Carcinomas of the colon, breast, lung, prostate, pancreas, stomach and ovary are frequently associated with increased expression and altered glycosylation of cell surface and secreted mucins. In particular, expression of sialyl Lewis/x (sLe/x) and/or sialyl Lewis/a (sLe/a) carbohydrates by such carcinomas correlates strongly with tumor progression, metastatic spread, and poor prognosis. We have found that carcinoma mucins expressing sLe/x/a can carry multiple distinct binding sites for each of the three members of the selectin family of vascular adhesion molecules. Furthermore, these mucins can mediate interactions with and amongst blood and vascular cells that normally express selectins. Thus, the overall hypothesis underlying this application is that cell surface and/or secreted tumor mucins bearing selectin ligands interact with leukocytes, platelets and endothelial cells expressing selectins, and that these interactions have important roles in the biology of carcinomas. In keeping with this, we have found that P-selectin deficient mice show reduced growth, seeding and metastasis of carcinomas. To further explore our hypothesis, we will: 1. Purify and carefully characterize colon carcinoma mucins, and then study their in vitro and in vivo interactions with selectins on normal human and murine leukocytes, endothelial cell and platelets. We will also ask if the purified mucins can reproduce the features of Trousseau's syndrome, which occurs in some patients with mucin-producing carcinomas. Sort-term mucin and selectin-dependent interactions of intravenously injected tumor cells will also be examined, to see if these are critical for long-term organ colonization. 2. The growth and metastatic potential of two murine carcinoma models that express selectin ligands will be studied in the setting of various selectin deficiencies, as well as in mice with a genetically-induced defect in a fucosyltransferase, known to be involved in creating selectin ligands. 3. The homing, growth and metastasis of human carcinoma cells expressing selectin ligands on cell surface and secreted mucins will be studied in genetically altered mice that are deficient in one, two or all three selectins. This last specific aim will be carried out in collaboration with Richard Hynes (MIT). These data will clarify if the prior correlation of sLe/x/a and mucin expression with poor prognosis is explained by selectin-carcinoma mucin interactions. If so, current approaches aimed at selectin inhibition for inflammatory states may become applicable to patients with early stage who are risk for metastatic progression.
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