title: Role of Tumor Pericytes in the Recruitment of Myeloid-Derived Suppressor Cells.
abstract: BACKGROUND
  Pericytes are members of the tumor stroma; however, little is known about their origin, function, or interaction with other tumor components. Emerging evidence suggest that pericytes may regulate leukocyte transmigration. Myeloid-derived suppressor cells (MDSC) are immature myeloid cells with powerful inhibitory effects on T-cell-mediated antitumor reactivity.
  
  
  METHODS
  We generated subcutaneous tumors in a genetic mouse model of pericyte deficiency (the pdgfb (ret/ret) mouse) and littermate control mice (n = 6-25). Gene expression profiles from 253 breast cancer patients (stage I-III) were evaluated for clinic-pathological parameters and survival using Cox proportional hazard ratios (HRs) and 95% confidence intervals (CIs) based on a two-sided Wald test.
  
  
  RESULTS
  We report that pericyte deficiency leads to increased transmigration of Gr1(+)/CD11b(+) cells in experimentally induced tumors. Pericyte deficiency produced defective tumor vasculature, resulting in a more hypoxic microenvironment promoting IL-6 upregulation in the malignant cells. Silencing IL-6 expression in tumor cells attenuated the observed differences in MDSC transmigration. Restoring the pericyte coverage in tumors abrogated the increased MDSC trafficking to pericyte-deficient tumors. MDSC accumulation in tumors led to increases in tumor growth and in circulating malignant cells. Finally, gene expression analysis from human breast cancer patients revealed increased expression of the human MDSC markers CD33 and S100A9 with concomitant decreased expression of pericyte genes and was associated with poor prognosis (HR = 1.88, 95% CI = 1.08 to 3.25, P = .03).
  
  
  CONCLUSIONS
  Our data uncovers a novel paracrine interaction between tumor pericytes and inflammatory cells and delineates the cellular events resulting in the recruitment of MDSC to tumors. Furthermore, we propose for the first time a role for tumor pericytes in modulating the expression of immune mediators in malignant cells by promoting a hypoxic microenvironment.
authors: Department of Medical Biochemistry and Biophysics, Division of Vascular Biology, Karolinska Institute, Stockholm, Sweden (JWH, TL, ML, YGI, HQ, MZ, MZA, IN, PR, GG); Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska University Hospital, Solna, Sweden (NPT, JP, JH, AÖ, JB); Department of Cell and Molecular Biology, Karolinska Institute, Stockholm, Sweden (HR, RSJ); Department of Physiology, Development, and Neuroscience, University of Cambridge, Cambridge, UK (RSJ); Department of Molecular Medicine and Surgery, Urology Laboratory, Karolinska Institute, Stockholm, Sweden (MP); Department of Urology, Karolinska University Hospital, Solna, Sweden (MP).Current affiliation: Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland (HQ).
authors: JongWook
authors: J
authors: Hong
authors: Department of Medical Biochemistry and Biophysics, Division of Vascular Biology, Karolinska Institute, Stockholm, Sweden (JWH, TL, ML, YGI, HQ, MZ, MZA, IN, PR, GG); Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska University Hospital, Solna, Sweden (NPT, JP, JH, AÖ, JB); Department of Cell and Molecular Biology, Karolinska Institute, Stockholm, Sweden (HR, RSJ); Department of Physiology, Development, and Neuroscience, University of Cambridge, Cambridge, UK (RSJ); Department of Molecular Medicine and Surgery, Urology Laboratory, Karolinska Institute, Stockholm, Sweden (MP); Department of Urology, Karolinska University Hospital, Solna, Sweden (MP).Current affiliation: Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland (HQ).
authors: Nicholas P
authors: NP
authors: Tobin
authors: Department of Medical Biochemistry and Biophysics, Division of Vascular Biology, Karolinska Institute, Stockholm, Sweden (JWH, TL, ML, YGI, HQ, MZ, MZA, IN, PR, GG); Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska University Hospital, Solna, Sweden (NPT, JP, JH, AÖ, JB); Department of Cell and Molecular Biology, Karolinska Institute, Stockholm, Sweden (HR, RSJ); Department of Physiology, Development, and Neuroscience, University of Cambridge, Cambridge, UK (RSJ); Department of Molecular Medicine and Surgery, Urology Laboratory, Karolinska Institute, Stockholm, Sweden (MP); Department of Urology, Karolinska University Hospital, Solna, Sweden (MP).Current affiliation: Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland (HQ).
