Compression of Pancreatic Tumor Blood Vessels by Hyaluronan Is Caused by Solid Stress and Not Interstitial Fluid Pressure

Tumor progression and response to treatment is determined in large part by the generation of mechanical stresses that stem from both the solid and the fluid phase of the tumor. Furthermore, elevated solid stress levels can regulate fluid stresses by compressing intratumoral blood and lymphatic vessels. Blood vessel compression reduces tumor perfusion, while compression of lymphatic vessels hinders the ability of the tumor to drain excessive fluid from its interstitial space contributing to the uniform elevation of the interstitial fluid pressure. Hypoperfusion and interstitial hypertension pose major barriers to the systemic administration of chemotherapeutic agents and nanomedicines to tumors, reducing treatment efficacies. Hypoperfusion can also create a hypoxic and acidic tumor microenvironment that promotes tumor progression and metastasis. Hence, alleviation of intratumoral solid stress levels can decompress tumor vessels and restore perfusion and interstitial fluid pressure. In this review, three major types of tissue level solid stresses involved in tumor growth, namely stress exerted externally on the tumor by the host tissue, swelling stress, and residual stress, are discussed separately and details are provided regarding their causes, magnitudes, and remedies. Subsequently, evidence of how stress-alleviating drugs could be used in combination with chemotherapy to improve treatment efficacy is presented, highlighting the potential of stress-alleviation strategies to enhance cancer therapy. Finally, a continuum-level, mathematical framework to incorporate these types of solid stress is outlined.

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Tumor Solid Stress: Assessment with MR Elastography under Compression of Patient-Derived Hepatocellular Carcinomas and Cholangiocarcinomas Xenografted in Mice

Cancers ◽

10.3390/cancers13081891 ◽

2021 ◽

Vol 13 (8) ◽

pp. 1891

Author(s):

Gwenaël Pagé ◽

Marion Tardieu ◽

Jean-Luc Gennisson ◽

Laurent Besret ◽

Philippe Garteiser ◽

...

Keyword(s):

Interstitial Fluid ◽

Liver Tumors ◽

Fluid Pressure ◽

Interstitial Fluid Pressure ◽

Collagen Content ◽

Mr Elastography ◽

Solid Stress ◽

Hepatocellular Carcinomas ◽

Malignant Liver Tumors ◽

Malignant Liver

Malignant tumors have abnormal biomechanical characteristics, including high viscoelasticity, solid stress, and interstitial fluid pressure. Magnetic resonance (MR) elastography is increasingly used to non-invasively assess tissue viscoelasticity. However, solid stress and interstitial fluid pressure measurements are performed with invasive methods. We studied the feasibility and potential role of MR elastography at basal state and under controlled compression in assessing altered biomechanical features of malignant liver tumors. MR elastography was performed in mice with patient-derived, subcutaneously xenografted hepatocellular carcinomas or cholangiocarcinomas to measure the basal viscoelasticity and the compression stiffening rate, which corresponds to the slope of elasticity versus applied compression. MR elastography measurements were correlated with invasive pressure measurements and digital histological readings. Significant differences in MR elastography parameters, pressure, and histological measurements were observed between tumor models. In multivariate analysis, collagen content and interstitial fluid pressure were determinants of basal viscoelasticity, whereas solid stress, in addition to collagen content, cellularity, and tumor type, was an independent determinant of compression stiffening rate. Compression stiffening rate had high AUC (0.87 ± 0.08) for determining elevated solid stress, whereas basal elasticity had high AUC for tumor collagen content (AUC: 0.86 ± 0.08). Our results suggest that MR elastography compression stiffening rate, in contrast to basal viscoelasticity, is a potential marker of solid stress in malignant liver tumors.

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Abstract LB-380: Apo2L/TRAIL reduces interstitial fluid pressure and enhances gemicitabine uptake in patient pancreatic tumor xenografts

10.1158/1538-7445.am10-lb-380 ◽

2010 ◽

Author(s):

Bonnie L. Hylander ◽

Arindam Sen ◽

Sarah Beachy ◽

John Gibbs ◽

Rose Pitoniak ◽

...

Keyword(s):

Interstitial Fluid ◽

Pancreatic Tumor ◽

Fluid Pressure ◽

Interstitial Fluid Pressure ◽

Tumor Xenografts

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The Mechanical Microenvironment in Breast Cancer

Cancers ◽

10.3390/cancers12061452 ◽

2020 ◽

Vol 12 (6) ◽

pp. 1452

Author(s):

Stephen J.P. Pratt ◽

Rachel M. Lee ◽

Stuart S. Martin

Keyword(s):

Breast Cancer ◽

Interstitial Fluid ◽

Fluid Pressure ◽

Normal Breast ◽

Interstitial Fluid Pressure ◽

Mechanical Stimuli ◽

Solid Stress ◽

Physical Cues

Mechanotransduction is the interpretation of physical cues by cells through mechanosensation mechanisms that elegantly translate mechanical stimuli into biochemical signaling pathways. While mechanical stress and their resulting cellular responses occur in normal physiologic contexts, there are a variety of cancer-associated physical cues present in the tumor microenvironment that are pathological in breast cancer. Mechanistic in vitro data and in vivo evidence currently support three mechanical stressors as mechanical modifiers in breast cancer that will be the focus of this review: stiffness, interstitial fluid pressure, and solid stress. Increases in stiffness, interstitial fluid pressure, and solid stress are thought to promote malignant phenotypes in normal breast epithelial cells, as well as exacerbate malignant phenotypes in breast cancer cells.

