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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA038701-16
Application #
6489056
Study Section
Pathobiochemistry Study Section (PBC)
Program Officer
Sathyamoorthy, Neeraja
Project Start
1985-08-01
Project End
2004-12-31
Budget Start
2002-01-01
Budget End
2002-12-31
Support Year
16
Fiscal Year
2002
Total Cost
$349,893
Indirect Cost
Name
University of California San Diego
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
077758407
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Läubli, Heinz; Varki, Ajit; Borsig, Lubor (2016) Antimetastatic Properties of Low Molecular Weight Heparin. J Clin Oncol 34:2560-1
Schwarz, Flavio; Fong, Jerry J; Varki, Ajit (2015) Human-specific evolutionary changes in the biology of siglecs. Adv Exp Med Biol 842:1-16
Samraj, Annie N; Pearce, Oliver M T; Läubli, Heinz et al. (2015) A red meat-derived glycan promotes inflammation and cancer progression. Proc Natl Acad Sci U S A 112:542-7
Varki, Nissi M; Varki, Ajit (2015) On the apparent rarity of epithelial cancers in captive chimpanzees. Philos Trans R Soc Lond B Biol Sci 370:
Samraj, Annie N; Läubli, Heinz; Varki, Nissi et al. (2014) Involvement of a non-human sialic Acid in human cancer. Front Oncol 4:33
Chang, Yung-Chi; Olson, Joshua; Beasley, Federico C et al. (2014) Group B Streptococcus engages an inhibitory Siglec through sialic acid mimicry to blunt innate immune and inflammatory responses in vivo. PLoS Pathog 10:e1003846
Pearce, Oliver Mt; Läubli, Heinz; Bui, Jack et al. (2014) Hormesis in cancer immunology: Does the quantity of an immune reactant matter? Oncoimmunology 3:e29312
Läubli, Heinz; Pearce, Oliver M T; Schwarz, Flavio et al. (2014) Engagement of myelomonocytic Siglecs by tumor-associated ligands modulates the innate immune response to cancer. Proc Natl Acad Sci U S A 111:14211-6
Deng, Lingquan; Song, Jeongmin; Gao, Xiang et al. (2014) Host adaptation of a bacterial toxin from the human pathogen Salmonella Typhi. Cell 159:1290-9
Pearce, Oliver M T; Läubli, Heinz; Verhagen, Andrea et al. (2014) Inverse hormesis of cancer growth mediated by narrow ranges of tumor-directed antibodies. Proc Natl Acad Sci U S A 111:5998-6003

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