authors: Helene
authors: H
authors: Rundqvist
authors: Department of Medical Biochemistry and Biophysics, Division of Vascular Biology, Karolinska Institute, Stockholm, Sweden (JWH, TL, ML, YGI, HQ, MZ, MZA, IN, PR, GG); Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska University Hospital, Solna, Sweden (NPT, JP, JH, AÖ, JB); Department of Cell and Molecular Biology, Karolinska Institute, Stockholm, Sweden (HR, RSJ); Department of Physiology, Development, and Neuroscience, University of Cambridge, Cambridge, UK (RSJ); Department of Molecular Medicine and Surgery, Urology Laboratory, Karolinska Institute, Stockholm, Sweden (MP); Department of Urology, Karolinska University Hospital, Solna, Sweden (MP).Current affiliation: Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland (HQ).
authors: Tian
authors: T
authors: Li
authors: Department of Medical Biochemistry and Biophysics, Division of Vascular Biology, Karolinska Institute, Stockholm, Sweden (JWH, TL, ML, YGI, HQ, MZ, MZA, IN, PR, GG); Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska University Hospital, Solna, Sweden (NPT, JP, JH, AÖ, JB); Department of Cell and Molecular Biology, Karolinska Institute, Stockholm, Sweden (HR, RSJ); Department of Physiology, Development, and Neuroscience, University of Cambridge, Cambridge, UK (RSJ); Department of Molecular Medicine and Surgery, Urology Laboratory, Karolinska Institute, Stockholm, Sweden (MP); Department of Urology, Karolinska University Hospital, Solna, Sweden (MP).Current affiliation: Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland (HQ).
authors: Marion
authors: M
authors: Lavergne
authors: Department of Medical Biochemistry and Biophysics, Division of Vascular Biology, Karolinska Institute, Stockholm, Sweden (JWH, TL, ML, YGI, HQ, MZ, MZA, IN, PR, GG); Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska University Hospital, Solna, Sweden (NPT, JP, JH, AÖ, JB); Department of Cell and Molecular Biology, Karolinska Institute, Stockholm, Sweden (HR, RSJ); Department of Physiology, Development, and Neuroscience, University of Cambridge, Cambridge, UK (RSJ); Department of Molecular Medicine and Surgery, Urology Laboratory, Karolinska Institute, Stockholm, Sweden (MP); Department of Urology, Karolinska University Hospital, Solna, Sweden (MP).Current affiliation: Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland (HQ).
authors: Yaiza
authors: Y
authors: García-Ibáñez
authors: Department of Medical Biochemistry and Biophysics, Division of Vascular Biology, Karolinska Institute, Stockholm, Sweden (JWH, TL, ML, YGI, HQ, MZ, MZA, IN, PR, GG); Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska University Hospital, Solna, Sweden (NPT, JP, JH, AÖ, JB); Department of Cell and Molecular Biology, Karolinska Institute, Stockholm, Sweden (HR, RSJ); Department of Physiology, Development, and Neuroscience, University of Cambridge, Cambridge, UK (RSJ); Department of Molecular Medicine and Surgery, Urology Laboratory, Karolinska Institute, Stockholm, Sweden (MP); Department of Urology, Karolinska University Hospital, Solna, Sweden (MP).Current affiliation: Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland (HQ).
authors: Hanyu
authors: H
authors: Qin
authors: Department of Medical Biochemistry and Biophysics, Division of Vascular Biology, Karolinska Institute, Stockholm, Sweden (JWH, TL, ML, YGI, HQ, MZ, MZA, IN, PR, GG); Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska University Hospital, Solna, Sweden (NPT, JP, JH, AÖ, JB); Department of Cell and Molecular Biology, Karolinska Institute, Stockholm, Sweden (HR, RSJ); Department of Physiology, Development, and Neuroscience, University of Cambridge, Cambridge, UK (RSJ); Department of Molecular Medicine and Surgery, Urology Laboratory, Karolinska Institute, Stockholm, Sweden (MP); Department of Urology, Karolinska University Hospital, Solna, Sweden (MP).Current affiliation: Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland (HQ).
