HSulf-1 inhibits angiogenesis and tumorigenesis in vivo

Keishi Narita, Julie Staub, Jeremy Chien, Kristy Meyer, Maret Bauer, Andreas Friedl, Sundaram Ramakrishnan, Vijayalakshmi Shridhar

Research output: Contribution to journalArticle

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Abstract

We previously identified HSulf-1 as a down-regulated gene in several tumor types including ovarian, breast, and hepatocellular carcinomas. Loss of HSulf-1, which selectively removes 6-O-sulfate from heparan sulfate, up-regulates heparin-binding growth factor signaling and confers resistance to chemotherapy-induced apoptosis. Here we report that HSulf-1 expression in MDA-MB-468 breast carcinoma clonal lines leads to reduced proliferation in vitro and reduced tumor burden in athymic nude mice in vivo. Additionally, xenografts derived from HSulf-1-expressing stable clones of carcinoma cells showed reduced vessel density, marked necrosis, and apoptosis, indicative of inhibition of angiogenesis. Consistent with this observation, HSulf-1-expressing clonal lines showed reduced staining with the endothelial marker CD31 in Matrigel plug assay, indicating that HSulf-1 expression inhibits angiogenesis. More importantly, HSulf-1 expression in the xenografts was associated with a reduced ability of vascular endothelial cell heparan sulfate to participate in a complex with fibroblast growth factor 2 (FGF-2) and its receptor tyrosine kinase FGF receptor 1c. In vitro, short hairpin RNA-mediated down-regulation of HSulf-1 in human umbilical vein endothelial cells (HUVEC) resulted in an increased proliferation mediated by heparan sulfate-dependent FGF-2, hepatocyte growth factor, and vascular endothelial growth factor 165 (VEGF165) but not by heparan sulfate-independent VEGF121. HSulf-1 down-regulation also enhanced downstream signaling through the extracellular signal-regulated kinase pathway compared with untreated cells. Consistent with the role of heparan sulfate glycosaminoglycan sulfation in VEGF-mediated signaling, treatment of HUVEC cells with chlorate, which inhibits heparan sulfate glycosaminoglycan sulfation and therefore mimics HSulf-1 overexpression, led to an attenuated VEGF-mediated signaling. Collectively, these observations provide the first evidence of a novel mechanism by which HSulf-1 modulates the function of heparan sulfate binding VEGF165 in proliferation and angiogenesis.

Original languageEnglish (US)
Pages (from-to)6025-6032
Number of pages8
JournalCancer Research
Volume66
Issue number12
DOIs
StatePublished - Jun 15 2006

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Heparitin Sulfate
Carcinogenesis
Human Umbilical Vein Endothelial Cells
Glycosaminoglycans
Heterografts
Nude Mice
Vascular Endothelial Growth Factor A
Down-Regulation
Receptor, Fibroblast Growth Factor, Type 2
Chlorates
Apoptosis
Breast Neoplasms
Fibroblast Growth Factor Receptors
Hepatocyte Growth Factor
Extracellular Signal-Regulated MAP Kinases
Receptor Protein-Tyrosine Kinases
Fibroblast Growth Factor 2
Tumor Burden
Small Interfering RNA
Sulfates

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Narita, K., Staub, J., Chien, J., Meyer, K., Bauer, M., Friedl, A., ... Shridhar, V. (2006). HSulf-1 inhibits angiogenesis and tumorigenesis in vivo. Cancer Research, 66(12), 6025-6032. https://doi.org/10.1158/0008-5472.CAN-05-3582

HSulf-1 inhibits angiogenesis and tumorigenesis in vivo. / Narita, Keishi; Staub, Julie; Chien, Jeremy; Meyer, Kristy; Bauer, Maret; Friedl, Andreas; Ramakrishnan, Sundaram; Shridhar, Vijayalakshmi.

In: Cancer Research, Vol. 66, No. 12, 15.06.2006, p. 6025-6032.

Research output: Contribution to journalArticle

Narita, K, Staub, J, Chien, J, Meyer, K, Bauer, M, Friedl, A, Ramakrishnan, S & Shridhar, V 2006, 'HSulf-1 inhibits angiogenesis and tumorigenesis in vivo', Cancer Research, vol. 66, no. 12, pp. 6025-6032. https://doi.org/10.1158/0008-5472.CAN-05-3582
Narita K, Staub J, Chien J, Meyer K, Bauer M, Friedl A et al. HSulf-1 inhibits angiogenesis and tumorigenesis in vivo. Cancer Research. 2006 Jun 15;66(12):6025-6032. https://doi.org/10.1158/0008-5472.CAN-05-3582
Narita, Keishi ; Staub, Julie ; Chien, Jeremy ; Meyer, Kristy ; Bauer, Maret ; Friedl, Andreas ; Ramakrishnan, Sundaram ; Shridhar, Vijayalakshmi. / HSulf-1 inhibits angiogenesis and tumorigenesis in vivo. In: Cancer Research. 2006 ; Vol. 66, No. 12. pp. 6025-6032.
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