Altered expression of certain types and linkages of sialic acids (Sias) are prominent features of human and murine tumors. We have proven novel roles for P- and L-selectin interactions with the sialylated, fucosylated, sulfated O-linked glycoproteins (mucins) of epithelial carcinomas, showing tumor cell interactions in the bloodstream with leukocytes, platelets and endothelial cells that play crucial roles in metastasis. Our observation that heparin inhibits P- and L-selectin then allowed us to propose parameters for a human clinical trial, to be done by others. We also provided an explanation for the relationship between Trousseau's Syndrome and mucin-producing adenocarcinomas, and discovered novel hepatic systems for clearance of circulating mucins. We will now turn attention to two (2) other well-described but poorly understood examples of """"""""tumor-specific"""""""" Sia changes: accumulation of the non-human Sia N-glycolylneuraminic acid (Neu5Gc) in the face of an anti-Neu5Gc antibody response;and enhanced expression of Siaa2-6GalB1-4GlcNAc (6'SiaLacNAc) glycan termini, which is associated with invasion and poor prognosis. The general hypothesis is that expression of such structures in naturally occurring human tumors facilitates growth, angiogenesis and/or invasion and progression. As with earlier work we will use mice with genetically defined changes, as well as cell lines derived from them - increasing the likelihood of definitive mechanistic conclusions rather than observational correlations.
Specific aims for the next period are: 1) Complete currently ongoing studies of selectin-mucin-heparin interactions, to set the stage for a proposed clinical trial of LMW heparin for interdicting early stage human carcinoma metastasis. 2) Study in vivo growth, invasion and metastasis of carcinomas with variations in the expression of Neu5Gc and/or circulating anti-Neu5Gc antibodies (mimicking the human condition in the mouse). We hypothesize that carcinomas accumulate Neu5Gc despite an ongoing anti-Neu5Gc antibody response because low-level inflammation actually facilitates growth and angiogenesis. We propose that boosting Neu5Gc accumulation and/or anti-Neu5Gc antibodies above a certain threshold will become detrimental to the tumor and/or its angiogenesis. These hypotheses have potential diagnostic and therapeutic implications. 3) Study in vivo growth, invasion and metastasis of carcinomas with variations in 6'SiaLacNAc residues (mimicking the human condition in mice). We hypothesize that tumors overexpress ST6Gal-I and its 6'SiaLacNAc product to facilitate growth and/or invasion, and will test the effects of altering 6'SiaLacNAc expression in vivo. Initial emphasis will be on aims involving Neu5Gc in tumors (Aim 2). The extent to which Aim 3 is pursued will depend on outcomes with Aim 2 and its ramifications;and on results of preliminary studies.
| 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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