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Cited by 171Pancreatic and Hepatic Oncology ResearchHydrogels: synthesis, properties, applicationsProteoglycans and glycosaminoglycans research

Interstitial Pressure in Pancreatic Ductal Adenocarcinoma Is Dominated by a Gel-Fluid Phase

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DuFort, Christopher C., DelGiorno, Kathleen E., Carlson, Markus A., Osgood, Ryan J., Zhao, Chunmei, Huang, Zhongdong, Thompson, Curtis B., Connor, Robert J. +6 more·2016·Biophysical Journal
DOI 10.1016/j.bpj.2016.03.040PMC PMC4939548
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Abstract

Elevated interstitial fluid pressure can present a substantial barrier to drug delivery in solid tumors. This is particularly true of pancreatic ductal adenocarcinoma, a highly lethal disease characterized by a robust fibroinflammatory response, widespread vascular collapse, and hypoperfusion that together serve as primary mechanisms of treatment resistance. Free-fluid pressures, however, are relatively low in pancreatic ductal adenocarcinoma and cannot account for the vascular collapse. Indeed, we have shown that the overexpression and deposition in the interstitium of high-molecular-weight hyaluronan (HA) is principally responsible for generating pressures that can reach 100 mmHg through the creation of a large gel-fluid phase. By interrogating a variety of tissues, tumor types, and experimental model systems, we show that an HA-dependent fluid phase contributes substantially to pressures in many solid tumors and has been largely unappreciated heretofore. We investigated the relative contributions of both freely mobile fluid and gel fluid to interstitial fluid pressure by performing simultaneous, real-time fluid-pressure measurements with both the classical wick-in-needle method (to estimate free-fluid pressure) and a piezoelectric pressure catheter transducer (which is capable of capturing pressures associated with either phase). We demonstrate further that systemic treatment with pegylated recombinant hyaluronidase (PEGPH20) depletes interstitial HA and eliminates the gel-fluid phase. This significantly reduces interstitial pressures and leaves primarily free fluid behind, relieving the barrier to drug delivery. These findings argue that quantifying the contributions of free- and gel-fluid phases to hydraulically transmitted pressures in a given cancer will be essential to designing the most appropriate and effective strategies to overcome this important and frequently underestimated resistance mechanism.

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  • Increased mechanical stress can collapse blood vessels, leading to hypoxia, thereby promoting more aggressive cancer phenotypes and reducing drug delivery.

    “Increased mechanical stress can collapse blood vessels, leading to hypoxia, thereby promoting more aggressive cancer phenotypes, and reducing drug delivery89,100–105.”

    From A framework for advancing our understanding of cancer-associated fibroblasts (2020) · cites this paper as [104]

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Authors
DuFort, C. C., DelGiorno, K. E., Carlson, M. A., Osgood, R. J., Zhao, C., Huang, Z., Thompson, C. B., Connor, R. J., Thanos, C. D., Scott Brockenbrough, J., Provenzano, P. P., Frost, G. I., Michael Shepard, H., & Hingorani, S. R.
Affiliations
  • Fred Hutch Cancer Center (US)
  • Halozyme Therapeutics (United States) (US)
  • University of Washington (US)
Corresponding author
Hingorani, Sunil R.
ORCID
Venue
Biophysical Journal
Publisher
Elsevier BV
Published
2016-05
Volume
110
Issue
9
Pages
2106-2119
ISSN
0006-3495 (ISSN-L)
DOI
10.1016/j.bpj.2016.03.040
PMC
PMC4939548
OpenAlex
W2376800108
Cited by
171
References
81
Citations by year
2026: 14 · 2025: 13 · 2024: 14 · 2023: 19 · 2022: 24 · 2021: 22 · 2020: 29 · 2019: 11 · 2018: 8 · 2017: 15 · 2016: 1
FWCI
6.29
Type
journal article
Language
en
Open access
Licence
Locations
  • Biophysical Journal (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Cancer Institute (R21CA152249, R01CA161112)
Topics
  • Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Medicine › Hydrogels: synthesis, properties, applications
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Proteoglycans and glycosaminoglycans research
Keywords
interstitial fluid pressure, pancreatic ductal adenocarcinoma, hyaluronic acid, tumor microenvironment, drug delivery barriers, PEGPH20, hyaluronidase, tumor fibrosis, vascular collapse
MeSH terms
Adenocarcinoma, Animals, Hyaluronic Acid, Hydrostatic Pressure, Pancreatic Neoplasms, Viscosity, NIH 3T3 Cells, Extracellular Fluid, Mice

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