Schrevel Marlies, Osse E Michelle, Prins Frans A, Trimbos J Baptist M Z, Fleuren Gert Jan, Gorter Arko, Jordanova Ekaterina S
Department of Pathology, Leiden University Medical Center (LUMC), Leiden, The Netherlands.
Department of Gynecology, Leiden University Medical Center (LUMC), Leiden, The Netherlands.
Int J Oncol. 2017 Jun;50(6):1947-1954. doi: 10.3892/ijo.2017.3980. Epub 2017 May 3.
In cervical cancer, the epidermal growth factor receptor (EGFR) is overexpressed in 70-90% of the cases and has been associated with poor prognosis. EGFR-based therapy is currently being explored in cervical cancer. We investigated which EGFR ligand is primarily expressed in cervical cancer and which cell type functions as the major source of this ligand. We hypothesized that macrophages are the main source of EGFR ligands and that a paracrine loop between tumor cells and macrophages is responsible for ligand expression. mRNA expression analysis was performed on 32 cervical cancer cases to determine the expression of the EGFR ligands amphiregulin, β-cellulin, epidermal growth factor (EGF), epiregulin, heparin-binding EGF-like growth factor (HB‑EGF) and transforming growth factor α (TGFα). Subsequently, protein expression was determined immunohistochemically on 36 additional cases. To assess whether macrophages are the major source of EGFR ligands, immunohistochemical double staining was performed on four representative tissue slides. Expression of the chemokines granulocyte-macrophage colony-stimulating factor (GM-CSF) and C-C motif ligand 2 (CCL2) was determined by mRNA in situ hybridization. Of the known EGFR ligands, HB‑EGF had the highest mRNA expression and HB‑EGF and EGFR protein expression were highly correlated. Tumor specimens with high EGFR expression showed higher numbers of macrophages, and higher expression of GM-CSF and CCL2, but only a small subset (9%) of macrophages was found to be HB‑EGF-positive. Strikingly, 78% of cervical cancer specimens were found to express HB‑EGF. Standardized assessment of staining intensity, using spectral imaging analysis, showed that HB‑EGF expression was higher in the tumor compartment than in the stromal compartment. These results suggest that HB‑EGF is an important EGFR ligand in cervical cancer and that cervical cancer cells are the predominant source of HB‑EGF. Therefore, we propose an autocrine EGFR stimulation model in cervical carcinomas.
在宫颈癌中，70%-90%的病例中表皮生长因子受体（EGFR）呈过表达，且与预后不良相关。目前正在探索基于EGFR的宫颈癌治疗方法。我们研究了哪种EGFR配体在宫颈癌中主要表达，以及哪种细胞类型是该配体的主要来源。我们假设巨噬细胞是EGFR配体的主要来源，并且肿瘤细胞与巨噬细胞之间的旁分泌环负责配体表达。对32例宫颈癌病例进行mRNA表达分析，以确定EGFR配体双调蛋白、β-细胞ulin、表皮生长因子（EGF）、上皮调节素、肝素结合表皮生长因子样生长因子（HB-EGF）和转化生长因子α（TGFα）的表达。随后，对另外36例病例进行免疫组织化学检测蛋白表达。为了评估巨噬细胞是否是EGFR配体的主要来源，在四张代表性组织切片上进行免疫组织化学双重染色。通过mRNA原位杂交确定趋化因子粒细胞-巨噬细胞集落刺激因子（GM-CSF）和C-C基序配体2（CCL2）的表达。在已知的EGFR配体中，HB-EGF的mRNA表达最高，且HB-EGF与EGFR蛋白表达高度相关。EGFR高表达的肿瘤标本显示巨噬细胞数量更多，GM-CSF和CCL2的表达更高，但仅发现一小部分（9%）巨噬细胞为HB-EGF阳性。令人惊讶的是，78%的宫颈癌标本被发现表达HB-EGF。使用光谱成像分析对染色强度进行标准化评估，结果显示肿瘤区域的HB-EGF表达高于基质区域。这些结果表明，HB-EGF是宫颈癌中一种重要的EGFR配体，且宫颈癌细胞是HB-EGF的主要来源。因此，我们提出了宫颈癌中的自分泌EGFR刺激模型。
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