Hermano Esther, Meirovitz Amichay, Meir Karen, Nussbaum Gabriel, Appelbaum Limor, Peretz Tamar, Elkin Michael
: 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).
J Natl Cancer Inst. 2014 Oct 18;106(12). doi: 10.1093/jnci/dju332. Print 2014 Dec.
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.
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.
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.
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.
肿瘤微环境，尤其是肿瘤相关巨噬细胞（TAM），是胰腺导管腺癌（PDAC）发病机制中的一个关键因素。在此，我们报告硫酸乙酰肝素酶（降解硫酸乙酰肝素的主要酶，硫酸乙酰肝素是细胞表面和细胞外基质中发现的主要多糖）可引导PDAC中TAM的促肿瘤行为。
对硫酸乙酰肝素酶过表达的胰腺癌小鼠模型（每组5只小鼠）、体外肿瘤相关巨噬细胞、原代野生型和硫酸乙酰肝素酶缺陷巨噬细胞以及PDAC患者的组织学标本（16例）进行分析，采用免疫染色、酶联免疫吸附测定、实时逆转录-聚合酶链反应、细胞增殖和硫酸乙酰肝素酶活性测定。所有统计检验均为双侧检验。
我们发现，在实验性（P = 0.002）和人类（P = 0.01）PDAC中，硫酸乙酰肝素酶的过表达与TAM浸润增加有关。此外，源自富含硫酸乙酰肝素酶肿瘤（在小鼠宿主中生长更快）的巨噬细胞表现出明显的促癌表型，MSR-2、IL-10、CCL2、VEGF的过表达以及IL-6产量的增加证明了这一点，IL-6是PDAC发病机制中的一个重要因素。此外，体外硫酸乙酰肝素酶处理的巨噬细胞（由PDAC组织中经常存在的坏死细胞刺激）具有促癌作用，例如它们增强了与PDAC相关的关键细胞因子（包括IL-6）的产生，以及它们诱导STAT3信号传导和增强胰腺癌细胞增殖的能力。一致的是，我们在硫酸乙酰肝素酶过表达的PDAC实验和临床标本中观察到了STAT3的激活。
我们的研究结果强调了硫酸乙酰肝素酶在指导TAM促癌作用的分子决策中的新功能，并表明硫酸乙酰肝素酶的表达状态可能与确定最有可能从靶向TAM/IL-6/STAT3的治疗方式中获益的目标患者亚组高度相关。
