Logo of pnasPNASInfo for AuthorsSubscriptionsAboutThis Article
Proc Natl Acad Sci U S A. 1996 Jul 23; 93(15): 7832–7837.

Expression of hyaluronidase by tumor cells induces angiogenesis in vivo.


Hyaluronic acid is a proteoglycan present in the extracellular matrix and is important for the maintenance of tissue architecture. Depolymerization of hyaluronic acid may facilitate tumor invasion. In addition, oligosaccharides of hyaluronic acid have been reported to induce angiogenesis. We report here that a hyaluronidase similar to the one on human sperm is expressed by metastatic human melanoma, colon carcinoma, and glioblastoma cell lines and by tumor biopsies from patients with colorectal carcinomas, but not by tissues from normal colon. Moreover, angiogenesis is induced by hyaluronidase+ tumor cells but not hyaluronidase- tumor cells and can be blocked by an inhibitor of hyaluronidase. Tumor cells thus use hyaluronidase as one of the "molecular saboteurs" to depolymerize hyaluronic acid to facilitate invasion. As a consequence, breakdown products of hyaluronic acid can further promote tumor establishment by inducing angiogenesis. Hyaluronidase on tumor cells may provide a target for anti-neoplastic drugs.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (1.8M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

Images in this article

Click on the image to see a larger version.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Poste G, Fidler IJ. The pathogenesis of cancer metastasis. Nature. 1980 Jan 10;283(5743):139–146. [PubMed]
  • Liotta LA. Tumor invasion and metastases--role of the extracellular matrix: Rhoads Memorial Award lecture. Cancer Res. 1986 Jan;46(1):1–7. [PubMed]
  • Folkman J. Tumor angiogenesis. Adv Cancer Res. 1974;19(0):331–358. [PubMed]
  • Craft PS, Harris AL. Clinical prognostic significance of tumour angiogenesis. Ann Oncol. 1994 Apr;5(4):305–311. [PubMed]
  • Ruoslahti E. Structure and biology of proteoglycans. Annu Rev Cell Biol. 1988;4:229–255. [PubMed]
  • Poole AR. Proteoglycans in health and disease: structures and functions. Biochem J. 1986 May 15;236(1):1–14. [PMC free article] [PubMed]
  • Matrisian LM. The matrix-degrading metalloproteinases. Bioessays. 1992 Jul;14(7):455–463. [PubMed]
  • Stetler-Stevenson WG, Aznavoorian S, Liotta LA. Tumor cell interactions with the extracellular matrix during invasion and metastasis. Annu Rev Cell Biol. 1993;9:541–573. [PubMed]
  • Iozzo RV. Proteoglycans and neoplasia. Cancer Metastasis Rev. 1988 Apr;7(1):39–50. [PubMed]
  • Nakajima M, Irimura T, Di Ferrante D, Di Ferrante N, Nicolson GL. Heparan sulfate degradation: relation to tumor invasive and metastatic properties of mouse B16 melanoma sublines. Science. 1983 May 6;220(4597):611–613. [PubMed]
  • Toole BP. Hyaluronan and its binding proteins, the hyaladherins. Curr Opin Cell Biol. 1990 Oct;2(5):839–844. [PubMed]
  • COBBIN LB, DICKER SE. Some characteristics of plasma and urine 'hyaluronidase'. J Physiol. 1962 Aug;163:168–174. [PMC free article] [PubMed]
  • Tu AT, Hendon RR. Characterization of lizard venom hyaluronidase and evidence for its action as a spreading factor. Comp Biochem Physiol B. 1983;76(2):377–383. [PubMed]
  • Ramanaiah M, Parthasarathy PR, Venkaiah B. Isolation and characterization of hyaluronidase from scorpion (Heterometrus fulvipes) venom. Biochem Int. 1990;20(2):301–310. [PubMed]
  • Primakoff P, Hyatt H, Myles DG. A role for the migrating sperm surface antigen PH-20 in guinea pig sperm binding to the egg zona pellucida. J Cell Biol. 1985 Dec;101(6):2239–2244. [PMC free article] [PubMed]
  • Lin Y, Kimmel LH, Myles DG, Primakoff P. Molecular cloning of the human and monkey sperm surface protein PH-20. Proc Natl Acad Sci U S A. 1993 Nov 1;90(21):10071–10075. [PMC free article] [PubMed]
  • Gmachl M, Kreil G. Bee venom hyaluronidase is homologous to a membrane protein of mammalian sperm. Proc Natl Acad Sci U S A. 1993 Apr 15;90(8):3569–3573. [PMC free article] [PubMed]
  • Guo Y, Ma J, Wang J, Che X, Narula J, Bigby M, Wu M, Sy MS. Inhibition of human melanoma growth and metastasis in vivo by anti-CD44 monoclonal antibody. Cancer Res. 1994 Mar 15;54(6):1561–1565. [PubMed]
  • Willson JK, Bittner GN, Oberley TD, Meisner LF, Weese JL. Cell culture of human colon adenomas and carcinomas. Cancer Res. 1987 May 15;47(10):2704–2713. [PubMed]
