Online citations, reference lists, and bibliographies.
← Back to Search

Hyaluronan And Tumor Growth.

B. Toole, V. Hascall
Published 2002 · Medicine, Biology

Cite This
Download PDF
Analyze on Scholarcy
Share
The study published in this issue of The American Journal of Pathology by Simpson et al 1 adds a new dimension to the role of hyaluronan in cancer by demonstrating that inhibition of endogenous hyaluronan synthesis dramatically reduces tumor growth in vivo. In previous studies, these investigators showed that aggressive PC3M-LN4 human prostate carcinoma cells contain two of the three synthases that synthesize hyaluronan, namely HAS2 and HAS3, and that transfectants of PC3M-LN4 with antisense to HAS2 and HAS3 mRNA synthesized significantly less hyaluronan. 2,3 In the present study, stable transfectants with antisense-HAS2 and antisense-HAS3 were used alone or in combination to study tumor growth after subcutaneous injection in immunocompromised mice. The antisense-HAS transfectants produced tumors that were three to four times smaller than control tumors after 3 weeks. Although inhibition of hyaluronan synthesis reduced rates of cell proliferation in culture, the antisense-HAS transfectant tumors contained similar proportions of dividing and apoptopic cells as did the control tumors at 3 weeks. This finding suggests that the reduced size of the antisense-HAS transfectant tumors is due to reduced rates of growth early in development of the tumor. The authors also found that blood vessel density was diminished by 70 to 80%, implying that hyaluronan levels may be an important determinant of vascularity, and that this rather than proliferation is the predominant factor in the effect of hyaluronan on tumor growth in this model. Interestingly, inclusion of exogenous hyaluronan with the initial injection of the transfected tumor cells restored levels of tumor growth and vascularity to those seen in control tumors, suggesting that early angiogenic events may be crucial. Numerous other studies have demonstrated a close correlation between tumor progression and hyaluronan production, either by tumor cells themselves or by stromal cells associated with tumors. This correlation has been observed in cell culture, in experimental animal models, and in human patients. In fact, recent work shows that hyaluronan content correlates with increased progression in several cancers, including breast, ovarian, prostate, and colorectal cancers. 4,5 In addition to the observation that hyaluronan is present in elevated amounts in numerous types of tumors, experimental manipulations of hyaluronan levels and interactions suggest a vital role for hyaluronan in promoting malignant cell behavior in vitro and in vivo. For example, experimental elevation of hyaluronan production in HT1080 human fibrosarcoma cells or TSU human prostate carcinoma cells enhances growth in vivo. 6,7 Also, low producers of hyaluronan selected from a population of mammary carcinoma cells are less metastatic than high producers, and metastatic capacity was restored to the low producers by elevating their hyaluronan production. 8
This paper references
10.1074/jbc.R100036200
Hyaluronan-binding Proteins: Tying Up the Giant*
A. J. Day (2002)
10.1006/SCDB.2000.0244
Hyaluronan in morphogenesis.
B. Toole (1997)
Overproduction of hyaluronan by expression of the hyaluronan synthase Has2 enhances anchorage-independent growth and tumorigenicity.
R. Kosaki (1999)
10.1002/IJC.2910600511
The role of hyaluronan in tumour neovascularization (review)
P. Rooney (1995)
Hyaluronan synthase 3 overexpression promotes the growth of TSU prostate cancer cells.
N. Liu (2001)
10.1074/JBC.M103481200
Hyaluronan Enters Keratinocytes by a Novel Endocytic Route for Catabolism*
R. Tammi (2001)
10.1074/jbc.R100038200
Signaling Properties of Hyaluronan Receptors*
E. Turley (2002)
10.1242/jcs.00042
Changed lamellipodial extension, adhesion plaques and migration in epidermal keratinocytes containing constitutively expressed sense and antisense hyaluronan synthase 2 (Has2) genes
K. Rilla (2002)
10.1111/j.1749-6632.2000.tb06704.x
CD44 Acts Both as a Growth‐ and Invasiveness‐Promoting Molecule and as a Tumor‐Suppressing Cofactor
P. Herrlich (2000)
10.1074/jbc.M110069200
Manipulation of Hyaluronan Synthase Expression in Prostate Adenocarcinoma Cells Alters Pericellular Matrix Retention and Adhesion to Bone Marrow Endothelial Cells*
M. Simpson (2002)
10.1023/A:1011371523994
CD44-Mediated Oncogenic Signaling and Cytoskeleton Activation During Mammary Tumor Progression
L. Bourguignon (2004)
Relationship between hyaluronan production and metastatic potential of mouse mammary carcinoma cells.
