Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma
Open accessAbstract
Pancreatic ductal adenocarcinomas (PDAs) are characterized by a robust fibroinflammatory response. We show here that this desmoplastic reaction generates inordinately high interstitial fluid pressures (IFPs), exceeding those previously measured or theorized for solid tumors, and induces vascular collapse, while presenting substantial barriers to perfusion, diffusion, and convection of small molecule therapeutics. We identify hyaluronan, or hyaluronic acid (HA), as the primary matrix determinant of these barriers and show that systemic administration of an enzymatic agent can ablate stromal HA from autochthonous murine PDA, normalize IFP, and re-expand the microvasculature. In combination with the standard chemotherapeutic, gemcitabine, the treatment permanently remodels the tumor microenvironment and consistently achieves objective tumor responses, resulting in a near doubling of overall survival.
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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 [103]
The Results section, “Enzymatic targeting of stromal HA restores tumor IFP and functional perfusion” (page not supplied), reports that high interstitial fluid pressure appears to collapse vessels in pancreatic ductal adenocarcinoma and that drug penetration is limited. The passages do not establish the claimed sequence from vessel collapse to hypoxia to more aggressive cancer phenotypes. (LLM, conf=0.87)
Experimental — accuracy not yet measuredFibroblasts are the most abundant cell type in the PDAC tumor microenvironment and are largely responsible for extracellular matrix deposition that drives characteristic physiological properties of PDAC.
“Fibroblasts represent the most abundant cell type in the TME and are largely responsible for the deposition of the extracellular matrix driving the characteristic physiological properties of PDAC140”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [140]
Initial preclinical data in mouse models suggested that hyaluronidase combined with chemotherapy showed promise.
“Initial preclinical data in mouse models suggested that use of hyaluronidase combined with chemotherapy showed great promise140,157”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [140]
Hyaluronic acid is a glycosaminoglycan polymer released predominantly by CAFs that retains water and promotes the high interstitial fluid pressure characteristic of pancreatic tumors.
“Hyaluronic acid is a glycosaminoglycan polymer, thought to be released by predominantly by CAFs, that avidly retains water and promotes the characteristically high interstitial fluid pressure found in pancreatic tumors140”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [140]
CAFs are largely responsible for deposition of the dense extracellular matrix in PDAC, which consists largely of collagen and hyaluronic acid.
“CAFs are largely responsible for deposition of the dense extracellular matrix found in PDAC, largely consisting of collagen and hyaluronic acid.”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [140]
Preclinical work proposed that systemic therapy would work better if it could penetrate the dense fibrosis and high interstitial pressure generated by CAFs in pancreatic tumors.
“One notable example of an ultimately unsuccessful but informative clinical paradigm came by way of a series of pre-clinical studies proposing the efficacy of systemic therapy would improve through efforts to penetrate the dense fibrosis and high interstitial pressure promoted by the CAFs in pancreatic tumors140,158.”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [140]
Systemic administration of PEGPH20 reduces stromal hyaluronic acid, normalizes interstitial fluid pressures, re-expands the microvasculature and leads to tumor suppression in pancreatic ductal adenocarcinomas murine models.
“Moreover, Provenzano et al. found that systemic administration of pegvorhyaluronidase alfa (PEGPH20), an enzyme against hyaluronic acid, reduced stromal hyaluronic acid, normalized interstitial fluid pressures, re‐expanded the microvasculature and led to tumor suppression in pancreatic ductal adenocarcinomas murine models [41].”
From Tumor microenvironment signaling and therapeutics in cancer progression (2023) · cites this paper as [41]
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- Authors
- Provenzano, P. P., Cuevas, C., Chang, A. E., Goel, V. K., Von Hoff, D. D., & Hingorani, S. R.
- Affiliations
- Fred Hutch Cancer Center (US)
- University of Washington (US)
- Corresponding author
- Hingorani, Sunil R.
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2012-03
- Volume
- 21
- Issue
- 3
- Pages
- 418-429
- ISSN
- 1535-6108 (ISSN-L)
- PMC
- PMC3371414
- OpenAlex
- W2055091294
- Cited by
- 2,195
- References
- 55
- Citations by year
- 2026: 187 · 2025: 161 · 2024: 123 · 2023: 140 · 2022: 174 · 2021: 217 · 2020: 169 · 2019: 161 · 2018: 152 · 2017: 165 · 2016: 168 · 2015: 127 · 2014: 120 · 2013: 93 · 2012: 35
- FWCI
- 59.36
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 994 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Giles W. and Elise G. Mead Foundation
- National Cancer Institute (CA109552, CA114028, CA152249, 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 › Cell Biology › Proteoglycans and glycosaminoglycans research
- Keywords
- pancreatic ductal adenocarcinoma, tumor stroma, hyaluronic acid, hyaluronidase, interstitial fluid pressure, desmoplasia, tumor microenvironment remodeling, gemcitabine, tumor perfusion
- MeSH terms
- Gemcitabine, Adenocarcinoma, Animals, Antineoplastic Combined Chemotherapy Protocols, Deoxycytidine, Drug Evaluation, Preclinical, Hyaluronic Acid, Hyaluronoglucosaminidase, Pancreatic Neoplasms, Polyethylene Glycols, Cell Adhesion Molecules, Stromal Cells, Carcinoma, Pancreatic Ductal, Animals, Genetically Modified, Extracellular Fluid, Mice, Microvessels, Tumor Microenvironment
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