Carbohydrate- Dependent Epithelial Cancer Metastasis

碳水化合物依赖性上皮癌转移

• 批准号: 8308590
• 负责人: Michiko Fukuda
• 金额: $ 22.63万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8308590
• 关键词: Adhesions; Anabolism; Annexin A1; Antibodies; Antigens; Apoptosis; Binding; Birth; Carbohydrates; Cell surface; Cells; Clinical; Clinical Research; Complex; Data; Embryo; Endothelial Cells; Epithelial; Epithelial Cells; Epitopes; Genes; Goals; Golgi Apparatus; Hematopoietic; Heparitin Sulfate; High Endothelial Venule; Isoenzymes; Knock-out; Knockout Mice; L-Selectin; Laboratories; Ligands; Lung; Malignant - descriptor; Malignant Neoplasms; Mannosidase; Methods; Minor; Monoclonal Antibodies; Mus; Mutant Strains Mice; Neoplasm Metastasis; Normal Cell; P-Selectin; Peptide Phage Display Library; Peptides; Polysaccharides; Process; Proteomics; RNA Splicing; Research; Role; Screening procedure; Selectins; Surface; Tumor-Associated Carbohydrate Antigens; Wild Type Mouse; angiogenesis; base; cancer cell; in vivo; lung melanoma; mRNA Precursor; neoplastic cell; novel therapeutics; outcome forecast; receptor; tumor

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.

有充分的证据表明，上皮细胞的恶性转化与结构有关