title: Glycan Sulfation Modulates Dendritic Cell Biology and Tumor Growth.
abstract: In cancer, proteoglycans have been found to play roles in facilitating the actions of growth factors, and effecting matrix invasion and remodeling. However, little is known regarding the genetic and functional importance of glycan chains displayed by proteoglycans on dendritic cells (DCs) in cancer immunity. In lung carcinoma, among other solid tumors, tumor-associated DCs play largely subversive/suppressive roles, promoting tumor growth and progression. Herein, we show that targeting of DC glycan sulfation through mutation in the heparan sulfate biosynthetic enzyme N-deacetylase/N-sulfotransferase-1 (Ndst1) in mice increased DC maturation and inhibited trafficking of DCs to draining lymph nodes. Lymphatic-driven DC migration and chemokine (CCL21)-dependent activation of a major signaling pathway required for DC migration (as measured by phospho-Akt) were sensitive to Ndst1 mutation in DCs. Lewis lung carcinoma tumors in mice deficient in Ndst1 were reduced in size. Purified CD11c+ cells from the tumors, which contain the tumor-infiltrating DC population, showed a similar phenotype in mutant cells. These features were replicated in mice deficient in syndecan-4, the major heparan sulfate proteoglycan expressed on the DC surface: Tumors were growth-impaired in syndecan-4-deficient mice and were characterized by increased infiltration by mature DCs. Tumors on the mutant background also showed greater infiltration by NK cells and NKT cells. These findings indicate the genetic importance of DC heparan sulfate proteoglycans in tumor growth and may guide therapeutic development of novel strategies to target syndecan-4 and heparan sulfate in cancer.
authors.affiliation: VA San Diego Healthcare System, Medical and Research Sections, La Jolla, CA 92161; Department of Medicine, Division of Pulmonary and Critical Care, University of California San Diego, La Jolla, CA 92037.
authors.forename: Roland
authors.initials: R
authors.lastname: El Ghazal
authors.affiliation: VA San Diego Healthcare System, Medical and Research Sections, La Jolla, CA 92161; Department of Medicine, Division of Pulmonary and Critical Care, University of California San Diego, La Jolla, CA 92037; Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, School of Pharmacy, Huaihai Institute of Technology, Lianyungang, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Yin
authors.affiliation: VA San Diego Healthcare System, Medical and Research Sections, La Jolla, CA 92161; Department of Medicine, Division of Pulmonary and Critical Care, University of California San Diego, La Jolla, CA 92037.
authors.forename: Scott C
authors.initials: SC
authors.lastname: Johns
authors.affiliation: Division of Gastroenterology, University of California San Diego, La Jolla, CA 92093.
authors.forename: Lee
authors.initials: L
authors.lastname: Swanson
authors.affiliation: Division of Biological Sciences, University of California San Diego, La Jolla, CA 92093.
authors.forename: Monica
authors.initials: M
authors.lastname: Macal
authors.affiliation: Division of Gastroenterology, University of California San Diego, La Jolla, CA 92093.
authors.forename: Pradipta
authors.initials: P
authors.lastname: Ghosh
authors.affiliation: Division of Biological Sciences, University of California San Diego, La Jolla, CA 92093.
authors.forename: Elina I
authors.initials: EI
authors.lastname: Zuniga
authors.affiliation: VA San Diego Healthcare System, Medical and Research Sections, La Jolla, CA 92161; Department of Medicine, Division of Pulmonary and Critical Care, University of California San Diego, La Jolla, CA 92037; Glycobiology Research and Training Center, University of California San Diego, La Jolla, CA 92093. Electronic address: mfuster@ucsd.edu.
authors.forename: Mark M
authors.initials: MM
authors.lastname: Fuster
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000276:immunology; D049109:Cell Proliferation; D018925:Chemokines / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism*; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism; D006497:Heparan Sulfate / Q000378:metabolism; D006801:Humans; D016130:Immunophenotyping; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009369:Neoplasms / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D011509:Proteoglycans / Q000378:metabolism*; D053671:Syndecan-4 / Q000235:genetics / Q000378:metabolism; D047368:Tumor Burden
chemical_list: D018925:Chemokines; D006497:Heparan Sulfate; D011509:Proteoglycans; D053671:Syndecan-4