Enzymatic Depletion of Tumor Hyaluronan Induces Antitumor Responses in Preclinical Animal Models
Published version of a preprint
Abstract
Hyaluronan (HA) is a glycosaminoglycan polymer that often accumulates in malignancy. Megadalton complexes of HA with proteoglycans create a hydrated connective tissue matrix, which may play an important role in tumor stroma formation. Through its colloid osmotic effects, HA complexes contribute to tumor interstitial fluid pressure, limiting the effect of therapeutic molecules on malignant cells. The therapeutic potential of enzymatic remodeling of the tumor microenvironment through HA depletion was initially investigated using a recombinant human HA-degrading enzyme, rHuPH20, which removed HA-dependent tumor cell extracellular matrices in vitro. However, rHuPH20 showed a short serum half-life (t(1/2) < 3 minutes), making depletion of tumor HA in vivo impractical. A pegylated variant of rHuPH20, PEGPH20, was therefore evaluated. Pegylation improved serum half-life (t(1/2) = 10.3 hours), making it feasible to probe the effects of sustained HA depletion on tumor physiology. In high-HA prostate PC3 tumors, i.v. administration of PEGPH20 depleted tumor HA, decreased tumor interstitial fluid pressure by 84%, decreased water content by 7%, decompressed tumor vessels, and increased tumor vascular area >3-fold. Following repeat PEGPH20 administration, tumor growth was significantly inhibited (tumor growth inhibition, 70%). Furthermore, PEGPH20 enhanced both docetaxel and liposomal doxorubicin activity in PC3 tumors (P < 0.05) but did not significantly improve the activity of docetaxel in low-HA prostate DU145 tumors. The ability of PEGPH20 to enhance chemotherapy efficacy is likely due to increased drug perfusion combined with other tumor structural changes. These results support enzymatic remodeling of the tumor stroma with PEGPH20 to treat tumors characterized by the accumulation of HA.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
HA-degradable PEGPH20 in integration with gemcitabine demonstrated enhanced therapeutic effects in animal models.
“HA-degradable PEGPH20 in integration with gemcitabine has demonstrated enhanced therapeutic effects in animal models [56,57].”
From Approaches to Improve EPR-Based Drug Delivery for Cancer Therapy and Diagnosis (2023) · cites this paper as [56]
Cites
Olive, K. P., Jacobetz, M. A., Davidson, C. J., Gopinathan, A., McIntyre, D., Honess, D., Madhu, B., Goldgraben, M. A., Caldwell, M. E., Allard, D., et al. (2009) · Science · doi:10.1126/science.1171362 · Cited by 3,170 · see citing works
Drug penetration in solid tumours
Minchinton, A. I., & Tannock, I. F. (2006) · Nature reviews. Cancer · doi:10.1038/nrc1893 · Cited by 2,805 · see citing works
High Interstitial Fluid Pressure - an Obstacle in Cancer Therapy
Heldin, C.-H., Rubin, K., Pietras, K., & Östman, A. (2004) · Nature reviews. Cancer · doi:10.1038/nrc1456 · Cited by 2,222 · see citing works
Willett, C. G., Boucher, Y., di Tomaso, E., Duda, D. G., Munn, L. L., Tong, R. T., Chung, D. C., Sahani, D. V., Kalva, S. P., Kozin, S. V., et al. (2004) · Nature Medicine · doi:10.1038/nm988 · Cited by 1,966 · see citing works
Hallmarks of cancer: Interactions with the tumor stroma
Pietras, K., & Östman, A. (2010) · Experimental Cell Research · doi:10.1016/j.yexcr.2010.02.045 · Cited by 1,137 · see citing works
Hyaluronan‐binding proteins in development, tissue homeostasis, and disease
Knudson, C. B., & Knudson, W. (1993) · The FASEB Journal · doi:10.1096/fasebj.7.13.7691670 · Cited by 651 · see citing works
The six hyaluronidase-like genes in the human and mouse genomes
Csoka, A. B., Frost, G. I., & Stern, R. (2001) · Matrix Biology · doi:10.1016/s0945-053x(01)00172-x · Cited by 590 · see citing works
Self-citationVEGF as a Therapeutic Target in Cancer
Ferrara, N. (2005) · Oncology · doi:10.1159/000088479 · Cited by 577 · see citing works
Auvinen, P., Tammi, R., Parkkinen, J. J., Tammi, M., Ågren, U. M., Johansson, R. T., Hirvikoski, P. P., Eskelinen, M. J., & Kosma, V. (2000) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)64757-8 · Cited by 494 · see citing works
Godár, S., Ince, T. A., Bell, G. W., Feldser, D. M., Donaher, J. L., Bergh, J. C. S., Liu, A. Y., Miu, K., Watnick, R. S., Reinhardt, F., et al. (2008) · Cell · doi:10.1016/j.cell.2008.06.006 · Cited by 455 · see citing works
Mammalian Hyaluronan Synthases
Itano, N., & Kimata, K. (2002) · IUBMB Life · doi:10.1080/15216540214929 · Cited by 428 · see citing works
Tumor cell-associated hyaluronan as an unfavorable prognostic factor in colorectal cancer.
