatially ( Fig.…”

“…Thus, when hyaluronic acid absorbs water and swells, it exerts pressure on the collagen-rich ECM that produces an equal but opposing force in the localized region. The magnitude of the resulting pressure depends on the amount of water absorbed and the shear modulus of the ECM (i.e., the higher the shear modulus, the higher the localized pressure) as we have demonstrated previously (33). We expect the global stiffness of the ECM will increase when the number of hyaluronic acid pockets exceeds a critical value or when the localized hyaluronic acid pockets are located in areas of abnormally high collagen density.…”

“…5F and is due to differences in the analysis in the two reports. Specifically, in (33), local analysis of hyaluronic acid and shear modulus was performed, whereas in our current work the analysis was performed globally. Hyaluronic acid concentrates in localized regions within many cancerous tissues.…”

“…We then combined local tissue density (r) with shear wave speed (SWS) to get regional shear modulus estimates (m ¼ r  SWS 2 ). All tumors were surgically removed and encased in a 216-mm 3 gelatin block as described previously (33) to minimize the impact of respiration and cardiac motion on shear wave estimates (see Supplementary Fig. S1A and S1B).…”

Plane-Wave Imaging Improves Single-Track Location Shear Wave Elasticity Imaging

“…12 , 13 , Table III ). The overall low CNR e of pancreatic tumors was caused by inherent tumor heterogeneity [31]. …”