title: Sphingosine-1-phosphate mediates a reciprocal signaling pathway between stellate cells and cancer cells that promotes pancreatic cancer growth.
abstract: Sphingosine-1-phosphate (S1P) is produced by sphingosine kinase 1 and is implicated in tumor growth, although the mechanisms remain incompletely understood. Pancreatic stellate cells (PSCs) reside within the tumor microenvironment and may regulate tumor progression. We hypothesized that S1P activates PSCs to release paracrine factors, which, in turn, increase cancer cell invasion and growth. We used a combination of human tissue, in vitro, and in vivo studies to mechanistically evaluate this concept. Sphingosine kinase 1 was overexpressed in human pancreatic tissue, especially within tumor cells. S1P activated PSCs in vitro and conditioned medium from S1P-stimulated PSCs, increased pancreatic cancer cell migration, and invasion, which was dependent on S1P2, ABL1 (alias c-Abl) kinase, and matrix metalloproteinase-9. In vivo studies showed that pancreatic cancer cells co-implanted with S1P2 receptor knockdown PSCs led to less cancer growth and metastasis in s.c. and orthotopic pancreatic cancer models compared with control PSCs. Pancreatic cancer cell-derived S1P activates PSCs to release paracrine factors, including matrix metalloproteinase-9, which reciprocally promotes tumor cell migration and invasion in vitro and cancer growth in vivo.
authors.affiliation: Gastroenterology Research Unit, the Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Yan
authors.initials: Y
authors.lastname: Bi
authors.affiliation: Gastroenterology Research Unit, the Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota; Department of Oncology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
authors.forename: Jiachu
authors.initials: J
authors.lastname: Li
authors.affiliation: Gastroenterology Research Unit, the Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Baoan
authors.initials: B
authors.lastname: Ji
authors.affiliation: Gastroenterology Research Unit, the Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Ningling
authors.initials: N
authors.lastname: Kang
authors.affiliation: Gastroenterology Research Unit, the Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Liu
authors.initials: L
authors.lastname: Yang
authors.affiliation: Gastroenterology Research Unit, the Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Simonetto
authors.affiliation: Gastroenterology Research Unit, the Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Jung H
authors.initials: JH
authors.lastname: Kwon
authors.affiliation: Gastroenterology Research Unit, the Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Marielle
authors.initials: M
authors.lastname: Kamath
authors.affiliation: Gastroenterology Research Unit, the Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Sheng
authors.initials: S
authors.lastname: Cao
authors.affiliation: Gastroenterology Research Unit, the Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota. Electronic address: shah.vijay@mayo.edu.
authors.forename: Vijay
authors.initials: V
authors.lastname: Shah
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008246:Lysophospholipids / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D010179:Pancreas / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D058954:Pancreatic Stellate Cells / Q000378:metabolism / Q000473:pathology*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism*; D049349:Receptors, Lysosphingolipid / Q000378:metabolism; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism; D059016:Tumor Microenvironment; D015854:Up-Regulation; D000099157:Sphingosine Kinase
chemical_list: D008246:Lysophospholipids; D020780:Matrix Metalloproteinase 9; D017853:Phosphotransferases (Alcohol Group Acceptor); D049349:Receptors, Lysosphingolipid; D013110:Sphingosine; D000099157:Sphingosine Kinase; C060506:sphingosine 1-phosphate; C579270:MMP9 protein, human
references.citation: Breast Cancer Res Treat. 2008 Nov;112(1):41-52
references.pmid: 18058224
references.citation: J Lipid Res. 2009 Mar;50(3):556-564
references.pmid: 18955732
references.citation: Science. 2002 Mar 29;295(5564):2387-92
references.pmid: 11923519
references.citation: Sci Signal. 2010 Sep 14;3(139):re6
references.pmid: 20841568