N. Itano (1999)
10.1128/MCB.20.10.3482-3496.2000
Enhanced Transformation by a Plasma Membrane-Associated Met Oncoprotein: Activation of a Phosphoinositide 3′-Kinase-Dependent Autocrine Loop Involving Hyaluronic Acid and CD44
D. Kamikura (2000)
10.1016/S0945-053X(01)00186-X
CD44-mediated uptake and degradation of hyaluronan.
W. Knudson (2002)
10.1097/00006123-200206000-00023
Overexpression of Hyaluronan Synthase-2 Reduces the Tumorigenic Potential of Glioma Cells Lacking Hyaluronidase Activity
Bouchra Enegd (2002)
10.1074/jbc.274.35.25085
Three Isoforms of Mammalian Hyaluronan Synthases Have Distinct Enzymatic Properties*
N. Itano (1999)
10.1074/jbc.R100039200
Hyaluronan-Cell Interactions in Cancer and Vascular Disease*
B. Toole (2002)
10.1002/9780470513774.CH12
Hyaluronan and angiogenesis.
D. West (1989)
10.1002/(SICI)1097-0215(19980729)77:3<396::AID-IJC15>3.0.CO;2-6
Inhibition of tumor growth in vivo by hyaluronan oligomers
C. Zeng (1998)
10.1172/JCI10272
Disruption of hyaluronan synthase-2 abrogates normal cardiac morphogenesis and hyaluronan-mediated transformation of epithelium to mesenchyme.
T. Camenisch (2000)
10.1091/MBC.12.6.1859
Hyaluronan activates cell motility of v-Src-transformed cells via Ras-mitogen-activated protein kinase and phosphoinositide 3-kinase-Akt in a tumor-specific manner.
Y. Sohara (2001)
10.1016/S0002-9440(10)64245-9
Inhibition of prostate tumor cell hyaluronan synthesis impairs subcutaneous growth and vascularization in immunocompromised mice.
M. Simpson (2002)
10.1093/GLYCOB/12.3.37R
Hyaluronan promotes the malignant phenotype.
B. Toole (2002)
10.1046/j.1365-2796.1997.00172.x
Hyaluronan: fundamental principles and applications in cancer
B. Delpech (1997)
10.1073/PNAS.93.15.7832
Expression of hyaluronidase by tumor cells induces angiogenesis in vivo.
D. Liu (1996)
10.1074/jbc.M010064200
Hyaluronan Synthase Elevation in Metastatic Prostate Carcinoma Cells Correlates with Hyaluronan Surface Retention, a Prerequisite for Rapid Adhesion to Bone Marrow Endothelial Cells*
M. Simpson (2001)
10.1074/jbc.M008432200
Stromal and Epithelial Expression of Tumor Markers Hyaluronic Acid and HYAL1 Hyaluronidase in Prostate Cancer*
V. Lokeshwar (2001)
10.1126/SCIENCE.1069659
Resolution of Lung Inflammation by CD44
P. Teder (2002)
10.1016/S1074-5521(01)00078-3
Peptides that mimic glycosaminoglycans: high-affinity ligands for a hyaluronan binding domain.
M. R. Ziebell (2001)
10.1101/GAD.11.8.996
Selective suppression of CD44 in keratinocytes of mice bearing an antisense CD44 transgene driven by a tissue-specific promoter disrupts hyaluronate metabolism in the skin and impairs keratinocyte proliferation.
G. Kaya (1997)
10.1084/JEM.186.12.1985
Induction of Apoptosis of Metastatic Mammary Carcinoma Cells In Vivo by Disruption of Tumor Cell Surface CD44 Function
Q. Yu (1997)
10.1073/pnas.052026799
Abnormal accumulation of hyaluronan matrix diminishes contact inhibition of cell growth and promotes cell migration
N. Itano (2002)



This paper is referenced by
10.1002/anie.201805138
Innovative Strategies for Hypoxic-Tumor Photodynamic Therapy.
Xingshu Li (2018)
10.1093/GLYCOB/CWG112
Devising a pathway for hyaluronan catabolism: are we there yet?
R. Stern (2003)
10.1039/c7ib00173h
In vitro elucidation of the role of pericellular matrix in metastatic extravasation and invasion of breast carcinoma cells.
Marie-Elena Brett (2018)
10.3389/fonc.2019.00492
Matrix Hyaluronan-CD44 Interaction Activates MicroRNA and LncRNA Signaling Associated With Chemoresistance, Invasion, and Tumor Progression
L. Bourguignon (2019)
10.1016/j.biomaterials.2013.08.047
A silk fibroin based hepatocarcinoma model and the assessment of the drug response in hyaluronan-binding protein 1 overexpressed HepG2 cells.
