title: Interstitial Fluid Sphingosine-1-Phosphate in Murine Mammary Gland and Cancer and Human Breast Tissue and Cancer Determined by Novel Methods.
abstract: The tumor microenvironment is a determining factor for cancer biology and progression. Sphingosine-1-phosphate (S1P), produced by sphingosine kinases (SphKs), is a bioactive lipid mediator that regulates processes important for cancer progression. Despite its critical roles, the levels of S1P in interstitial fluid (IF), an important component of the tumor microenvironment, have never previously been measured due to a lack of efficient methods for collecting and quantifying IF. The purpose of this study is to clarify the levels of S1P in the IF from murine mammary glands and its tumors utilizing our novel methods. We developed an improved centrifugation method to collect IF. Sphingolipids in IF, blood, and tissue samples were measured by mass spectrometry. In mice with a deletion of SphK1, but not SphK2, levels of S1P in IF from the mammary glands were greatly attenuated. Levels of S1P in IF from mammary tumors were reduced when tumor growth was suppressed by oral administration of FTY720/fingolimod. Importantly, sphingosine, dihydro-sphingosine, and S1P levels, but not dihydro-S1P, were significantly higher in human breast tumor tissue IF than in the normal breast tissue IF. To our knowledge, this is the first reported S1P IF measurement in murine normal mammary glands and mammary tumors, as well as in human patients with breast cancer. S1P tumor IF measurement illuminates new aspects of the role of S1P in the tumor microenvironment.
authors.affiliation: Division of Surgical Oncology, Department of Surgery, Virginia Commonwealth University School of Medicine, and Massey Cancer Center, PO Box 980011, West Hospital 7-402, 1200 East Broad Street, Richmond, VA, 23298-0011, USA. mnagahashi@med.niigata-u.ac.jp.|Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, and the Massey Cancer Center, PO Box 980011, West Hospital 7-402, 1200 East Marshall Street, Richmond, VA, 23298, USA. mnagahashi@med.niigata-u.ac.jp.|Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata City, Niigata, 951-8510, Japan. mnagahashi@med.niigata-u.ac.jp.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Nagahashi
authors.affiliation: Division of Surgical Oncology, Department of Surgery, Virginia Commonwealth University School of Medicine, and Massey Cancer Center, PO Box 980011, West Hospital 7-402, 1200 East Broad Street, Richmond, VA, 23298-0011, USA.|Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, and the Massey Cancer Center, PO Box 980011, West Hospital 7-402, 1200 East Marshall Street, Richmond, VA, 23298, USA.
authors.forename: Akimitsu
authors.initials: A
authors.lastname: Yamada
authors.affiliation: Section of General Internal Medicine, Kojin Hospital, 1-710 Shikenya, Moriyama, Nagoya, 463-8530, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Miyazaki
authors.affiliation: Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, and the Massey Cancer Center, PO Box 980011, West Hospital 7-402, 1200 East Marshall Street, Richmond, VA, 23298, USA.
authors.forename: Jeremy C
authors.initials: JC
authors.lastname: Allegood
authors.affiliation: Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata City, Niigata, 951-8510, Japan.
authors.forename: Junko
authors.initials: J
authors.lastname: Tsuchida
authors.affiliation: Division of Surgical Oncology, Department of Surgery, Virginia Commonwealth University School of Medicine, and Massey Cancer Center, PO Box 980011, West Hospital 7-402, 1200 East Broad Street, Richmond, VA, 23298-0011, USA.|Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, and the Massey Cancer Center, PO Box 980011, West Hospital 7-402, 1200 East Marshall Street, Richmond, VA, 23298, USA.
authors.forename: Tomoyoshi
authors.initials: T
authors.lastname: Aoyagi
authors.affiliation: Division of Surgical Oncology, Department of Surgery, Virginia Commonwealth University School of Medicine, and Massey Cancer Center, PO Box 980011, West Hospital 7-402, 1200 East Broad Street, Richmond, VA, 23298-0011, USA.|Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, and the Massey Cancer Center, PO Box 980011, West Hospital 7-402, 1200 East Marshall Street, Richmond, VA, 23298, USA.
