Sialofucosylated podocalyxin is a functional E- and L-selectin ligand expressed by metastatic pancreatic cancer cells.

Publisher: American Physiological Society Country of Publication: United States NLM ID: 100901225 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1522-1563 (Electronic) Linking ISSN: 03636143 NLM ISO Abbreviation: Am J Physiol Cell Physiol Subsets: MEDLINE

Original Publication: Bethesda, Md. : American Physiological Society,

Gene Expression Regulation, Neoplastic*; E-Selectin/*metabolism ; Fucose/*metabolism ; L-Selectin/*metabolism ; N-Acetylneuraminic Acid/*metabolism ; Pancreatic Neoplasms/*metabolism ; Sialoglycoproteins/*physiology; Animals ; CHO Cells ; Cell Line, Tumor ; Cricetinae ; Cricetulus ; Gene Knockdown Techniques ; Humans ; Ligands ; Pancreatic Neoplasms/secondary ; Sialoglycoproteins/metabolism

Selectin-mediated interactions in the vasculature promote metastatic spread by facilitating circulating tumor cell binding to selectin-expressing host cells. Therefore, identifying the selectin ligand(s) on tumor cells is critical to the prevention of blood-borne metastasis. A current challenge is to distinguish between structures expressed by circulating tumor cells that can bind selectins in vitro from the functional ligands whose depletion suppresses selectin-dependent binding under flow in vivo. Interestingly, podocalyxin (PODXL), which can bind E- and L-selectin, is upregulated in a number of cancers, including those of the breast, colon, and pancreas. In this work, we show that metastatic pancreatic cancer cells overexpress PODXL compared with nonmalignant pancreatic epithelial cells. We further demonstrate via tissue microarray that 69% of pancreatic ductal adenocarcinomas stain positive for PODXL. In cases of focal expression, positive staining is restricted to the invasive front of primary tumors. By combining immunoblot, immunodepletion, short-hairpin RNA-mediated gene silencing, and flow-based adhesion assays, we evaluated the functional role of sialofucosylated PODXL in selectin-mediated adhesion under flow. Our data indicate that sialofucosylated PODXL is a functional E- and L-selectin ligand expressed by metastatic pancreatic cancer cells, as specific depletion of this molecule from the cell surface significantly interferes with selectin-dependent interactions. Cumulatively, these data support a correlation between sialofucosylated PODXL expression and enhanced binding to selectins by metastatic pancreatic cancer cells and offer additional perspective on the upregulation of PODXL in aggressive cancers.

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R01-CA-101135 United States CA NCI NIH HHS; U54- CA-143868 United States CA NCI NIH HHS

0 (E-Selectin)
0 (Ligands)
0 (Sialoglycoproteins)
0 (podocalyxin)
126880-86-2 (L-Selectin)
28RYY2IV3F (Fucose)
GZP2782OP0 (N-Acetylneuraminic Acid)

Date Created: 20120721 Date Completed: 20121123 Latest Revision: 20211021

20240829

PMC3468350

10.1152/ajpcell.00149.2012

22814396