  • West DC, Hampson IN, Arnold F, Kumar S. Angiogenesis induced by degradation products of hyaluronic acid. Science. 1985 Jun 14;228(4705):1324–1326. [PubMed]
  • Rooney P, Kumar S, Ponting J, Wang M. The role of hyaluronan in tumour neovascularization (review). Int J Cancer. 1995 Mar 3;60(5):632–636. [PubMed]
  • Kuppusamy UR, Das NP. Inhibitory effects of flavonoids on several venom hyaluronidases. Experientia. 1991 Dec 1;47(11-12):1196–1200. [PubMed]
  • Kuppusamy UR, Das NP. Protective effects of tannic acid and related natural compounds on Crotalus adamenteus subcutaneous poisoning in mice. Pharmacol Toxicol. 1993 Apr-May;72(4-5):290–295. [PubMed]
  • Feinberg RN, Beebe DC. Hyaluronate in vasculogenesis. Science. 1983 Jun 10;220(4602):1177–1179. [PubMed]
  • Klagsbrun M. The affinity of fibroblast growth factors (FGFs) for heparin; FGF-heparan sulfate interactions in cells and extracellular matrix. Curr Opin Cell Biol. 1990 Oct;2(5):857–863. [PubMed]
  • Ruoslahti E, Yamaguchi Y. Proteoglycans as modulators of growth factor activities. Cell. 1991 Mar 8;64(5):867–869. [PubMed]
  • Thompson WD, Shiach KJ, Fraser RA, McIntosh LC, Simpson JG. Tumours acquire their vasculature by vessel incorporation, not vessel ingrowth. J Pathol. 1987 Apr;151(4):323–332. [PubMed]
  • Havsteen B. Flavonoids, a class of natural products of high pharmacological potency. Biochem Pharmacol. 1983 Apr 1;32(7):1141–1148. [PubMed]
  • Adlercreutz H. Does fiber-rich food containing animal lignan precursors protect against both colon and breast cancer? An extension of the "fiber hypothesis". Gastroenterology. 1984 Apr;86(4):761–764. [PubMed]
  • Correa P. Epidemiological correlations between diet and cancer frequency. Cancer Res. 1981 Sep;41(9 Pt 2):3685–3690. [PubMed]
  • Hirano T, Oka K, Akiba M. Antiproliferative effects of synthetic and naturally occurring flavonoids on tumor cells of the human breast carcinoma cell line, ZR-75-1. Res Commun Chem Pathol Pharmacol. 1989 Apr;64(1):69–78. [PubMed]
  • Wei H, Tye L, Bresnick E, Birt DF. Inhibitory effect of apigenin, a plant flavonoid, on epidermal ornithine decarboxylase and skin tumor promotion in mice. Cancer Res. 1990 Feb 1;50(3):499–502. [PubMed]
  • Katiyar SK, Agarwal R, Mukhtar H. Protection against malignant conversion of chemically induced benign skin papillomas to squamous cell carcinomas in SENCAR mice by a polyphenolic fraction isolated from green tea. Cancer Res. 1993 Nov 15;53(22):5409–5412. [PubMed]
  • Bracke ME, Vyncke BM, Van Larebeke NA, Bruyneel EA, De Bruyne GK, De Pestel GH, De Coster WJ, Espeel MF, Mareel MM. The flavonoid tangeretin inhibits invasion of MO4 mouse cells into embryonic chick heart in vitro. Clin Exp Metastasis. 1989 May-Jun;7(3):283–300. [PubMed]
  • Narisawa T, Fukaura Y. A very low dose of green tea polyphenols in drinking water prevents N-methyl-N-nitrosourea-induced colon carcinogenesis in F344 rats. Jpn J Cancer Res. 1993 Oct;84(10):1007–1009. [PubMed]
  • Tsubura E, Yamashita T, Kobayashi M, Higuchi Y. Effect of sulfated polysaccharides on blood-borne pulmonary metastasis in rats. Gan. 1976 Dec;67(6):849–856. [PubMed]
  • Zimmermann K, Preinl G, Ludwig H, Greulich KO. Inhibition of hyaluronidase by dextran sulfate and its possible application in anticancer treatment. J Cancer Res Clin Oncol. 1983;105(2):189–190. [PubMed]
  • Herrlich P, Zöller M, Pals ST, Ponta H. CD44 splice variants: metastases meet lymphocytes. Immunol Today. 1993 Aug;14(8):395–399. [PubMed]
  • Sy MS, Liu D, Schiavone R, Ma J, Mori H, Guo Y. Interactions between CD44 and hyaluronic acid: their role in tumor growth and metastasis. Curr Top Microbiol Immunol. 1996;213(Pt 3):129–153. [PubMed]
  • Culty M, Shizari M, Thompson EW, Underhill CB. Binding and degradation of hyaluronan by human breast cancer cell lines expressing different forms of CD44: correlation with invasive potential. J Cell Physiol. 1994 Aug;160(2):275–286. [PubMed]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences


Save items

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...


  • Cited in Books
    Cited in Books
    PubMed Central articles cited in books
  • MedGen
    Related information in MedGen
  • PubMed
    PubMed citations for these articles
  • Substance
    PubChem Substance links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...