title: Inhibition of Stabilin-2 elevates circulating hyaluronic acid levels and prevents tumor metastasis.
abstract: Hyaluronic acid (HA) has been implicated in the proliferation and metastasis of tumor cells. However, most previous studies were conducted on extracellular matrix or pericellular HA, and the role of circulating HA in vivo has not been studied. HA is rapidly cleared from the bloodstream. The scavenger receptor Stabilin-2 (Stab2) is considered a major clearance receptor for HA. Here we report a dramatic elevation in circulating HA levels in Stab2-deficient mice without any overt phenotype. Surprisingly, the metastasis of B16F10 melanoma cells to the lungs was markedly suppressed in the Stab2-deficient mice, whereas cell proliferation was not affected. Furthermore, administration of an anti-Stab2 antibody in Stab2(+) mice elevated serum HA levels and prevented the metastasis of melanoma to the lung, and also suppressed spontaneous metastasis of mammary tumor and human breast tumor cells inoculated in the mammary gland. Administration of the antibody or high-dose HA in mice blocked the lodging of melanoma cells to the lungs. Furthermore, HA at high concentrations inhibited the rolling/tethering of B16 cells to lung endothelial cells. These results suggest that blocking Stab2 function prevents tumor metastasis by elevating circulating HA levels. Stab2 may be a potential target in antitumor therapy.
authors.affiliation: Laboratory of Cell Growth and Differentiation and Laboratory of Nuclear Signaling, Institute of Molecular and Cellular Biosciences,  University of Tokyo, Tokyo 113-0032,  Japan.
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Hirose
authors.forename: Eiko
authors.initials: E
authors.lastname: Saijou
authors.forename: Yasuyoshi
authors.initials: Y
authors.lastname: Sugano
authors.forename: Fumitaka
authors.initials: F
authors.lastname: Takeshita
authors.forename: Satoshi
authors.initials: S
authors.lastname: Nishimura
authors.forename: Hidenori
authors.initials: H
authors.lastname: Nonaka
authors.forename: Yen-Rong
authors.initials: YR
authors.lastname: Chen
authors.forename: Keisuke
authors.initials: K
authors.lastname: Sekine
authors.forename: Taketomo
authors.initials: T
authors.lastname: Kido
authors.forename: Takashi
authors.initials: T
authors.lastname: Nakamura
authors.forename: Shigeaki
authors.initials: S
authors.lastname: Kato
authors.forename: Toru
authors.initials: T
authors.lastname: Kanke
authors.forename: Koji
authors.initials: K
authors.lastname: Nakamura
authors.forename: Ryozo
authors.initials: R
authors.lastname: Nagai
authors.forename: Takahiro
authors.initials: T
authors.lastname: Ochiya
authors.forename: Atsushi
authors.initials: A
authors.lastname: Miyajima
mesh_terms: D000818:Animals; D000906:Antibodies / Q000008:administration & dosage / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects; D015816:Cell Adhesion Molecules, Neuronal / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D006820:Hyaluronic Acid / Q000097:blood*; D008175:Lung Neoplasms / Q000097:blood / Q000556:secondary; D008546:Melanoma, Experimental / Q000097:blood / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009362:Neoplasm Metastasis / Q000276:immunology / Q000473:pathology* / Q000517:prevention & control*
chemical_list: D000906:Antibodies; D015816:Cell Adhesion Molecules, Neuronal; C486733:Stab2 protein, mouse; D006820:Hyaluronic Acid