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(American Journal of Pathology. 2007;170:1086-1099.)
© 2007 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2007.060793

Hyperproduction of Hyaluronan in Neu-Induced Mammary Tumor Accelerates Angiogenesis through Stromal Cell Recruitment

Possible Involvement of Versican/PG-M

Hiroshi Koyama^*, Terumasa Hibi, Zenzo Isogai, Masahiko Yoneda^¶, Minoru Fujimori, Jun Amano, Masatomo Kawakubo^||, Reiji Kannagi^**, Koji Kimata, Shun’ichiro Taniguchi^* and Naoki Itano^*

From the Department of Molecular Oncology,^* Division of Molecular and Cellular Biology, Institute on Aging and Adaptation, Shinshu University Graduate School of Medicine, Nagano; the Department of Surgery, Shinshu University School of Medicine, Nagano; Biomedical Research Center,|| Department of Laboratory Medicine, Shinshu University Hospital, Nagano; Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, Saitama; the Division of Pharmacotherapy, Department of Advanced Medicine, National Center for Geriatrics and Gerontology, Aichi; Biochemistry and Molecular Biology Laboratory,^¶ Aichi Prefectural College of Nursing and Health, Aichi; Program of Molecular Pathology,^** Aichi Cancer Center, Research Institute, Aichi; and Institute for Molecular Science of Medicine, Aichi Medical University, Aichi, Japan

Elevated concentrations of hyaluronan are often associated with human breast cancer malignancy. Here, we investigated the roles of hyaluronan in carcinogenesis and cancer progression using the mouse mammary tumor virus (MMTV)-Neu transgenic model of spontaneous breast cancer. Conditional transgenic mice that express murine hyaluronan synthase 2 (Has2) by Cre-mediated recombination were generated and crossed with the MMTV-Neu mice. In expressing Cre recombinase under the control of the MMTV promoter, the bigenic mice bearing Has2 and neu transgenes exhibited a deposition of hyaluronan matrix and aggressive growth of Neu-initiated mammary tumors. Notably, forced expression of Has2 impaired intercellular adhesion machinery and elicited cell survival signals in tumor cells. Concurrent with these alterations of tumor cells, intratumoral stroma and microvessels were markedly induced. To reveal the molecular basis of hyaluronan-mediated neovascularization, various hyaluronan samples were examined for their ability to potentiate in vivo angiogenesis. In Matrigel plug assays, basic fibroblast growth factor-induced neovascularization was elevated in the presence of either hyaluronan oligosaccharides or a hyaluronan aggregate containing versican. Administration of hyaluronan-versican aggregates, but not native hyaluronan alone, promoted stromal cell recruitment concurrently with the infiltration of endothelial cells. Taken together, these results suggest that hyaluronan overproduction accelerates tumor angiogenesis through stromal reaction, notably in the presence of versican.

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