authors: Janna
authors: J
authors: Paulsson
authors: Department of Medical Biochemistry and Biophysics, Division of Vascular Biology, Karolinska Institute, Stockholm, Sweden (JWH, TL, ML, YGI, HQ, MZ, MZA, IN, PR, GG); Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska University Hospital, Solna, Sweden (NPT, JP, JH, AÖ, JB); Department of Cell and Molecular Biology, Karolinska Institute, Stockholm, Sweden (HR, RSJ); Department of Physiology, Development, and Neuroscience, University of Cambridge, Cambridge, UK (RSJ); Department of Molecular Medicine and Surgery, Urology Laboratory, Karolinska Institute, Stockholm, Sweden (MP); Department of Urology, Karolinska University Hospital, Solna, Sweden (MP).Current affiliation: Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland (HQ).
authors: Manuel
authors: M
authors: Zeitelhofer
authors: Department of Medical Biochemistry and Biophysics, Division of Vascular Biology, Karolinska Institute, Stockholm, Sweden (JWH, TL, ML, YGI, HQ, MZ, MZA, IN, PR, GG); Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska University Hospital, Solna, Sweden (NPT, JP, JH, AÖ, JB); Department of Cell and Molecular Biology, Karolinska Institute, Stockholm, Sweden (HR, RSJ); Department of Physiology, Development, and Neuroscience, University of Cambridge, Cambridge, UK (RSJ); Department of Molecular Medicine and Surgery, Urology Laboratory, Karolinska Institute, Stockholm, Sweden (MP); Department of Urology, Karolinska University Hospital, Solna, Sweden (MP).Current affiliation: Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland (HQ).
authors: Milena Z
authors: MZ
authors: Adzemovic
authors: Department of Medical Biochemistry and Biophysics, Division of Vascular Biology, Karolinska Institute, Stockholm, Sweden (JWH, TL, ML, YGI, HQ, MZ, MZA, IN, PR, GG); Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska University Hospital, Solna, Sweden (NPT, JP, JH, AÖ, JB); Department of Cell and Molecular Biology, Karolinska Institute, Stockholm, Sweden (HR, RSJ); Department of Physiology, Development, and Neuroscience, University of Cambridge, Cambridge, UK (RSJ); Department of Molecular Medicine and Surgery, Urology Laboratory, Karolinska Institute, Stockholm, Sweden (MP); Department of Urology, Karolinska University Hospital, Solna, Sweden (MP).Current affiliation: Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland (HQ).
authors: Ingrid
authors: I
authors: Nilsson
authors: Department of Medical Biochemistry and Biophysics, Division of Vascular Biology, Karolinska Institute, Stockholm, Sweden (JWH, TL, ML, YGI, HQ, MZ, MZA, IN, PR, GG); Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska University Hospital, Solna, Sweden (NPT, JP, JH, AÖ, JB); Department of Cell and Molecular Biology, Karolinska Institute, Stockholm, Sweden (HR, RSJ); Department of Physiology, Development, and Neuroscience, University of Cambridge, Cambridge, UK (RSJ); Department of Molecular Medicine and Surgery, Urology Laboratory, Karolinska Institute, Stockholm, Sweden (MP); Department of Urology, Karolinska University Hospital, Solna, Sweden (MP).Current affiliation: Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland (HQ).
authors: Pernilla
authors: P
authors: Roswall
authors: Department of Medical Biochemistry and Biophysics, Division of Vascular Biology, Karolinska Institute, Stockholm, Sweden (JWH, TL, ML, YGI, HQ, MZ, MZA, IN, PR, GG); Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska University Hospital, Solna, Sweden (NPT, JP, JH, AÖ, JB); Department of Cell and Molecular Biology, Karolinska Institute, Stockholm, Sweden (HR, RSJ); Department of Physiology, Development, and Neuroscience, University of Cambridge, Cambridge, UK (RSJ); Department of Molecular Medicine and Surgery, Urology Laboratory, Karolinska Institute, Stockholm, Sweden (MP); Department of Urology, Karolinska University Hospital, Solna, Sweden (MP).Current affiliation: Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland (HQ).
authors: Johan
authors: J
authors: Hartman
authors: Department of Medical Biochemistry and Biophysics, Division of Vascular Biology, Karolinska Institute, Stockholm, Sweden (JWH, TL, ML, YGI, HQ, MZ, MZA, IN, PR, GG); Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska University Hospital, Solna, Sweden (NPT, JP, JH, AÖ, JB); Department of Cell and Molecular Biology, Karolinska Institute, Stockholm, Sweden (HR, RSJ); Department of Physiology, Development, and Neuroscience, University of Cambridge, Cambridge, UK (RSJ); Department of Molecular Medicine and Surgery, Urology Laboratory, Karolinska Institute, Stockholm, Sweden (MP); Department of Urology, Karolinska University Hospital, Solna, Sweden (MP).Current affiliation: Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland (HQ).