Ropponen, K. M., Tammi, M., Parkkinen, J. J., Eskelinen, M., Tammi, R., Lipponen, P., Ågren, U. M., ALHAVA, E. M., & Kosma, V. (1998) · PubMed · Cited by 327 · see citing works
High levels of stromal hyaluronan predict poor disease outcome in epithelial ovarian cancer.
Anttila, M., Tammi, R., Tammi, M., Syrjänen, K. J., Saarikoski, S., & Kosma, V. (2000) · PubMed · Cited by 327 · see citing works
Kamoun, W. S., Ley, C. D., Farrar, C. T., Duyverman, A. M., Lahdenranta, J., Lacorre, D. A., Batchelor, T. T., di Tomaso, E., Duda, D. G., Munn, L. L., et al. (2009) · Journal of Clinical Oncology · doi:10.1200/jco.2008.19.9356 · Cited by 309 · see citing works
Vecchi, A., Garlanda, C., Lampugnani, M. G., Resnati, M., Matteucci, C., Stoppacciaro, A., Schnürch, H., Risau, W., Ruco, L., & Mantovani, A. (1994) · PubMed · Cited by 301 · see citing works
A recombinant human enzyme for enhanced interstitial transport of therapeutics
Bookbinder, L. H., Hofer, A., Haller, M. F., Zepeda, M. L., Keller, G.-A., Lim, J. E., Edgington, T. S., Shepard, H. M., Patton, J. S., & Frost, G. I. (2006) · Journal of Controlled Release · doi:10.1016/j.jconrel.2006.05.027 · Cited by 282 · see citing works
Self-citationTammi, R., Kultti, A. H., Kosma, V., Pirinen, R. T., Auvinen, P., & Tammi, M. (2008) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2008.03.005 · Cited by 273 · see citing works
Purification, Cloning, and Expression of Human Plasma Hyaluronidase
Frost, G. I., Csóka, T. B., Wong, T., & Stern, R. S. (1997) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1997.6773 · Cited by 236 · see citing works
Self-citationEikenes, L., Tari, M., Tufto, I., Bruland, Ø. S., & de Lange Davies, C. (2005) · British Journal of Cancer · doi:10.1038/sj.bjc.6602626 · Cited by 221 · see citing works
Lokeshwar, V. B., & Selzer, M. G. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m003084200 · Cited by 213 · see citing works
VEGF inhibitors in the treatment of cerebral edema in patients with brain cancer
Gerstner, E. R., Duda, D. G., di Tomaso, E., Ryg, P. A., Loeffler, J. S., Sorensen, A. G., Ivy, P. S., Jain, R. K., & Batchelor, T. T. (2009) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2009.14 · Cited by 208 · see citing works
Two-photon fluorescence correlation microscopy reveals the two-phase nature of transport in tumors
Alexandrakis, G., Brown, E. B., Tong, R. T., McKee, T. D., Campbell, R. B., Boucher, Y., & Jain, R. K. (2004) · Nature Medicine · doi:10.1038/nm981 · Cited by 178 · see citing works
The dual functions of GPI-anchored PH-20: hyaluronidase and intracellular signaling
Cherr, G. N., Yudin, A. I., & Overstreet, J. W. (2001) · Matrix Biology · doi:10.1016/s0945-053x(01)00171-8 · Cited by 177 · see citing works
Theocharis, A. D., Tsara, M. E., Papageorgacopoulou, N., Karavias, D. D., & Theocharis, D. A. (2000) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/s0925-4439(00)00051-x · Cited by 169 · see citing works
Lipponen, P., Aaltomaa, S. H., Tammi, R., Tammi, M., Ågren, U. M., & Kosma, V. (2001) · European Journal of Cancer · doi:10.1016/s0959-8049(00)00448-2 · Cited by 168 · see citing works
Setälä, L. P., Tammi, M., Tammi, R., Eskelinen, M. J., Lipponen, P., Ågren, U. M., Parkkinen, J. J., ALHAVA, E. M., & Kosma, V. (1999) · British Journal of Cancer · doi:10.1038/sj.bjc.6690180 · Cited by 159 · see citing works
