Carbohydrate- Dependent Epithelial Cancer Metastasis

有充分的证据表明，上皮细胞的恶性转化与结构有关

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.