Published online before print December 13, 2007

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(American Journal of Pathology. 2008;172:179-193.)
© 2008 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2008.070360

Significance of Tumor-Associated Stroma in Promotion of Intratumoral Lymphangiogenesis

Pivotal Role of a Hyaluronan-Rich Tumor Microenvironment

Hiroshi Koyama^*, Nobutaka Kobayashi^*, Michihiko Harada^*, Michiko Takeoka^*, Yoshiko Kawai, Kenji Sano, Minoru Fujimori, Jun Amano, Toshio Ohhashi, 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 Departments of Surgery,and Physiology,Shinshu University School of Medicine, Nagano; the Department of Laboratory Medicine,Biomedical Research Center, Shinshu University Hospital, Nagano; Core Research for Evolutional Science and Technology,^¶Japan Science and Technology Agency, Saitama; the Program of Molecular Pathology,||Aichi Cancer Center, Research Institute, Aichi; and the Institute for Molecular Science of Medicine,^**Aichi Medical University, Aichi, Japan

Stromal cells, together with extracellular matrix components, provide a tumor microenvironment that is pivotal for cancer cell growth and progression. In our previous study using a conditional transgenic mouse model of breast cancer, the overproduction of hyaluronan, a major extracellular constituent, accelerated tumor angiogenesis through stromal cell recruitment. This finding led us to investigate the role of hyaluronan in the lymphatic vessel system. Here, we have found that microenvironmental hyaluronan promoted tumor lymphangiogenesis concurrently with the formation of stromal structures. Additionally, lymphatic vessels frequently penetrated and accumulated into stromal compartments, and up-regulation of vascular endothelial growth factor-C and -D was detected at tumor-stromal interfaces. To assess the contribution of stromal cells to lymphangiogenesis in vivo, we established tumor-associated fibroblasts from hyaluronan-overproducing mammary tumors and implanted them together with carcinoma cells from control tumors or MCF-7 human breast carcinoma cells in nude mice. Carcinoma cells grew rapidly in association with marked stromal reactions and lymphangiogenesis. Without the stromal cells, however, the tumors developed slowly with less stroma and lymphatic vessels. These findings underline the significance of tumor-associated stroma in the promotion of intratumoral lymphangiogenesis and suggest a pivotal role for the hyaluronan-rich tumor microenvironment.

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