title: Interstitial Pressure in Pancreatic Ductal Adenocarcinoma Is Dominated by a Gel-Fluid Phase.
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.
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Christopher C
authors.initials: CC
authors.lastname: DuFort
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Kathleen E
authors.initials: KE
authors.lastname: DelGiorno
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Markus A
authors.initials: MA
authors.lastname: Carlson
authors.affiliation: Halozyme Therapeutics, Inc., San Diego, California.
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Osgood
authors.affiliation: Halozyme Therapeutics, Inc., San Diego, California.
authors.forename: Chunmei
authors.initials: C
authors.lastname: Zhao
authors.affiliation: Halozyme Therapeutics, Inc., San Diego, California.
authors.forename: Zhongdong
authors.initials: Z
authors.lastname: Huang
authors.affiliation: Halozyme Therapeutics, Inc., San Diego, California.
authors.forename: Curtis B
authors.initials: CB
authors.lastname: Thompson
authors.affiliation: Halozyme Therapeutics, Inc., San Diego, California.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Connor
authors.affiliation: Halozyme Therapeutics, Inc., San Diego, California.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Thanos
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: J
authors.initials: J
authors.lastname: Scott Brockenbrough
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Paolo P
authors.initials: PP
authors.lastname: Provenzano
authors.affiliation: Halozyme Therapeutics, Inc., San Diego, California.
authors.forename: Gregory I
authors.initials: GI
authors.lastname: Frost
authors.affiliation: Halozyme Therapeutics, Inc., San Diego, California.
authors.forename: H
authors.initials: H
authors.lastname: Michael Shepard
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Division of Medical Oncology, University of Washington School of Medicine, Seattle, Washington. Electronic address: srh@fhcrc.org.
authors.forename: Sunil R
authors.initials: SR
authors.lastname: Hingorani
mesh_terms: D000230:Adenocarcinoma / Q000473:pathology*; D000818:Animals; D045604:Extracellular Fluid / Q000187:drug effects / Q000378:metabolism*; D006820:Hyaluronic Acid / Q000494:pharmacology; D006874:Hydrostatic Pressure; D051379:Mice; D041681:NIH 3T3 Cells; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D014783:Viscosity
chemical_list: D006820:Hyaluronic Acid