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Coevolution of Solid Stress and Interstitial Fluid Pressure in Tumors During Progression: Implications for Vascular Collapse

Cancer Research ◽

10.1158/0008-5472.can-12-4521 ◽

2013 ◽

Vol 73 (13) ◽

pp. 3833-3841 ◽

Cited By ~ 193

Author(s):

Triantafyllos Stylianopoulos ◽

John D. Martin ◽

Matija Snuderl ◽

Fotios Mpekris ◽

Saloni R. Jain ◽

...

Keyword(s):

Interstitial Fluid ◽

Fluid Pressure ◽

Interstitial Fluid Pressure ◽

Solid Stress

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Separation of Solid Stress From Interstitial Fluid Pressure in Pancreas Cancer Correlates With Collagen Area Fraction

Journal of Biomechanical Engineering ◽

10.1115/1.4036392 ◽

2017 ◽

Vol 139 (6) ◽

Cited By ~ 11

Author(s):

Michael D. Nieskoski ◽

Kayla Marra ◽

Jason R. Gunn ◽

Stephen C. Kanick ◽

Marvin M. Doyley ◽

...

Keyword(s):

Interstitial Fluid ◽

Cellular Proliferation ◽

Fluid Pressure ◽

Tumor Location ◽

Interstitial Fluid Pressure ◽

Tissue Pressure ◽

Solid Stress ◽

Tissue Matrix ◽

The Relationship ◽

Total Tissue

Elevated total tissue pressure (TTP) in pancreatic adenocarcinoma is often associated with stress applied by cellular proliferation and hydrated hyaluronic acid osmotic swelling; however, the causal roles of collagen in total tissue pressure have yet to be clearly measured. This study illustrates one direct correlation between total tissue pressure and increased deposition of collagen within the tissue matrix. This observation comes from a new modification to a conventional piezoelectric pressure catheter, used to independently separate and quantify total tissue pressure, solid stress (SS), and interstitial fluid pressure (IFP) within the same tumor location, thereby clarifying the relationship between these parameters. Additionally, total tissue pressure shows a direct correlation with verteporfin uptake, demonstrating the impediment of systemically delivered molecules with increased tissue hypertension.

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Control of interstitial fluid pressure: Role of [beta ]-integrins

Seminars in Nephrology ◽

10.1053/snep.2001.21646 ◽

2001 ◽

Vol 21 (3) ◽

pp. 222-230 ◽

Cited By ~ 42

Author(s):

Rolf K. Reed ◽

Ansgar Berg ◽

Eli-Anne B. Gjerde ◽

Kristofer Rubin

Keyword(s):

Interstitial Fluid ◽

Fluid Pressure ◽

Interstitial Fluid Pressure

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Dynamics of Interstitial Fluid Pressure in Extracellular Matrix Hydrogels in Microfluidic Devices

Journal of Biomechanical Engineering ◽

10.1115/1.4031020 ◽

2015 ◽

Vol 137 (9) ◽

Cited By ~ 5

Author(s):

Joe Tien ◽

Le Li ◽

Ozgur Ozsun ◽

Kamil L. Ekinci

Keyword(s):

Extracellular Matrix ◽

Pressure Distribution ◽

Interstitial Fluid ◽

Scaling Laws ◽

Fluid Pressure ◽

Interstitial Fluid Pressure ◽

External Loading ◽

Interstitial Pressure ◽

Time Resolved ◽

Long Time

In order to understand how interstitial fluid pressure and flow affect cell behavior, many studies use microfluidic approaches to apply externally controlled pressures to the boundary of a cell-containing gel. It is generally assumed that the resulting interstitial pressure distribution quickly reaches a steady-state, but this assumption has not been rigorously tested. Here, we demonstrate experimentally and computationally that the interstitial fluid pressure within an extracellular matrix gel in a microfluidic device can, in some cases, react with a long time delay to external loading. Remarkably, the source of this delay is the slight (∼100 nm in the cases examined here) distension of the walls of the device under pressure. Finite-element models show that the dynamics of interstitial pressure can be described as an instantaneous jump, followed by axial and transverse diffusion, until the steady pressure distribution is reached. The dynamics follow scaling laws that enable estimation of a gel's poroelastic constants from time-resolved measurements of interstitial fluid pressure.

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