Hyaluronan impairs vascular function and drug delivery in a mouse model of pancreatic cancer
Open accessAbstract
Objective: Pancreatic ductal adenocarcinoma (PDA) is characterised by stromal desmoplasia and vascular dysfunction, which critically impair drug delivery. This study examines the role of an abundant extracellular matrix component, the megadalton glycosaminoglycan hyaluronan (HA), as a novel therapeutic target in PDA. Methods: Using a genetically engineered mouse model of PDA, the authors enzymatically depleted HA by a clinically formulated PEGylated human recombinant PH20 hyaluronidase (PEGPH20) and examined tumour perfusion, vascular permeability and drug delivery. The preclinical utility of PEGPH20 in combination with gemcitabine was assessed by short-term and survival studies. Results: PEGPH20 rapidly and sustainably depleted HA, inducing the re-expansion of PDA blood vessels and increasing the intratumoral delivery of two chemotherapeutic agents, doxorubicin and gemcitabine. Moreover, PEGPH20 triggered fenestrations and interendothelial junctional gaps in PDA tumour endothelia and promoted a tumour-specific increase in macromolecular permeability. Finally, combination therapy with PEGPH20 and gemcitabine led to inhibition of PDA tumour growth and prolonged survival over gemcitabine monotherapy, suggesting immediate clinical utility. Conclusions: The authors demonstrate that HA impedes the intratumoral vasculature in PDA and propose that its enzymatic depletion be explored as a means to improve drug delivery and response in patients with pancreatic cancer.
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The high-density stroma of PDAC, comprised of CAFs, adipocytes, immune cells, ECs, nerve cells, PSCs, and ECM components like collagen and hyaluronic acid, constitutes up to 90% of tumor volume.
“The high-density stroma of PDAC, comprised of cancer-associated fibroblasts (CAFs), adipocytes, immune cells, ECs, nerve cells, pancreatic stellate cells (PSCs), and extracellular matrix components (ECM) like collagen and hyaluronic acid, constitutes up to 90% of the tumor volume (Jacobetz et al., 2013; Poh and Ernst, 2021; Wu et al., 2021).”
From Microphysiological systems as models for immunologically ‘cold’ tumors (2024) · cites this paper as Jacobetz et al., 2013
The Results section ('HA accumulates in PDA'; page unavailable) places hyaluronan predominantly in PDAC’s desmoplastic stroma, and the paper describes extensive extracellular-matrix deposits and tumour–fibroblast interactions. It does not establish the full list of stromal cell types or that stroma constitutes up to 90% of tumour volume. The 90% in Table 1 is the proportion of sampled PDAC cases with positive hyaluronan staining, not a volume measurement. (LLM, conf=0.88)
Experimental — accuracy not yet measuredPDAC is marked by poor vascularization and abnormal leaky blood vessels, creating hypoxic conditions and elevated interstitial pressure.
“Additionally, PDAC is marked by poor vascularization and abnormal leaky blood vessels, creating hypoxic conditions and elevated interstitial pressure (Jacobetz et al., 2013).”
From Microphysiological systems as models for immunologically ‘cold’ tumors (2024) · cites this paper as Jacobetz et al., 2013
The 'What is already known' section describes PDA as hypovascular, and the Introduction links poor tumour perfusion to interstitial hypertension. But the Results and Discussion report that untreated KPC tumour vessels have intact junctions and little leakage; leakiness increased after treatment. The cited passages do not establish the claimed hypoxic conditions or the proposed causal chain. (LLM, conf=0.88)
Experimental — accuracy not yet measuredCAF populations and their organization of tumor architecture vary across different tumor regions, creating sub-tumor microenvironments within patients.
“CAF populations and their organization of tumor architecture can vary across different regions of tumors creating “sub-tumor microenvironments” within patients156”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [156]
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- Authors
- Jacobetz, M. A., Chan, D. S., Neesse, A., Bapiro, T. E., Cook, N., Frese, K. K., Feig, C., Nakagawa, T., Caldwell, M. E., Zecchini, H. I., Lolkema, M. P., Jiang, P., Kultti, A., Thompson, C. B., Maneval, D. C., Jodrell, D. I., Frost, G. I., Shepard, H. M., Skepper, J. N., & Tuveson, D. A.
- Affiliations
- Cancer Research UK (GB)
- Halozyme Therapeutics (United States) (US)
- University of Cambridge (GB)
- Corresponding author
- Tuveson, David A
- ORCID
- Venue
- Gut
- Publisher
- BMJ
- Published
- 2012-03-30
- Volume
- 62
- Issue
- 1
- Pages
- 112-120
- ISSN
- 0017-5749 (ISSN-L)
- 1468-3288
- PMC
- PMC3551211
- OpenAlex
- W2130464657
- Cited by
- 1,120
- References
- 46
- Citations by year
- 2026: 70 · 2025: 70 · 2024: 66 · 2023: 82 · 2022: 93 · 2021: 115 · 2020: 88 · 2019: 103 · 2018: 77 · 2017: 85 · 2016: 81 · 2015: 61 · 2014: 57 · 2013: 48 · 2012: 22
- FWCI
- 29.76
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc
- Locations
- Gut (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Research Explorer (The University of Manchester) (publishedVersion)
- Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (acceptedVersion)
- HighWire Press Open Archive (submittedVersion)
- Apollo (University of Cambridge) (submittedVersion, cc-by-nc-nd)
- Apollo
- Funders
- Li Ka Shing Foundation
- Halozyme
- Cancer Research UK (15678)
- National Institute for Health and Care Research
- University of Cambridge
- European Commission (256974)
- Ministerio de Economía y Competitividad
- Deutsche Krebshilfe
- Hutchison Whampoa Limited
- NIHR Cambridge Biomedical Research Centre
- FP7 Health
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Proteoglycans and glycosaminoglycans research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Medicine › Hydrogels: synthesis, properties, applications
- Keywords
- hyaluronic acid, pancreatic ductal adenocarcinoma, PEGPH20, hyaluronidase, tumor perfusion, vascular permeability, drug delivery, gemcitabine, doxorubicin, tumor angiogenesis, extracellular matrix, combination therapy
- MeSH terms
- Gemcitabine, Animals, Antineoplastic Agents, Antineoplastic Combined Chemotherapy Protocols, Deoxycytidine, Doxorubicin, Hyaluronic Acid, Hyaluronoglucosaminidase, Immunohistochemistry, Mice, Transgenic, Pancreatic Neoplasms, Recombinant Proteins, Biomarkers, Tumor, Cell Adhesion Molecules, Drug Delivery Systems, Treatment Outcome, Drug Resistance, Neoplasm, Carcinoma, Pancreatic Ductal, Tissue Array Analysis, Mice, Kaplan-Meier Estimate
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