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Blockade of RAGE–amphoterin signalling suppresses tumour growth and metastases

Nature volume 405, pages 354–360 (2000)Cite this article

Abstract

The receptor for advanced glycation end products (RAGE), a multi-ligand member of the immunoglobulin superfamily of cell surface molecules1,2, interacts with distinct molecules implicated in homeostasis, development and inflammation, and certain diseases such as diabetes and Alzheimer's disease 3–8. Engagement of RAGE by a ligand triggers activation of key cell signalling pathways, such as p21ras, MAP kinases, NF-κB and cdc42/rac, thereby reprogramming cellular properties9,10,11. RAGE is a central cell surface receptor for amphoterin, a polypeptide linked to outgrowth of cultured cortical neurons derived from developing brain3,12,13,14,15. Indeed, the co-localization of RAGE and amphoterin at the leading edge of advancing neurites indicated their potential contribution to cellular migration, and in pathologies such as tumour invasion. Here we demonstrate that blockade of RAGE–amphoterin decreased growth and metastases of both implanted tumours and tumours developing spontaneously in susceptible mice. Inhibition of the RAGE–amphoterin interaction suppressed activation of p44/p42, p38 and SAP/JNK MAP kinases; molecular effector mechanisms importantly linked to tumour proliferation, invasion and expression of matrix metalloproteinases16,17,18,19,20,21,22,23.

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Figure 1: RAGE and amphoterin are expressed in tumour cells.
Figure 2: RAGE–amphoterin blockade suppresses growth of implanted C6 glioma. a, C6 glioma cells were implanted into immunocompromised mice and mean tumour volume on day 21 is shown, n = 10 per group.
Figure 3: Blockade of RAGE suppresses tumour proliferation and expression of MMPs.
Figure 4: Effects of RAGE–amphoterin blockade on C6 glioma: in vitro analyses.
Figure 5: Blockade of RAGE suppresses endogenous growth of papillomas. a–d , After six weeks of local application of PMA, papillomas forming in transgenic mice overexpressing v-Ha-ras were examined by immunohistochemistry using the indicated IgG.

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Acknowledgements

We thank P. D'Amore for advice and B. Tycko for assistance in these studies. This work was supported by the Surgical Research Fund of the College of Physicians & Surgeons, Columbia University, and by grants from the United States Public Health Service, Juvenile Diabetes Foundation International, and the American Heart Association, New York affiliate. G.D.T. is a recipient of a Faculty Development Award from the Robert Wood Johnson Foundation. A.M.S. is a recipient of a Burroughs Wellcome Fund Clinical Scientist Award in Translational Research.

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Authors and Affiliations

  1. College of Physicians & Surgeons, Columbia University, New York, 10032 , New York, USA

    Akihiko Taguchi, David C. Blood, Gustavo del Toro, Anthony Canet, Daniel C. Lee, Wu Qu, Nozomu Tanji, Yan Lu, Evanthia Lalla, Caifeng Fu, Marion A. Hofmann, Thomas Kislinger, Mark Ingram, Amy Lu, David M. Stern & Ann Marie Schmidt

  2. Osaka University School of Medicine, Osaka, 565-0871, Japan

    Hidekazu Tanaka

  3. Kanazawa University School of Medicine, Kanazawa, 920-8640, Japan

    Osamu Hori & Satoshi Ogawa

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  1. Akihiko Taguchi
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Correspondence to Ann Marie Schmidt.

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Taguchi, A., Blood, D., del Toro, G. et al. Blockade of RAGE–amphoterin signalling suppresses tumour growth and metastases. Nature 405, 354–360 (2000). https://doi.org/10.1038/35012626

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