authors.forename: Wei-Ching
authors.initials: WC
authors.lastname: Huang
authors.affiliation: Division of Surgical Oncology, Department of Surgery, Virginia Commonwealth University School of Medicine, and Massey Cancer Center, PO Box 980011, West Hospital 7-402, 1200 East Broad Street, Richmond, VA, 23298-0011, USA.|Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, and the Massey Cancer Center, PO Box 980011, West Hospital 7-402, 1200 East Marshall Street, Richmond, VA, 23298, USA.
authors.forename: Krista P
authors.initials: KP
authors.lastname: Terracina
authors.affiliation: Division of Surgical Oncology, Department of Surgery, Virginia Commonwealth University School of Medicine, and Massey Cancer Center, PO Box 980011, West Hospital 7-402, 1200 East Broad Street, Richmond, VA, 23298-0011, USA.|Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, and the Massey Cancer Center, PO Box 980011, West Hospital 7-402, 1200 East Marshall Street, Richmond, VA, 23298, USA.
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: Adams
authors.affiliation: Holy Cross Hospital Michael and Dianne Bienes Comprehensive Cancer Center, 4725 North Federal Highway, Fort Lauderdale, FL, 33308, USA.|Massachusetts General Hospital, 55 Fruit St, Boston, MA, 02114, USA.|University of Miami Miller School of Medicine, 1600 NW 10th Ave, Miami, FL, 33136, USA.
authors.forename: Omar M
authors.initials: OM
authors.lastname: Rashid
authors.affiliation: Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, and the Massey Cancer Center, PO Box 980011, West Hospital 7-402, 1200 East Marshall Street, Richmond, VA, 23298, USA.
authors.forename: Sheldon
authors.initials: S
authors.lastname: Milstien
authors.affiliation: Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata City, Niigata, 951-8510, Japan.
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Wakai
authors.affiliation: Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, and the Massey Cancer Center, PO Box 980011, West Hospital 7-402, 1200 East Marshall Street, Richmond, VA, 23298, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Spiegel
authors.affiliation: Division of Surgical Oncology, Department of Surgery, Virginia Commonwealth University School of Medicine, and Massey Cancer Center, PO Box 980011, West Hospital 7-402, 1200 East Broad Street, Richmond, VA, 23298-0011, USA. kazutakabe@gmail.com.|Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, and the Massey Cancer Center, PO Box 980011, West Hospital 7-402, 1200 East Marshall Street, Richmond, VA, 23298, USA. kazutakabe@gmail.com.|Breast Surgery, Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, NY, 14263, USA. kazutakabe@gmail.com.
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Takabe
mesh_terms: D065767:Activation, Metabolic; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use; D001940:Breast / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D045744:Cell Line, Tumor; D045604:Extracellular Fluid / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D000068876:Fingolimod Hydrochloride / Q000493:pharmacokinetics / Q000627:therapeutic use; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008246:Lysophospholipids / Q000097:blood / Q000378:metabolism*; D008321:Mammary Glands, Animal / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism; D011355:Prodrugs / Q000493:pharmacokinetics / Q000627:therapeutic use; D011897:Random Allocation; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism; D059016:Tumor Microenvironment / Q000187:drug effects; D000099157:Sphingosine Kinase
chemical_list: D000970:Antineoplastic Agents; D000068876:Fingolimod Hydrochloride; D007527:Isoenzymes; D008246:Lysophospholipids; D017853:Phosphotransferases (Alcohol Group Acceptor); D011355:Prodrugs; D013110:Sphingosine; D000099157:Sphingosine Kinase; C060506:sphingosine 1-phosphate
keywords: Cancer; Endothelial cells; Interstitial fluid; Mass spectrometry; Sphingolipids; Sphingosine-1-phosphate