Hyaluronan deficiency in tumor stroma impairs macrophage trafficking and tumor neovascularization.
Despite the importance of stromal cells in tumor progression, our overall understanding of the molecular signals that regulate the complex cellular interactions within tumor stroma is limited. Here, we provide multiple lines of evidence that tumor-associated macrophages (TAM) preferentially traffic to stromal areas formed within tumors in a manner dependent on a hyaluronan (HA)-rich tumor microenvironment. To address the role of stroma-derived HA in macrophage recruitment, we disrupted the HA synthase 2 (Has2) gene in stromal fibroblasts using conditional gene targeting. The Has2 null fibroblasts showed severe impairment in recruiting macrophages when inoculated with tumor cells into nude mice, which shows the contribution of stroma-derived HA in intratumoral macrophage mobilization. Furthermore, a deficiency in stromal HA attenuated tumor angiogenesis and lymphangiogenesis concomitantly with impaired macrophage recruitment. Taken together, our results suggest that stromal HA serves as a microenvironmental signal for the recruitment of TAMs, which are key regulatory cells involved in tumor neovascularization.
Kobayashi
Nobutaka
N
Department of Molecular Oncology, Division of Molecular and Cellular Biology, Institute on Aging and Adaptation, Shinshu University Graduate School of Medicine, Nagano, Japan.
Miyoshi
Seiji
S
Mikami
Takahide
T
Koyama
Hiroshi
H
Kitazawa
Masato
M
Takeoka
Michiko
M
Sano
Kenji
K
Amano
Jun
J
Isogai
Zenzo
Z
Niida
Shumpei
S
Oguri
Kayoko
K
Okayama
Minoru
M
McDonald
John A
JA
Kimata
Koji
K
Taniguchi
Shun'ichiro
S
Itano
Naoki
N
D000818:Animals; D005260:Female; D014453:Glucuronosyltransferase / Q000235:genetics; D000076002:Hyaluronan Synthases; D006820:Hyaluronic Acid / Q000172:deficiency*; D042583:Lymphangiogenesis; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000473:pathology*; D008325:Mammary Neoplasms, Experimental / Q000098:blood supply / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology; D017154:Stromal Cells / Q000473:pathology
D006820:Hyaluronic Acid; D014453:Glucuronosyltransferase; C491099:Has2 protein, mouse; D000076002:Hyaluronan Synthases