Macrophage polarization in pancreatic carcinoma: Role of heparanase enzyme: Role of heparanase enzyme

Esther Hermano, Amichay Meirovitz, Karen Meir, Gabriel Nussbaum, Limor Appelbaum, Tamar Peretz, Michael Elkin

Research output: Contribution to journalArticlepeer-review

46 Scopus citations

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.
Original languageEnglish
JournalJournal of the National Cancer Institute
Volume106
Issue number12
DOIs
StatePublished - 1 Dec 2014

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint

Dive into the research topics of 'Macrophage polarization in pancreatic carcinoma: Role of heparanase enzyme: Role of heparanase enzyme'. Together they form a unique fingerprint.

Cite this