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Cited by 144Pancreatic and Hepatic Oncology ResearchCellular Mechanics and InteractionsHydrogels: synthesis, properties, applications

Mounting Pressure in the Microenvironment: Fluids, Solids, and Cells in Pancreatic Ductal Adenocarcinoma

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DuFort, Christopher C., DelGiorno, Kathleen E., Hingorani, Sunil R.·2016·Gastroenterology
DOI 10.1053/j.gastro.2016.03.040PMC PMC4957812
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Abstract

The microenvironment influences the pathogenesis of solid tumors and plays an outsized role in some. Our understanding of the stromal response to cancers, particularly pancreatic ductal adenocarcinoma, has evolved from that of host defense to tumor offense. We know that most, although not all, of the factors and processes in the microenvironment support tumor epithelial cells. This reappraisal of the roles of stromal elements has also revealed potential vulnerabilities and therapeutic opportunities to exploit. The high concentration in the stroma of the glycosaminoglycan hyaluronan, together with the large gel-fluid phase and pressures it generates, were recently identified as primary sources of treatment resistance in pancreas cancer. Whereas the relatively minor role of free interstitial fluid in the fluid mechanics and perfusion of tumors has been long appreciated, the less mobile, gel-fluid phase has been largely ignored for historical and technical reasons. The inability of classic methods of fluid pressure measurement to capture the gel-fluid phase, together with a dependence on xenograft and allograft systems that inaccurately model tumor vascular biology, has led to an undue emphasis on the role of free fluid in impeding perfusion and drug delivery and an almost complete oversight of the predominant role of the gel-fluid phase. We propose that a hyaluronan-rich, relatively immobile gel-fluid phase induces vascular collapse and hypoperfusion as a primary mechanism of treatment resistance in pancreas cancers. Similar properties may be operant in other solid tumors as well, so revisiting and characterizing fluid mechanics with modern techniques in other autochthonous cancers may be warranted.

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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 [105]

    The Clinical Implications section says excessive gel-fluid pressure can compress tumor vessels and block drug perfusion, supporting the vessel-collapse and reduced-drug-delivery parts of the claim. The passages found do not establish the intervening claim that this causes hypoxia and thereby promotes more aggressive cancer phenotypes. The Solids and Cells section instead discusses more aggressive tumors after stromal depletion and increased vascularity, a different mechanism; page numbers were not available in our copy. (LLM, conf=0.85)

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Cited by

Sorted by citations

Authors
DuFort, C. C., DelGiorno, K. E., & Hingorani, S. R.
Affiliations
  • Fred Hutch Cancer Center (US)
  • University of Washington (US)
Corresponding author
Hingorani, Sunil R.
ORCID
Venue
Gastroenterology
Publisher
Elsevier BV
Published
2016-06
Volume
150
Issue
7
Pages
1545-1557.e2
ISSN
0016-5085 (ISSN-L)
DOI
10.1053/j.gastro.2016.03.040
PMC
PMC4957812
OpenAlex
W2315129148
Cited by
144
References
6
Citations by year
2026: 11 · 2025: 12 · 2024: 20 · 2023: 13 · 2022: 14 · 2021: 22 · 2020: 19 · 2019: 9 · 2018: 10 · 2017: 11 · 2016: 2
FWCI
1.04
Type
journal article
Language
en
Open access
Licence
Locations
  • Gastroenterology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Lustgarten Foundation (CA161112)
  • Giles W. and Elise G. Mead Foundation (CA161112)
  • National Institutes of Health (CA161112)
Topics
  • Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Medicine › Hydrogels: synthesis, properties, applications
Keywords
pancreatic ductal adenocarcinoma, tumor microenvironment, hyaluronic acid, interstitial fluid pressure, tumor stroma, treatment resistance, tumor perfusion, vascular collapse, hypoperfusion, drug delivery
MeSH terms
Adenoma, Humans, Pancreatic Neoplasms, Pressure, Stromal Cells, Carcinoma, Pancreatic Ductal, Tumor Microenvironment

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