Inhibition of Stabilin-2 elevates circulating hyaluronic acid levels and prevents tumor metastasis

Yoshikazu Hirose, Eiko Saijou, Yasuyoshi Sugano, Fumitaka Takeshita, Satoshi Nishimura, Hidenori Nonaka, Yen Rong Chen, Keisuke Sekine, Taketomo Kido, Takashi Nakamura, Shigeaki Kato, Toru Kanke, Koji Nakamura, Ryozo Nagai, Takahiro Ochiya, Atsushi Miyajima

Research output: Contribution to journalArticle

44 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)4263-4268
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number11
DOIs
Publication statusPublished - 2012 Mar 13
Externally publishedYes

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Hyaluronic Acid
Neoplasm Metastasis
Neoplasms
Melanoma
Lung
Breast Neoplasms
Scavenger Receptors
Antibodies
Human Mammary Glands
Extracellular Matrix
Endothelial Cells
Cell Proliferation
Phenotype

Keywords

  • Antibody therapy
  • Cancer
  • Hyaluronan
  • Imaging
  • Sinusoid

ASJC Scopus subject areas

  • General

Cite this

Inhibition of Stabilin-2 elevates circulating hyaluronic acid levels and prevents tumor metastasis. / Hirose, Yoshikazu; Saijou, Eiko; Sugano, Yasuyoshi; Takeshita, Fumitaka; Nishimura, Satoshi; Nonaka, Hidenori; Chen, Yen Rong; Sekine, Keisuke; Kido, Taketomo; Nakamura, Takashi; Kato, Shigeaki; Kanke, Toru; Nakamura, Koji; Nagai, Ryozo; Ochiya, Takahiro; Miyajima, Atsushi.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 109, No. 11, 13.03.2012, p. 4263-4268.

Research output: Contribution to journalArticle

Hirose, Y, Saijou, E, Sugano, Y, Takeshita, F, Nishimura, S, Nonaka, H, Chen, YR, Sekine, K, Kido, T, Nakamura, T, Kato, S, Kanke, T, Nakamura, K, Nagai, R, Ochiya, T & Miyajima, A 2012, 'Inhibition of Stabilin-2 elevates circulating hyaluronic acid levels and prevents tumor metastasis', Proceedings of the National Academy of Sciences of the United States of America, vol. 109, no. 11, pp. 4263-4268. https://doi.org/10.1073/pnas.1117560109
Hirose, Yoshikazu ; Saijou, Eiko ; Sugano, Yasuyoshi ; Takeshita, Fumitaka ; Nishimura, Satoshi ; Nonaka, Hidenori ; Chen, Yen Rong ; Sekine, Keisuke ; Kido, Taketomo ; Nakamura, Takashi ; Kato, Shigeaki ; Kanke, Toru ; Nakamura, Koji ; Nagai, Ryozo ; Ochiya, Takahiro ; Miyajima, Atsushi. / Inhibition of Stabilin-2 elevates circulating hyaluronic acid levels and prevents tumor metastasis. In: Proceedings of the National Academy of Sciences of the United States of America. 2012 ; Vol. 109, No. 11. pp. 4263-4268.
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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.",
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AU - Kato, Shigeaki

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