Higashi, Y., Kanekura, T., & Kanzaki, T. (2000) · International Journal of Cancer · doi:10.1002/(sici)1097-0215(20000601)86:5 · Cited by 155 · see citing works
Tumor stroma derived biomarkers in cancer
Sund, M., & Kalluri, R. (2009) · Cancer and Metastasis Reviews · doi:10.1007/s10555-008-9175-2 · Cited by 151 · see citing works
Magzoub, M. M., Jin, S., & Verkman, A. S. (2007) · The FASEB Journal · doi:10.1096/fj.07-9150com · Cited by 143 · see citing works
A Microtiter-Based Assay for Hyaluronidase Activity Not Requiring Specialized Reagents
Frost, G. I., & Stern, R. (1997) · Analytical Biochemistry · doi:10.1006/abio.1997.2262 · Cited by 135 · see citing works
Self-citationKim, E., Baba, D., Kimura, M., et al. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0506825102 · Cited by 134 · see citing works
Baumgartner, G., Gomar-Höss, C., Sakr, L., Ulsperger, E., & Wogritsch, C. (1998) · Cancer Letters · doi:10.1016/s0304-3835(98)00204-3 · Cited by 122 · see citing works
Hyaluronidase Expression Induces Prostate Tumor Metastasis in an Orthotopic Mouse Model
Kovar, J. L., Johnson, M. A., Volcheck, W. M., Chen, J., & Simpson, M. A. (2006) · American Journal Of Pathology · doi:10.2353/ajpath.2006.060324 · Cited by 115 · see citing works
Kristensen, C. A., Nozue, M., Boucher, Y., & Jain, R. (1996) · British Journal of Cancer · doi:10.1038/bjc.1996.397 · Cited by 113 · see citing works
Shepard, H. M., Brdlik, C. M., & Schreiber, H. W. (2008) · Journal of Clinical Investigation · doi:10.1172/jci36049 · Cited by 109 · see citing works
Self-citationRHAMM is differentially expressed in the cell cycle and downregulated by the tumor suppressor p53
Sohr, S., & Engeland, K. (2008) · Cell Cycle · doi:10.4161/cc.7.21.7014 · Cited by 99 · see citing works
Hyaluronidase reduces human breast cancer xenografts in SCID mice
Shuster, S., Frost, G. I., Csoka, A. B., Formby, B., & Stern, R. (2002) · International Journal of Cancer · doi:10.1002/ijc.10668 · Cited by 95 · see citing works
Self-citationGanesh, S., Gonzalez-Edick, M., Gibbons, D., Roey, M. V., & Jooss, K. U. (2008) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-07-4732 · Cited by 95 · see citing works
Transformation‐dependent loss of the hyaluronate‐containing coats of cultured cells
Underhill, C. B., & Toole, B. P. (1982) · Journal of Cellular Physiology · doi:10.1002/jcp.1041100204 · Cited by 83 · see citing works
Strong Stromal Hyaluronan Expression Is Associated with PSA Recurrence in Local Prostate Cancer
Aaltomaa, S. H., Lipponen, P., Tammi, R., Tammi, M., Viitanen, J., Kankkunen, J.-P., & Kosma, V. M. (2002) · Urologia Internationalis · doi:10.1159/000066123 · Cited by 75 · see citing works
A simple method for measuring interstitial fluid pressure in cancer tissues
Özerdem, U., & Hargens, A. R. (2005) · Microvascular Research · doi:10.1016/j.mvr.2005.07.003 · Cited by 74 · see citing works
Nykopp, T. K., Rilla, K. J., Sironen, R. K., Tammi, M., Tammi, R., Hämäläinen, K. M., Heikkinen, A. M., Komulainen, M. H., Kosma, V., & Anttila, M. (2009) · BMC Cancer · doi:10.1186/1471-2407-9-143 · Cited by 58 · see citing works
Brekken, C., & Davies, C. D. L. (1998) · Cancer Letters · doi:10.1016/s0304-3835(98)00202-x · Cited by 54 · see citing works
