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Steve Rosen, PhD

Steve Rosen, PhD
Professor, Department of Anatomy
Investigator, CVRI
Program Member, Helen Diller Family Comprehensive Cancer Center
Research Summary:
Roles of biological sulfation in leukocyte trafficking and tumorigenesis

We currently are pursuing two main areas of research: 1) molecular mechanisms of leukocyte trafficking; and 2) the role of heparan sulfate degrading sulfatases in cancer. A major emphasis of the trafficking studies has been L-selectin, a lectin-type receptor on leukocytes that mediates leukocyte adhesion to activated endothelium. This receptor recognizes endothelial ligands that contain key sulfated carbohydrate determinants. We are studying the sulfotransferases that synthesize these ligands and how these enzymes are regulated. We are studying the role of the L-selectin/endothelial ligand adhesion system in the recruitment of lymphocytes and other leukocytes to sites of chronic inflammation, in particular joints in rheumatoid arthritis and airways in asthma. We are also interested in the signaling responses that are induced in leukocytes when L-selectin is ligated through interaction with appropriate ligands. The second main direction of the lab concerns two novel sulfatases, called Sulf-1 and Sulf-2 which we cloned and characterized 6 years ago. These enzymes are secreted and act extracellularly. They remove specific internal sulfate residues (i.e., glucosamine-6-sulfate) from heparan sulfate proteoglycans (HSPGs) on the cell surface and in the extracellular matrix. This desulfation step regulates the ability of heparan sulfate chains to bind particular protein ligands and therefore controls the bioavailability of the ligands. Wnt ligands are one of the ligand families that are regulated by the Sulfs. In a number of cancers, this developmental signaling pathway is reactivated where it promotes cell proliferation and survival. We and others have observed the upregulation of Sulf expression in several cancers, including pancreatic, breast and lung adenocarcinomas. Using pancreatic cancer cell lines and non-small cell lung cancer lines, we have shown that the Sulfs facilitate Wnt signaling in these cells and in so doing promotes cell proliferation and survival in vitro and tumorigenicity in nude mice. Since the Sulfs are extracellular enzymes, they could emerge as therapeutic targets for the treatment of pancreatic and lung carcinomas, diseases which have a poor prognosis with current therapies. The Sulfs are also important in development and during wound repair. The latter aspect is being investigated by us in corneal injury models.

Selected Publications

van Zante, A., Gauguet, J.M., Bistrup, A., Tsay, D., vn Andrian, U.H., and Rosen, S.D. 2003. Lymphocyte-HEV interactions in lymph nodes of a sulfotransferase-deficient mouse. J Exp Med 198:1289-1300.

Rosen, S.D. 2004. Ligands for L-selectin: homing, inflammation, and beyond. Ann Rev Immunol 22:129-156.

Pablos, J.L., Santiago, B., Tsay, D., Singer, M.S., Palao, G., Galindo, M., and Rosen, S.D. 2005. A HEV-restricted sulfotransferase is expressed in rheumatoid arthritis synovium and is induced by lymphotoxin-alpha/beta and TNF-alpha in cultured endothelial cells. BMC Immunol 6:6.

Uchimura, K., Gauguet, J.M., Singer, M.S., Tsay, D., Kannagi, R., Muramatsu, T., von Andrian, U.H., and Rosen, S.D. 2005. A major class of L-selectin ligands is eliminated in mice deficient in two sulfotransferases expressed in high endothelial venules. Nat Immunol 6:1105-1113.

Rosen, S.D., Tsay, D., Singer, M.S., Hemmerich, S., and Abraham, W.M. 2005. Therapeutic targeting of endothelial ligands for L-selectin (PNAd) in a sheep model of asthma. Am J Pathol 166:935-944.

Uchimura, K., Gauguet, J.M., Singer, M.S., Tsay, D., Kannagi, R., Muramatsu, T., von Andrian, U.H., and Rosen, S.D. 2005. A major class of L-selectin ligands is eliminated in mice deficient in two sulfotransferases expressed in high endothelial venules. Nat Immunol 6:1105-1113.

Uchimura, K., and Rosen, S.D. 2006. Sulfated L-selectin ligands as a therapeutic target in chronic inflammation. Trends Immunol 27:559-565.

Morimoto-Tomita, M., Uchimura, K., Werb, Z., Hemmerich, S., and Rosen, S.D. 2002. Cloning and Characterization of Two Extracellular Heparin-degrading Endosulfatases in Mice and Humans. J Biol Chem 277:49175-49185.

Morimoto-Tomita, M., Uchimura, K., Bistrup, A., Lum, D.H., Egeblad, M., Werb, Z., and Rosen, S.D. 2005. Sulf-2, a pro-angiogenic heparan sulfate endosulfatase, is upregulated in breast cancer. Neoplasia 7:1001-1010

Uchimura, K., Morimoto-Tomita, M., Bistrup, A., Li, J., Lyon, M., Gallagher, J., Werb, Z., and Rosen, S.D. 2006. HSulf-2, an extracellular endoglucosamine-6-sulfatase, selectively mobilizes heparin-bound growth factors and chemokines: effects on VEGF, FGF-1, and SDF-1. BMC Biochemistry 7:2.

Nawroth, R., van Zante, A., Cervantes, S., McManus, M., Hebrok, M., and Rosen, S.D. 2007. Extracellular sulfatases, elements of the wnt signaling pathway, positively regulate growth and tumorigenicity of human pancreatic cancer cells. PLoS ONE 2:e392.