authors: Randall S
authors: RS
authors: Johnson
authors: Department of Medical Biochemistry and Biophysics, Division of Vascular Biology, Karolinska Institute, Stockholm, Sweden (JWH, TL, ML, YGI, HQ, MZ, MZA, IN, PR, GG); Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska University Hospital, Solna, Sweden (NPT, JP, JH, AÖ, JB); Department of Cell and Molecular Biology, Karolinska Institute, Stockholm, Sweden (HR, RSJ); Department of Physiology, Development, and Neuroscience, University of Cambridge, Cambridge, UK (RSJ); Department of Molecular Medicine and Surgery, Urology Laboratory, Karolinska Institute, Stockholm, Sweden (MP); Department of Urology, Karolinska University Hospital, Solna, Sweden (MP).Current affiliation: Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland (HQ).
authors: Arne
authors: A
authors: Östman
authors: Department of Medical Biochemistry and Biophysics, Division of Vascular Biology, Karolinska Institute, Stockholm, Sweden (JWH, TL, ML, YGI, HQ, MZ, MZA, IN, PR, GG); Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska University Hospital, Solna, Sweden (NPT, JP, JH, AÖ, JB); Department of Cell and Molecular Biology, Karolinska Institute, Stockholm, Sweden (HR, RSJ); Department of Physiology, Development, and Neuroscience, University of Cambridge, Cambridge, UK (RSJ); Department of Molecular Medicine and Surgery, Urology Laboratory, Karolinska Institute, Stockholm, Sweden (MP); Department of Urology, Karolinska University Hospital, Solna, Sweden (MP).Current affiliation: Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland (HQ).
authors: Jonas
authors: J
authors: Bergh
authors: Department of Medical Biochemistry and Biophysics, Division of Vascular Biology, Karolinska Institute, Stockholm, Sweden (JWH, TL, ML, YGI, HQ, MZ, MZA, IN, PR, GG); Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska University Hospital, Solna, Sweden (NPT, JP, JH, AÖ, JB); Department of Cell and Molecular Biology, Karolinska Institute, Stockholm, Sweden (HR, RSJ); Department of Physiology, Development, and Neuroscience, University of Cambridge, Cambridge, UK (RSJ); Department of Molecular Medicine and Surgery, Urology Laboratory, Karolinska Institute, Stockholm, Sweden (MP); Department of Urology, Karolinska University Hospital, Solna, Sweden (MP).Current affiliation: Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland (HQ).
authors: Mirjana
authors: M
authors: Poljakovic
authors: Department of Medical Biochemistry and Biophysics, Division of Vascular Biology, Karolinska Institute, Stockholm, Sweden (JWH, TL, ML, YGI, HQ, MZ, MZA, IN, PR, GG); Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska University Hospital, Solna, Sweden (NPT, JP, JH, AÖ, JB); Department of Cell and Molecular Biology, Karolinska Institute, Stockholm, Sweden (HR, RSJ); Department of Physiology, Development, and Neuroscience, University of Cambridge, Cambridge, UK (RSJ); Department of Molecular Medicine and Surgery, Urology Laboratory, Karolinska Institute, Stockholm, Sweden (MP); Department of Urology, Karolinska University Hospital, Solna, Sweden (MP).Current affiliation: Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland (HQ). guillem.genove@ki.se.
authors: Guillem
authors: G
authors: Genové
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D039481:CD11b Antigen / Q000378:metabolism*; D015687:Cell Hypoxia; D002465:Cell Movement; D005260:Female; D005434:Flow Cytometry; D020868:Gene Silencing; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics; D051379:Mice; D022423:Myeloid Cells; D009374:Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology*; D020286:Pericytes; D019707:Receptors, Chemokine / Q000378:metabolism*; D040521:Subcutaneous Tissue; D013548:Sweden; D059467:Transcriptome; D059016:Tumor Microenvironment
chemical_list: D000954:Antigens, Surface; D039481:CD11b Antigen; C503133:Gr-1 protein, mouse; D015850:Interleukin-6; D019707:Receptors, Chemokine