Significance of tumor-associated stroma in promotion of intratumoral lymphangiogenesis: pivotal role of a hyaluronan-rich tumor microenvironment.
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.
Koyama
Hiroshi
H
Department of Molecular Oncology, Division of Molecular and Cellular Biology, Institute on Aging and Adaptation, Shinshu University Graduate School of Medicine, Matsumoto, Nagano 390-8621, Japan.
Kobayashi
Nobutaka
N
Harada
Michihiko
M
Takeoka
Michiko
M
Kawai
Yoshiko
Y
Sano
Kenji
K
Fujimori
Minoru
M
Amano
Jun
J
Ohhashi
Toshio
T
Kannagi
Reiji
R
Kimata
Koji
K
Taniguchi
Shun'ichiro
S
Itano
Naoki
N
D000818:Animals; D002465:Cell Movement; D004195:Disease Models, Animal; D018450:Disease Progression; D004730:Endothelium, Vascular / Q000166:cytology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D006820:Hyaluronic Acid / Q000494:pharmacology; D007150:Immunohistochemistry / Q000379:methods; D042583:Lymphangiogenesis; D042601:Lymphatic Vessels / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D009369:Neoplasms / Q000473:pathology*
D006820:Hyaluronic Acid