Journal Article

Connective tissue growth factor increased by hypoxia may initiate angiogenesis in collaboration with matrix metalloproteinases

Seiji Kondo, Satoshi Kubota, Tsuyoshi Shimo, Takashi Nishida, Gen Yosimichi, Takanori Eguchi, Toshio Sugahara and Masaharu Takigawa

in Carcinogenesis

Volume 23, issue 5, pages 769-776
Published in print May 2002 | ISSN: 0143-3334
Published online May 2002 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/23.5.769
Connective tissue growth factor increased by hypoxia may initiate angiogenesis in collaboration with matrix metalloproteinases

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Connective tissue growth factor (CTGF) is known to be a potent angiogenic factor. Here we investigated how CTGF and matrix metalloproteinases (MMPs) are involved in the early stage of hypoxia-induced angiogenesis using human breast cancer cell line, MDA231, and vascular endothelial cells. Hypoxic stimulation (5% O2) of MDA231 cells increased their steady-state level of ctgf mRNA by ∼2-fold within 1.5 h, and the levels remained at a plateau up to 6 h, and then decreased by 12 h as compared with the cells cultured under the normoxic condition. Membrane-type 1 MMP (MT1-MMP) mRNA levels was also increased within a few hours of the exposure to hypoxia. Indeed, ELISA revealed that the CTGF protein/cell in medium conditioned by MDA231 cells exposed to hypoxia was maximally greater at 24 h than in the medium from normoxic cultures and that the secretion rate (supernatant CTGF/cell layer CTGF) increased in a time-dependent manner from 24 to 72 h of hypoxic exposure. Hypoxic induction of CTGF was also confirmed by immunohistochemical analyses. Furthermore, zymogram analysis revealed that the production of active MMP-9 was also induced in MDA231 cells incubated under hypoxic conditions. Finally, we found that recombinant CTGF also increased the expression of a number of metalloproteinases that play a role in the vascular invasive processes and decreased the expression of tissue inhibitors of metalloproteinases by vascular endothelial cells. These findings suggest that hypoxia stimulates MDA231 cells to release CTGF as an angiogenic modulator, which initiates the invasive angiogenesis cascade by modulating the balance of extracellular matrix synthesis and degradation via MMPs secreted by endothelial cells in response to CTGF. This cascade may play critical roles in the hypoxia-induced neovascularization that accompanies tumor invasion in vivo.

Keywords: BFGF, basis fibroblast growth factor; CTGF, connective tissue growth factor; ECM, extracellular matrix; ELISA, enzyme-linked immunosorbent assay; HUVEC, human umbilical vein endothelial cells; MMP, matrix metalloproteinase; MT1-MMP, membrane-type 1 MMP; TIMP, tissue inhibitors of metalloproteinase; UTR, untranslated region; VEGF, vascular endothelial growth factor

Journal Article.  7095 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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