Brekken, C., Hjelstuen, M., Bruland, Ø. S., & Davies, C. D. L. (2000) · PubMed · Cited by 53 · see citing works
Maier, U., & Baumgartner, G. (1989) · The Journal of Urology · doi:10.1016/s0022-5347(17)40881-0 · Cited by 47 · see citing works
Hofinger, E. S. A., Hoechstetter, J., Oettl, M., Bernhardt, G., & Buschauer, A. (2007) · Glycoconjugate Journal · doi:10.1007/s10719-007-9058-8 · Cited by 41 · see citing works
Muckenschnabel, I., Bernhardt, G., Spruß, T., & Buschauer, A. (1998) · Cancer Letters · doi:10.1016/s0304-3835(98)00203-1 · Cited by 37 · see citing works
Hofmann, M., McCormack, E., Mujić, M., Roßberg, M., Bernd, A., Bereiter‐Hahn, J., Gjertsen, B. T., Wiig, H., & Kippenberger, S. (2009) · Neoplasia · doi:10.1593/neo.09662 · Cited by 36 · see citing works
The impact of enzymatic degradation on the uptake of differently sized therapeutic molecules.
Erikson, A., Tufto, I., Bjønnum, A. B., Bruland, Ø. S., & Davies, C. D. L. (2008) · PubMed · Cited by 24 · see citing works
Hyaluronan content in experimental carcinoma is not correlated to interstitial fluid pressure
Jacobson, A., Salnikov, A. V., Lammerts, E., Roswall, P., Sundberg, C., Heldin, P., Rubin, K., & Heldin, N. (2003) · Biochemical and Biophysical Research Communications · doi:10.1016/s0006-291x(03)00872-6 · Cited by 12 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Provenzano, P. P., Cuevas, C., Chang, A. E., Goel, V. K., Von Hoff, D. D., & Hingorani, S. R. (2012) · Cancer Cell · doi:10.1016/j.ccr.2012.01.007 · Cited by 2,195 · see citing works
The Pancreas Cancer Microenvironment
Feig, C., Gopinathan, A., Neesse, A., Chan, D. S., Cook, N., & Tuveson, D. A. (2012) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-11-3114 · Cited by 1,316 · see citing works
Tumor targeting via EPR: Strategies to enhance patient responses
Golombek, S. K., May, J.-N., Theek, B., Appold, L., Drude, N., Kiessling, F., & Lammers, T. (2018) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2018.07.007 · Cited by 1,262 · see citing works
Hyaluronan impairs vascular function and drug delivery in a mouse model of pancreatic cancer
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., et al. (2013) · Gut · doi:10.1136/gutjnl-2012-302529 · Cited by 1,120 · see citing works
Self-citationPancreatic cancer stroma: an update on therapeutic targeting strategies
Hosein, A. N., Brekken, R. A., & Maitra, A. (2020) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-020-0300-1 · Cited by 950 · see citing works
Transport of drugs from blood vessels to tumour tissue
Dewhirst, M. W., & Secomb, T. W. (2017) · Nature Reviews Cancer · doi:10.1038/nrc.2017.93 · Cited by 749 · see citing works
Van Cutsem, E., Tempero, M. A., Sigal, D., Oh, D.-Y., Fazio, N., Macarulla, T., Hitre, E., Hammel, P., Hendifar, A. E., Bates, S. E., et al. (2020) · Journal of Clinical Oncology · doi:10.1200/jco.20.00590 · Cited by 499 · see citing works
Ramanathan, R. K., McDonough, S. L., Philip, P. A., Hingorani, S. R., Lacy, J., Kortmansky, J. S., Thumar, J., Chiorean, E. G., Shields, A. F., Behl, D., et al. (2019) · Journal of Clinical Oncology · doi:10.1200/jco.18.01295 · Cited by 336 · see citing works
Rahbari, N. N., Kedrin, D., Incio, J., Liu, H., Ho, W. W., Nia, H. T., Edrich, C. M., Jung, K., Daubriac, J., Chen, I., et al. (2016) · Science Translational Medicine · doi:10.1126/scitranslmed.aaf5219 · Cited by 258 · see citing works
