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

Christopher C. Dufort, Kathleen E. DelGiorno, Markus A. Carlson, Ryan J. Osgood, Chunmei Zhao, Zhongdong Huang, Curtis B. Thompson, Robert J. Connor, Christopher D. Thanos, J. Scott Brockenbrough, Paolo P. Provenzano, Gregory I. Frost, H. Michael Shepard, Sunil R. Hingorani

Research output: Contribution to journalArticlepeer-review

62 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)2106-2119
Number of pages14
JournalBiophysical journal
Issue number9
StatePublished - May 10 2016
Externally publishedYes

Bibliographical note

Funding Information:
This work was supported by National Institutes of Health National Cancer Institute grants (CA161112 to S.R.H. and CA152249 to S.R.H and P.P.P.), Lustgarten Foundation (S.R.H.), and the Giles W. and Elise G. Mead Foundation (S.R.H.).

Publisher Copyright:
© 2016 Biophysical Society.


Dive into the research topics of 'Interstitial Pressure in Pancreatic Ductal Adenocarcinoma Is Dominated by a Gel-Fluid Phase'. Together they form a unique fingerprint.

Cite this