title: Heparan sulfate proteoglycans mediate renal carcinoma metastasis.
abstract: The surface proteoglycan/glycoprotein layer (glycocalyx) on tumor cells has been associated with cellular functions that can potentially enable invasion and metastasis. In addition, aggressive tumor cells with high metastatic potential have enhanced invasion rates in response to interstitial flow stimuli in vitro. Our previous studies suggest that heparan sulfate (HS) in the glycocalyx plays an important role in this flow mediated mechanostransduction and upregulation of invasive and metastatic potential. In this study, highly metastatic renal cell carcinoma cells were genetically modified to suppress HS production by knocking down its synthetic enzyme NDST1. Using modified Boyden chamber and microfluidic assays, we show that flow-enhanced invasion is suppressed in HS deficient cells. To assess the ability of these cells to metastasize in vivo, parental or knockdown cells expressing fluorescence reporters were injected into kidney capsules in SCID mice. Histological analysis confirmed that there was a large reduction (95%) in metastasis to distant organs by tumors formed from the NDST1 knockdown cells compared to control cells with intact HS. The ability of these cells to invade surrounding tissue was also impaired. The substantial inhibition of metastasis and invasion upon reduction of HS suggests an active role for the tumor cell glycocalyx in tumor progression.
authors.affiliation: Wallace H. Coulter Laboratory, Department of Biomedical Engineering, The City College of New York, The City University of New York, New York, NY 10032, USA.
authors.forename: Henry
authors.initials: H
authors.lastname: Qazi
authors.affiliation: Developmental Biology Program, Sloan-Kettering Institute, New York, NY 10065, USA.
authors.forename: Zhong-Dong
authors.initials: ZD
authors.lastname: Shi
authors.affiliation: Comprehensive Cancer Center, Department of Mechanical and Aerospace Engineering, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Jonathan W
authors.initials: JW
authors.lastname: Song
authors.affiliation: Wallace H. Coulter Laboratory, Department of Biomedical Engineering, The City College of New York, The City University of New York, New York, NY 10032, USA.
authors.forename: Limary M
authors.initials: LM
authors.lastname: Cancel
authors.affiliation: Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Peigen
authors.initials: P
authors.lastname: Huang
authors.affiliation: Wallace H. Coulter Laboratory, Department of Biomedical Engineering, The City College of New York, The City University of New York, New York, NY 10032, USA.|Institute of Biomedical Engineering, School of Preclinical and Forensic Medicine, Sichuan University, China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Zeng
authors.affiliation: Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Roberge
authors.affiliation: Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA. tarbell@ccny.cuny.edu.
authors.forename: Lance L
authors.initials: LL
authors.lastname: Munn
authors.affiliation: Wallace H. Coulter Laboratory, Department of Biomedical Engineering, The City College of New York, The City University of New York, New York, NY 10032, USA. lmunn@mgh.harvard.edu.
authors.forename: John M
authors.initials: JM
authors.lastname: Tarbell
mesh_terms: D000818:Animals; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D004195:Disease Models, Animal; D015870:Gene Expression; D055786:Gene Knockout Techniques; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism*; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009362:Neoplasm Metastasis; D010641:Phenotype; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D018874:Spheroids, Cellular; D015238:Sulfotransferases / Q000235:genetics / Q000378:metabolism; D047368:Tumor Burden; D014407:Tumor Cells, Cultured
chemical_list: D019812:Heparan Sulfate Proteoglycans; D034741:RNA, Small Interfering; D015238:Sulfotransferases; C021350:heparitin sulfotransferase
keywords: NDST1; glycocalyx; interstitial flow; mechanobiology; metastasis