Collagen Complexity Spatially Defines Microregions of Total Tissue Pressure in Pancreatic Cancer

Abstract

The poor efficacy of systemic cancer therapeutics in pancreatic ductal adenocarcinoma (PDAC) is partly attributed to deposition of collagen and hyaluronan, leading to interstitial hypertension collapsing blood and lymphatic vessels, limiting drug delivery. The intrinsic micro-regional interactions between hyaluronic acid (HA), collagen and the spatial origins of mechanical stresses that close off blood vessels was investigated here. Multiple localized pressure measurements were analyzed with spatially-matched histochemical images of HA, collagen and vessel perfusion. HA is known to swell, fitting a linear elastic model with total tissue pressure (TTP) increasing above interstitial fluid pressure (IFP) directly with collagen content. However, local TTP appears to originate from collagen area fraction, as well as increased its entropy and fractal dimension, and morphologically appears to be maximized when HA regions are encapsulated by collagen. TTP was inversely correlated with vascular patency and verteporfin uptake, suggesting interstitial hypertension results in vascular compression and decreased molecular delivery in PDAC. Collagenase injection led to acute decreases in total tissue pressure and increased drug perfusion. Large microscopic variations in collagen distributions within PDAC leads to microregional TPP values that vary on the hundred micron distance scale, causing micro-heterogeneous limitations in molecular perfusion, and narrows viable treatment regimes for systemically delivered therapeutics.

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

“…4E). The fluorescence intensities of AsPC-1 tumors were consistently higher than those obtained from BxPC-3 tumors, a trend that was consistent with our previous study performed with a pressure probe (26).…”

“…The fluorescence slide scanner was used to image each section, and a three-step color segmentation process (see Supplementary Fig. S3) was implemented in MATLAB (v2016b, The Mathworks Inc.) to estimate collagen density from the Masson trichrome stained images (26). Collagen density (%) was calculated by dividing the number of blue collagen pixels by the total number of pixels in the tumor.…”

“…Researchers have also used a wick-in-needle pressure catheter to predict the outcome of patients with cervical cancer (25). Despite these important preclinical and clinical results, the invasive nature of pressure catheters and their inability to measure the spatial variation of tissue pressure (23,26) have limited their clinical use. Elastography could overcome these limitations by providing a surrogate measure to tissue pressure.…”

Optical elastography and tissue biomechanics

“…The acquired tumor stiffness data were found to be strongly correlated with collagen content at regional levels for two different pancreatic tumor cell lines, which highlight distinctive collagen patterns. 14 Light scattering can be used in a different manner to get local viscoelastic properties of tissues. Dr. Seemantini Nadkarni's group at Harvard Medical School, Massachusetts, USA, is using laser speckle imaging, 15 which they developed for noninvasive evaluation of tissue stiffness.…”

Computer-aided assessment of the extra-cellular matrix during pancreatic carcinogenesis: a pilot study

“…This framework represents the bulk of the cancer mass [22]. Interactions between the neoplastic and non-neoplastic cells and ECM have been proposed to stimulate the extensive desmoplastic reaction [23][24][25][26]. Although a critical role of stroma in pancreatic carcinogenesis had been recognized for many years, only recently the study of this crucial tissue component has gained a considerable interest and has been considered in clinical practice [14,27].…”