It is well documented that malignant transformation of epithelial cells is associated with structural changes in cell surface carbohydrates. Many clinical studies have correlated those cancer-associated carbohydrate antigens with poor clinical prognosis, including metastasis. Carbohydrate-dependent cancer metastasis has been observed, but the mechanisms underlying this process are not yet defined. We previously identified IELLQAR (l-peptide) that mimics the epitope of anti-Lewis A antibody by screening peptide displaying phage libraries. When l-peptides were injected into wild type mice, they inhibited sLex-dependent melanoma lung colonization. However, lung colonization also occurs in mutant mice lacking both E- and P-selectins and l-peptide inhibits the colonization, excluding the involvement of these selectins in this process. These findings suggest that l-peptide interference with colonization does not require E- and P-selectins. Our preliminary data show that the l-peptide receptors are pre-mRNA splicing factor (Sfrs) and AnnexinAI (Anxal). The PI also studied the in vivo roles of the Golgi processing a-mannosidase II (Mil) and alphamannosidase llx (MX). Mil/MX double null mouse embryos showed no complex type A/-glycans, indicating that Mil and MX together are responsible for the complex type N-glycan synthesis. Mil/MX double nulls were lethal shortly after birth. Based on these findings, the specific aims are: (1) To determine A/-glycan-based L-selectin ligand activity in vivo using conditional Mil/MX double null mice. Endothelial and hematopoietic cell-specific Mil/MX double knockouts (Tie2-Cre:Mllftaxp/floxp/MX-/-) will be generated and analyzed for L-selectin ligand activity in high endothelial venules (HEVs), (2) to define carbohydrate-binding activity of Sfrs and Anxal, (3) to determine if targeted apoptosis occurs by Anxal binding. Anxal has been identified as a tumor-specific endothelial marker, and we identified IFpeptide, which binds preferentially to Anxal. Thus we will develop a method to target apoptosis to endothelial cells of tumor vasculature in the mouse using IF-peptide, and (4) to determine if Anxal expressed on the endothelial surface promotes angiogenesis and identify mechanisms underlying Anxal-dependent endothelial cell activation including binding to heparan sulfate. These studies will provide information for better understand of the mechanisms underlying carbohydrate-dependent cancer metastasis and help for developing new therapeutic strategies against epithelial cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA071932-15
Application #
8380247
Study Section
Special Emphasis Panel (ZCA1-RPRB-O)
Project Start
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
15
Fiscal Year
2012
Total Cost
$229,761
Indirect Cost
$76,602
Name
Sanford-Burnham Medical Research Institute
Department
Type
DUNS #
020520466
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Nonaka, Motohiro; Fukuda, Michiko N; Gao, Chao et al. (2014) Determination of carbohydrate structure recognized by prostate-specific F77 monoclonal antibody through expression analysis of glycosyltransferase genes. J Biol Chem 289:16478-86
Nonaka, Motohiro; Bao, Xingfeng; Matsumura, Fumiko et al. (2014) Synthetic di-sulfated iduronic acid attenuates asthmatic response by blocking T-cell recruitment to inflammatory sites. Proc Natl Acad Sci U S A 111:8173-8
Tsuboi, Koichiro; Hirakawa, Jotaro; Seki, Emiko et al. (2013) Role of high endothelial venule-expressed heparan sulfate in chemokine presentation and lymphocyte homing. J Immunol 191:448-55
Sugihara, Kazuhiro; Shibata, Toshiaki K; Takata, Kayoko et al. (2013) Attenuation of fibroblast growth factor signaling by poly-N-acetyllactosamine type glycans. FEBS Lett 587:3195-201
Lee, Seung Ho; Fukuda, Minoru (2013) Study of the biological functions of mucin type core 3 O-glycans. Methods Mol Biol 1022:41-50
Suzuki-Anekoji, Misa; Suzuki, Atsushi; Wu, Sz-Wei et al. (2013) In vivo regulation of steroid hormones by the Chst10 sulfotransferase in mouse. J Biol Chem 288:5007-16
Okamoto, Teppei; Yoneyama, Mihoko Sutoh; Hatakeyama, Shingo et al. (2013) Core2 O-glycan-expressing prostate cancer cells are resistant to NK cell immunity. Mol Med Rep 7:359-64
Pols, Maaike S; van Meel, Eline; Oorschot, Viola et al. (2013) hVps41 and VAMP7 function in direct TGN to late endosome transport of lysosomal membrane proteins. Nat Commun 4:1361
Ito, Yuki; Vela, Jose Luis; Matsumura, Fumiko et al. (2013) Helicobacter pylori cholesteryl α-glucosides contribute to its pathogenicity and immune response by natural killer T cells. PLoS One 8:e78191
Hatakeyama, Shingo; Shibata, Toshiaki K; Tobisawa, Yuki et al. (2013) Tumor targeting by a carbohydrate ligand-mimicking peptide. Methods Mol Biol 1022:369-86

Showing the most recent 10 out of 161 publications