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 Blood, 1 May 2006, Vol. 107, No. 9, pp. 3531-3536.
Prepublished online as a Blood First Edition Paper on January 19, 2006; DOI 10.1182/blood-2005-06-2538.

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Submitted June 27, 2005
Accepted December 15, 2005

Hepatocyte growth factor is a novel lymphangiogenic factor with an indirect mechamism of action

Renhai Cao, Meit A Bjorndahl, Marta I Gallego, Shaohua Chen, Piotr Religa, Anker J Hansen, and Yihai Cao*

Laboratory of Angiogenesis Research, Microbiology and Tumor Biology Center, Karolinska Institute, Stockholm, Sweden
Project on Breast Cancer, Centro de Investigaciones Energeticas, Medioambientales y Tecnologicas, Madrid, Spain
Department of Cancer & ImmunoBiology, Novo Nordisk A/S, Maaloev, Denmark

* Corresponding author; email: yihai.cao{at}mtc.ki.se.

Hepatocyte growth factor (HGF) has previously been reported to act as a hemangiogenic factor, as well as a mitogenic factor for a variety of tumors cells. Here we demonstrate that HGF is a novel lymphangiogenic factor, which may contribute to lymphatic metastasis when overexpressed in tumors. In a mouse corneal lymphangiogenesis model, implantation of HGF induces sprouting and growth of new lymphatic vessel endothelial hyaluronan receptor-1 (Lyve-1) expressing lymphatic vessels. Unlike blood vessels, the Lyve-1-positive structures consist of blunt-ended vessels of large diameters that generally lack expression of CD31. The growth of HGF-induced lymphatic vessels can be partially blocked by a soluble VEGFR-3, suggesting that HGF may stimulate lymphatic vessel growth through an indirect mechanism. Consistent with this finding, the HGF receptor (c-Met) is only localized on corneal blood vessels but is absent on lymphatic vessels in a mouse corneal assay. In a transgenic mouse model that expresses HGF under the control of the whey acidic protein (WAP) gene promoter, transgenic females develop tumors in the mammary glands after several pregnancies. Interestingly, dilated Lyve-1 positive lymphatic vessels accumulate in the peritumoral area and occasionally penetrate into the tumor tissue. Our findings indicate that HGF may play a critical role in lymphangiogenesis and potentially contribute to lymphatic metastasis.


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