The long-term theme of this grant has been to compare and contrast oligosaccharides (glycans) of normal and malignant cells, and to define the pathological and therapeutic significance of the differences. Sialic acids (Sias) are attached to underlying glycans in various linkages, and can be modified in several ways. Altered expression of specific types and linkages of Sias are prominent features of human and murine tumors. All work in our lab is now focused on the biology and evolution of Sias and Sia-binding proteins in health and disease. Thus, the recent focus of this grant has been on "tumor-specific" changes in Sia-terminated glycans, and on their interactions with Sia-binding proteins such as Selectins and Siglecs. During the last funding period we completed all of our previously stated aims on Selectins and on alpha2-6-linked Sias in cancer, and also generated novel data about a human-specific diet- and antibody-mediated mechanism for chronic inflammation in tumor progression. The latter involves human metabolic incorporation of the non-human sialic acid N-glycolylneuraminic acid (Neu5Gc) from dietary sources (primarily red meats), in the face of human-specific circulating anti-Neu5Gc antibodies. We also now have preliminary evidence for a second mechanism of human-specific chronic inflammation, involving the reduced expression of inhibitory CD33-related Siglecs (CD33rSiglecs) on leukocytes. Given the known importance of chronic inflammation in carcinoma progression, these two human-specific mechanisms may help explain the unusual propensity of humans (as compared to other primates) to develop carcinomas, and have possible relevance for diagnosis, prognosis and therapy. Thus, the current proposal will focus only on the human-specific changes in Sia biology. The general hypothesis is that the human propensity to develop carcinomas is partly related to Neu5Gc incorporation into tumors in the face of anti-Neu5Gc antibody production, and also to relative leukocyte over-reactivity, arising due to human-specific reduction of CD33rSiglec expression. Our studies will focus on carcinomas of human or syngeneic mouse origin - growing in Cmah-/- mice with a human-like defect in Neu5Gc production and/or in mice with deletions or over-expression of myelomonocytic CD33rSiglecs. We will further explore the significance of Neu5Gc incorporation into primary and metastatic tumors in Cmah-/- mice, in the face of circulating anti-Neu5Gc antibodies, and use mouse models to explore the role of human myelomonocytic cell over-reactivity associated with reduced CD33rSiglec expression in chronic inflammation and progression of primary and metastatic human tumors. Finally, we will ask if the combination of Neu5Gc and anti-Neu5Gc antibodies interactions along with Siglec-deficiency-related myelomonocytic cell hyper-reactivity has even greater facilitating effect on progression of carcinomas. As time allows, we will also do pilot studies of human tumor samples for Neu5Gc expression and infiltrating leukocyte Siglec expression to see if either or both are predictive of prognosis and/or disease progression.
We have found that a non-human molecule in certain foods of animal origin is becoming incorporated from our diet into the human cancers, even while we are making antibodies against it, and that human immune cells are relatively over-reactive to stimuli do to loss of certain inhibitory molecules. These findings have implications for the human propensity to develop carcinomas, and also provide one explanation for the association of red meat consumption with cancer risk. We propose to study all of these issues in detail, using carefully designed mouse models.
|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|
|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|
|Padler-Karavani, Vered; Tremoulet, Adriana H; Yu, Hai et al. (2013) A simple method for assessment of human anti-Neu5Gc antibodies applied to Kawasaki disease. PLoS One 8:e58443|
|Löfling, Jonas; Lyi, Sangbom Michael; Parrish, Colin R et al. (2013) Canine and feline parvoviruses preferentially recognize the non-human cell surface sialic acid N-glycolylneuraminic acid. Virology 440:89-96|
|Varki, Ajit; Gagneux, Pascal (2012) Multifarious roles of sialic acids in immunity. Ann N Y Acad Sci 1253:16-36|
|Mitra, Nivedita; Banda, Kalyan; Altheide, Tasha K et al. (2011) SIGLEC12, a human-specific segregating (pseudo)gene, encodes a signaling molecule expressed in prostate carcinomas. J Biol Chem 286:23003-11|
|Shao, Bojing; Wahrenbrock, Mark G; Yao, Longbiao et al. (2011) Carcinoma mucins trigger reciprocal activation of platelets and neutrophils in a murine model of Trousseau syndrome. Blood 118:4015-23|
|Chandrasekharan, Kumaran; Yoon, Jung Hae; Xu, Ying et al. (2010) A human-specific deletion in mouse Cmah increases disease severity in the mdx model of Duchenne muscular dystrophy. Sci Transl Med 2:42ra54|
|Ghaderi, Darius; Taylor, Rachel E; Padler-Karavani, Vered et al. (2010) Implications of the presence of N-glycolylneuraminic acid in recombinant therapeutic glycoproteins. Nat Biotechnol 28:863-7|
|Varki, Ajit; Freeze, Hudson H; Manzi, Adriana E (2009) Overview of glycoconjugate analysis. Curr Protoc Protein Sci Chapter 12:Unit 12.1 12.1.1-8|
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