P-selectin deficiency attenuates tumor growth and metastasis
- Glycobiology Program and University of California at San Diego Cancer Center, Divisions of Hematology–Oncology and Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 92093
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Communicated by Richard O. Hynes, Massachusetts Institute of Technology, Cambridge, MA (received for review January 28, 1998)
Abstract
Selectins are adhesion receptors that normally recognize certain vascular mucin-type glycoproteins bearing the carbohydrate structure sialyl-Lewisx. The clinical prognosis and metastatic progression of many epithelial carcinomas has been correlated independently with production of tumor mucins and with enhanced expression of sialyl-Lewisx. Metastasis is thought to involve the formation of tumor-platelet-leukocyte emboli and their interactions with the endothelium of distant organs. We provide a link between these observations by showing that P-selectin, which normally binds leukocyte ligands, can promote tumor growth and facilitate the metastatic seeding of a mucin-producing carcinoma. P-selectin-deficient mice showed significantly slower growth of subcutaneously implanted human colon carcinoma cells and generated fewer lung metastases from intravenously injected cells. Three potential pathophysiological mechanisms are demonstrated: first, intravenously injected tumor cells home to the lungs of P-selectin deficient mice at a lower rate; second, P-selectin-deficient mouse platelets fail to adhere to tumor cell-surface mucins; and third, tumor cells lodged in lung vasculature after intravenous injection often are decorated with platelet clumps, and these are markedly diminished in P-selectin-deficient animals.
Footnotes
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↵ * To whom correspondence should be addressed at: University of California at San Diego School of Medicine, La Jolla, CA 92093-0687. e-mail: avarki{at}ucsd.edu.
- ABBREVIATIONS:
- sLex,
- sialyl Lewisx;
- sLea,
- sialyl Lewisa
- Copyright © 1998, The National Academy of Sciences