Banani Kundu (2013)
Immunohistochemical Studies of Expression and Correlation of Osteopontin, CD44, and Integrin αVβ3 in Selected Benign and Malignant Salivary Gland Tumours
Tommy Fok (2012)
Óscar José Maciel Barros
J. M. Barros (2016)
10.1002/ADFM.201902440
Hyaluronidase with pH‐responsive Dextran Modification as an Adjuvant Nanomedicine for Enhanced Photodynamic‐Immunotherapy of Cancer
Hairong Wang (2019)
10.1007/s11670-011-0059-6
Correlation between hyaluronic acid, hyaluronic acid synthase and human renal clear cell carcinoma
Jian-liang Cai (2011)
10.1016/J.BBRC.2004.09.120
Modulation of matrix metalloproteinase-9 activity by hyaluronan is dependent on NF-kappaB activity in lymphoma cell lines with dissimilar invasive behavior.
L. Alaniz (2004)
10.1155/2015/834893
Roles of Proteoglycans and Glycosaminoglycans in Wound Healing and Fibrosis
S. Ghatak (2015)
10.1016/S1572-5995(08)80035-X
Hyaluronic Acid: Its Function and Degradation in in vivo Systems
Grigorij Kogan (2008)
10.1074/jbc.M607787200
Expression, Processing, and Glycosaminoglycan Binding Activity of the Recombinant Human 315-kDa Hyaluronic Acid Receptor for Endocytosis (HARE)*
E. N. Harris (2007)
10.1016/j.biomaterials.2016.08.052
Heralding a new paradigm in 3D tumor modeling.
E. L. Fong (2016)
10.1016/B978-012374178-3.10001-8
CHAPTER 1 – Association Between Cancer and “Acid Mucopolysaccharides”: An Old Concept Comes of Age, Finally
Robert H. Stern (2009)
10.1074/jbc.M706001200
Mannose Inhibits Hyaluronan Synthesis by Down-regulation of the Cellular Pool of UDP-N-acetylhexosamines*
T. Jokela (2008)
10.1016/j.htct.2018.01.008
Prognostic significance of receptor for hyaluronan acid-mediated motility (CD168) in acute pediatric leukemias – assessment of clinical outcome, post induction, end of treatment and minimal residual disease
C. N. Shalini (2018)
10.1016/j.cbi.2007.11.015
Effect of gamma irradiated hyaluronic acid on acetaminophen induced acute hepatotoxicity.
J. K. Kim (2008)
10.2147/IJN.S257164
Mechanism Investigation of Hyaluronidase-Combined Multistage Nanoparticles for Solid Tumor Penetration and Antitumor Effect
Enrui Chen (2020)
10.1078/0171-9335-00392
Hyaluronan catabolism: a new metabolic pathway.
R. Stern (2004)
10.4161/cbt.3.2.775
Glycobiology and Cancer: Meeting Summary and Future Directions
G. Hart (2004)
10.1001/ARCHOTOL.132.1.19
Hyaluronan-CD44 promotes phospholipase C-mediated Ca2+ signaling and cisplatin resistance in head and neck cancer.
S. Wang (2006)
10.1038/ja.2006.101
F-16438s, Novel Binding Inhibitors of CD44 and Hyaluronic Acid
Hosami Harada (2006)
10.1016/j.semcancer.2008.03.014
Association between cancer and "acid mucopolysaccharides": an old concept comes of age, finally.
R. Stern (2008)
10.1369/jhc.3A6221.2004
Neurocan–GFP Fusion Protein
H. Zhang (2004)
Development of a pre-vascularized 3 D scaffold-hydrogel composite graft using an arteriovenous loop
J. Beier (2012)
10.1016/j.biomaterials.2018.04.039
Highly enhanced cancer immunotherapy by combining nanovaccine with hyaluronidase.
Xiu-wen Guan (2018)
10.1039/b910552m
Therapeutic applications of hyaluronan.
J. Gaffney (2010)
10.1016/B978-1-4557-3146-6.00014-3
Biofunctionalization of Hydrogels for Engineering the Cellular Microenvironment
Maniraj Bhagawati (2014)
10.1089/TEN.2006.12.2131
Review. Hyaluronan: a powerful tissue engineering tool.
D. D. Allison (2006)
10.1016/j.nantod.2019.100800
Engineered nanomedicines with enhanced tumor penetration
Jianxun Ding (2019)
10.1155/2012/893947
Chain Gangs: New Aspects of Hyaluronan Metabolism
Michael Erickson (2012)
See more
Semantic Scholar Logo Some data provided by SemanticScholar