references.citation: FASEB J. 2009 Feb;23(2):405-14
references.pmid: 18824518
references.citation: Nat Rev Cancer. 2013 Aug;13(8):559-71
references.pmid: 23842646
references.citation: Am J Pathol. 1996 May;148(5):1345-50
references.pmid: 8623905
references.citation: J Clin Invest. 2007 Jan;117(1):50-9
references.pmid: 17200706
references.citation: Biomolecules. 2013;3(3):
references.pmid: 24286034
references.citation: Anticancer Res. 2011 Mar;31(3):789-95
references.pmid: 21498698
references.citation: Clin Cancer Res. 2009 Feb 15;15(4):1393-9
references.pmid: 19228740
references.citation: J Clin Invest. 2004 Nov;114(9):1308-16
references.pmid: 15520863
references.citation: J Clin Invest. 2013 Mar;123(3):1138-56
references.pmid: 23454766
references.citation: Nat Cell Biol. 2000 Oct;2(10):737-44
references.pmid: 11025665
references.citation: Mol Cell Biol. 2003 Jun;23(11):3884-96
references.pmid: 12748290
references.citation: Oncogene. 1993 Feb;8(2):395-405
references.pmid: 8426746
references.citation: Leuk Lymphoma. 2008 May;49(5):948-54
references.pmid: 18452097
references.citation: Nat Rev Cancer. 2006 Mar;6(3):227-39
references.pmid: 16498445
references.citation: Proteomics. 2013 May;13(9):1499-1512
references.pmid: 23456891
references.citation: Mol Cell Biol. 2002 Sep;22(17):6079-88
references.pmid: 12167702
references.citation: Cancer Res. 2012 Oct 1;72(19):4890-5
references.pmid: 23002203
references.citation: J Biol Chem. 2013 May 24;288(21):14839-51
references.pmid: 23589284
references.citation: Cancer Metastasis Rev. 2006 Mar;25(1):9-34
references.pmid: 16680569
references.citation: Cancer Res. 2008 Feb 1;68(3):918-26
references.pmid: 18245495
references.citation: EMBO Mol Med. 2012 Aug;4(8):761-75
references.pmid: 22707406
references.citation: Gut. 2011 Oct;60(10):1379-88
references.pmid: 21471572
references.citation: Nat Rev Drug Discov. 2013 Sep;12(9):688-702
references.pmid: 23954895
references.citation: Cancer Cell. 2013 Jan 14;23(1):107-20
references.pmid: 23273921
references.citation: Am J Pathol. 2010 Nov;177(5):2585-96
references.pmid: 20934972
references.citation: Crit Rev Biochem Mol Biol. 2002 Dec;37(6):375-536
references.pmid: 12540195
references.citation: FASEB J. 1995 Jul;9(10):974-80
references.pmid: 7615167
references.citation: Cell. 2000 Oct 27;103(3):481-90
references.pmid: 11081634
references.citation: Biol Cell. 2008 Nov;100(11):617-31
references.pmid: 18851712
references.citation: Neoplasia. 1999 Apr;1(1):50-62
references.pmid: 10935470
references.citation: Cancer Res. 2008 Apr 1;68(7):2085-93
references.pmid: 18381413
references.citation: J Cell Sci. 2007 Feb 1;120(Pt 3):512-9
references.pmid: 17227797
references.citation: In Vitro. 1982 Jan;18(1):24-34
references.pmid: 7182348
references.citation: Mol Cancer Ther. 2009 Apr;8(4):809-20
references.pmid: 19372554
references.citation: Nat Rev Gastroenterol Hepatol. 2012 Aug;9(8):454-67
references.pmid: 22710569
references.citation: In Vitro Cell Dev Biol Anim. 2002 Apr;38(4):246-53
references.pmid: 12197778
references.citation: Cancer Res. 2007 Dec 15;67(24):11798-810
references.pmid: 18089810
references.citation: J Biol Chem. 2006 Dec 22;281(51):39105-13
references.pmid: 17071613
references.citation: Nat Rev Cancer. 2010 Jul;10(7):489-503
references.pmid: 20555359
references.citation: Gastroenterology. 2013 Jun;144(6):1210-9
references.pmid: 23622130
references.citation: Int J Cancer. 1975 May 15;15(5):741-7
references.pmid: 1140870
references.citation: Gastrointest Cancer Res. 2012 May;5(3):77-83
references.pmid: 22888387
references.citation: Pancreatology. 2010;10(4):505-16
references.pmid: 20847583
references.citation: Clin Cancer Res. 2008 Nov 1;14(21):6996-7003
references.pmid: 18980995
references.citation: J Gastroenterol Hepatol. 2012 Mar;27 Suppl 2:127-34
references.pmid: 22320930
references.citation: J Histochem Cytochem. 2005 Sep;53(9):1159-66
references.pmid: 15923363
references.citation: Oncogene. 2000 Dec 27;19(56):6642-50
references.pmid: 11426650
references.citation: J Biol Chem. 1993 Nov 5;268(31):23460-8
references.pmid: 8226872
references.citation: J Cancer. 2013;4(4):315-9
references.pmid: 23569464
references.citation: Arterioscler Thromb Vasc Biol. 2009 Apr;29(4):562-70
references.pmid: 19150878