title: Macrophage polarization in pancreatic carcinoma: role of heparanase enzyme.
abstract: BACKGROUND
  Tumor microenvironment, and particularly tumor-associated macrophages (TAMs), represent a key contributing factor in pancreatic ductal adenocarcinoma (PDAC) pathogenesis. Here we report that heparanase (predominant enzyme degrading heparan sulfate, the main polysaccharide found at the cell surface and extracellular matrix) directs tumor-promoting behavior of TAM in PDAC.
  
  
  METHODS
  A mouse model of heparanase-overexpressing pancreatic carcinoma (n = 5 mice/group), tumor-associated macrophages ex vivo, primary wild-type and heparanase-null macrophages, and histological specimens from PDAC patients (n = 16), were analyzed, applying immunostaining, enzyme-linked immunosorbent assay, real-time reverse transcription-polymerase chain reaction, cell proliferation, and heparanase activity assays. All statistical tests are two-sided.
  
  
  RESULTS
  We found that overexpression of heparanase is associated with increased TAM infiltration in both experimental (P = .002) and human (P = .01) PDAC. Moreover, macrophages derived from heparanase-rich tumors (which grew faster in mouse hosts), display pronounced procancerous phenotype, evidenced by overexpression of MSR-2, IL-10, CCL2, VEGF, and increased production of IL-6, an important player in PDAC pathogenesis. Furthermore, in vitro heparanase enzyme-rendered macrophages (stimulated by necrotic cells which are often present in PDAC tissue) procancerous, as exemplified by their enhanced production of key cytokines implicated in PDAC (including IL-6), as well as by their ability to induce STAT3 signaling and to augment pancreatic carcinoma cell proliferation. In agreement, we observed activation of STAT3 in experimental and clinical specimens of heparanase-overexpressing PDAC.
  
  
  CONCLUSIONS
  Our findings underscore a novel function of heparanase in molecular decision-making that guides cancer-promoting action of TAM and imply that heparanase expression status may become highly relevant in defining a target patient subgroup that is likely to benefit the most from treatment modalities targeting TAM/IL-6/STAT3.
authors.affiliation: : Department of Oncology, Sharett Oncology Institute, Hadassah-Hebrew University Medical Center, Jerusalem, Israel (EH, AM, LA, TP, ME); Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel (KM); Institute of Dental Sciences, Hebrew University-Hadassah Faculty of Dental Medicine, Jerusalem, Israel (GN). melkin@hadassah.org.il.
authors.forename: Esther
authors.initials: E
authors.lastname: Hermano
authors.affiliation: : Department of Oncology, Sharett Oncology Institute, Hadassah-Hebrew University Medical Center, Jerusalem, Israel (EH, AM, LA, TP, ME); Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel (KM); Institute of Dental Sciences, Hebrew University-Hadassah Faculty of Dental Medicine, Jerusalem, Israel (GN). melkin@hadassah.org.il.
authors.forename: Amichay
authors.initials: A
authors.lastname: Meirovitz
authors.affiliation: : Department of Oncology, Sharett Oncology Institute, Hadassah-Hebrew University Medical Center, Jerusalem, Israel (EH, AM, LA, TP, ME); Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel (KM); Institute of Dental Sciences, Hebrew University-Hadassah Faculty of Dental Medicine, Jerusalem, Israel (GN).
authors.forename: Karen
authors.initials: K
authors.lastname: Meir
authors.affiliation: : Department of Oncology, Sharett Oncology Institute, Hadassah-Hebrew University Medical Center, Jerusalem, Israel (EH, AM, LA, TP, ME); Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel (KM); Institute of Dental Sciences, Hebrew University-Hadassah Faculty of Dental Medicine, Jerusalem, Israel (GN).
authors.forename: Gabriel
authors.initials: G
authors.lastname: Nussbaum
authors.affiliation: : Department of Oncology, Sharett Oncology Institute, Hadassah-Hebrew University Medical Center, Jerusalem, Israel (EH, AM, LA, TP, ME); Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel (KM); Institute of Dental Sciences, Hebrew University-Hadassah Faculty of Dental Medicine, Jerusalem, Israel (GN).
authors.forename: Limor
authors.initials: L
authors.lastname: Appelbaum
authors.affiliation: : Department of Oncology, Sharett Oncology Institute, Hadassah-Hebrew University Medical Center, Jerusalem, Israel (EH, AM, LA, TP, ME); Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel (KM); Institute of Dental Sciences, Hebrew University-Hadassah Faculty of Dental Medicine, Jerusalem, Israel (GN).
authors.forename: Tamar
authors.initials: T
authors.lastname: Peretz
authors.affiliation: : Department of Oncology, Sharett Oncology Institute, Hadassah-Hebrew University Medical Center, Jerusalem, Israel (EH, AM, LA, TP, ME); Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel (KM); Institute of Dental Sciences, Hebrew University-Hadassah Faculty of Dental Medicine, Jerusalem, Israel (GN). melkin@hadassah.org.il.
authors.forename: Michael
authors.initials: M
authors.lastname: Elkin
mesh_terms: D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018932:Chemokine CCL2 / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D005966:Glucuronidase / Q000378:metabolism*; D007150:Immunohistochemistry; D016753:Interleukin-10 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D051379:Mice; D016513:Mice, SCID; D010190:Pancreatic Neoplasms / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D060888:Real-Time Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D000099175:Heparanase
chemical_list: D018932:Chemokine CCL2; D005966:Glucuronidase; D016753:Interleukin-10; D015850:Interleukin-6; D050796:STAT3 Transcription Factor; D042461:Vascular Endothelial Growth Factor A; D000099175:Heparanase; C491768:Ccl2 protein, mouse; C494087:Stat3 protein, mouse; C467480:vascular endothelial growth factor A, mouse