P-selectin deficiency attenuates tumor growth and metastasis.
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.
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, USA.
Y J
YJ
Kim
L
L
Borsig
N M
NM
Varki
A
A
Varki
D000818:Animals; D001483:Base Sequence; D001792:Blood Platelets / Q000473:pathology; D002455:Cell Division / Q000502:physiology; D015179:Colorectal Neoplasms / Q000473:pathology*; D003433:Crosses, Genetic; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000556:secondary; D008297:Male; D051379:Mice; D009077:Mucins / Q000502:physiology; D009362:Neoplasm Metastasis / Q000235:genetics; D009368:Neoplasm Transplantation; D019007:P-Selectin / Q000235:genetics / Q000502:physiology*; D012397:Rosette Formation
D009077:Mucins; D019007:P-Selectin