Interstitial Pressure in Pancreatic Ductal Adenocarcinoma Is Dominated by a Gel-Fluid Phase
DuFort, C. C., DelGiorno, K. E., Carlson, M. A., Osgood, R. J., Zhao, C., Huang, Z., Thompson, C. B., Connor, R. J., Thanos, C. D., Scott Brockenbrough, J., et al. (2016) · Biophysical Journal · doi:10.1016/j.bpj.2016.03.040 · Cited by 171 · see citing works
Self-citationPerez, V. M., Kearney, J. F., & Yeh, J. J. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.751311 · Cited by 143 · see citing works
Hyaluronan Accumulates With High-Fat Feeding and Contributes to Insulin Resistance
Kang, L., Lantier, L., Kennedy, A., Bonner, J. S., Mayes, W. H., Bracy, D. P., Bookbinder, L. H., Hasty, A. H., Thompson, C. B., & Wasserman, D. H. (2013) · Diabetes · doi:10.2337/db12-1502 · Cited by 133 · see citing works
Self-citationEpithelial and stromal co-evolution and complicity in pancreatic cancer
Hingorani, S. R. (2023) · Nature Reviews Cancer · doi:10.1038/s41568-022-00530-w · Cited by 108 · see citing works
Approaches to Improve EPR-Based Drug Delivery for Cancer Therapy and Diagnosis
Subhan, M. A., Parveen, F., Filipczak, N., Yalamarty, S. S. K., & Torchilin, V. P. (2023) · Journal of Personalized Medicine · doi:10.3390/jpm13030389 · Cited by 98 · see citing works
“HA-degradable PEGPH20 in integration with gemcitabine has demonstrated enhanced therapeutic effects in animal models [56,57].”
BackgroundInfante, J. R., Korn, R. L., Rosen, L. S., LoRusso, P., Dychter, S. S., Zhu, J., Maneval, D. C., Jiang, P., Shepard, H. M., Frost, G., et al. (2018) · British Journal of Cancer · doi:10.1038/bjc.2017.327 · Cited by 83 · see citing works
Self-citationWasserman, R. L. (2017) · Immunotherapy · doi:10.2217/imt-2017-0092 · Cited by 77 · see citing works
- Authors
- Thompson, C. B., Shepard, H. M., O'Connor, P. M., Kadhim, S., Jiang, P., Osgood, R. J., Bookbinder, L. H., Li, X., Sugarman, B. J., Connor, R. J., Nadjsombati, S., & Frost, G. I.
- Affiliations
- Halozyme Therapeutics (United States) (US)
- ORCID
- Venue
- Molecular Cancer Therapeutics
- Published
- 2010-11-01
- Volume
- 9
- Issue
- 11
- Pages
- 3052-3064
- ISSN
- 1535-7163 (ISSN-L)
- 1538-8514
- OpenAlex
- W2168467781
- Cited by
- 298
- References
- 50
- Citations by year
- 2026: 12 · 2025: 14 · 2024: 12 · 2023: 28 · 2022: 24 · 2021: 30 · 2020: 22 · 2019: 36 · 2018: 19 · 2017: 19 · 2016: 17 · 2015: 11 · 2014: 19 · 2013: 12 · 2012: 18
- FWCI
- 4.75
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Molecular Cancer Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- Topics
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- PEGPH20, rHuPH20, hyaluronidase, tumor stroma remodeling, tumor microenvironment, interstitial fluid pressure, prostate cancer, docetaxel, liposomal doxorubicin, chemotherapy enhancement, drug delivery, PEGylation, serum half-life
- MeSH terms
- Animals, Antineoplastic Agents, Cricetulus, Drug Synergism, Cricetinae, Humans, Hyaluronic Acid, Hyaluronoglucosaminidase, Male, Mice, Inbred ICR, Mice, Nude, Polyethylene Glycols, Recombinant Proteins, Tumor Cells, Cultured, Cell Adhesion Molecules, Up-Regulation, CHO Cells, Xenograft Model Antitumor Assays, Mice, Rats
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
