Churchill Cancer Centre, Gynecologic Oncology Department, Old Road, Headington, Oxford OX3 7LE, UK; S. Carlo Borromeo's Hospital, Gynecologic and Obstetrics Department, Via Pio II n. 3, 20153 MI, Italy; Immunology and Inflammation Department, IRCCS Humanitas, Via A. Manzoni 53, Rozzano, MI, Italy.
Cytokine. 2013 Nov;64(2):509-15. doi: 10.1016/j.cyto.2013.07.024. Epub 2013 Aug 25.
Tumor microenvironment inflammatory cells play a major role in cancer progression. Among these, the Tumor Associated Macrophages (TAMs) infiltration depends on the kind of chemokine, cytokines and growth factors secreted by the tumor cells and by the stroma in response to the cancer invasion. TAMs have been found to promote anti-tumor response in early stages and to stimulate neovascularization and metastases in advanced disease. In the microenvironment chemo-attractants of many human cancers, MIF and VEGF correlate with an increased TAMs recruitment. In addition, MIF enhances tumor cells metastases by modulating the immune responses and by promoting the angiogenesis related to VEGF. On the contrary the inhibition of MIF can lead to cell cycle arrest and apoptosis. Some chemokines (e.g. CXCL12, CXCL11, CXCL8) and their receptors, thanks to their ability to modulate migration and proliferation, are involved in the angiogenetic process. In this study we compared the expression of MIF mRNA with VEGF mRNA expression and with mRNA expression of other chemokines related to neo-angiogenesis, such as CXCL12, CXCL11, CXCL8 and CXCR4, in human endometrial cancer tissue (EC) and normal endometrium (NE). Fresh samples of EC tissue and NE were extracted from 15 patients with FIGO stage I-III undergoing primary surgery. Some of the tissue was sent for histology and part of it was treated with RNA later and stored at -80°C. Four patients dropped out. A significant up-regulation of MIF mRNA in EC tissue versus NE samples (P=0.01) was observed in all 11 patients. The MIF mRNA over-expression was coincident with a VEGF mRNA overexpression in 54% of patients (P=NS). MIF mRNA was inversely related to CXCL12 mRNA expression (P=0.01). MIF over-expression was significantly related to low grading G1-2 (P=0.01), endometrial type I (P=0.05), no lymphovascular spaces invasion (P=0.01) and 3years DFS (P=0.01). As reported in previous studies on patients with breast cancer, our data suggest that the up-regulation of MIF in patients with endometrial cancer might be related to the inhibition of distant and lymphatic spread.
肿瘤微环境中的炎症细胞在癌症进展中起着重要作用。在这些细胞中，肿瘤相关巨噬细胞（TAMs）的浸润取决于肿瘤细胞和基质分泌的趋化因子、细胞因子和生长因子的种类，这些因子会对癌症的侵袭做出反应。已经发现 TAMs 在早期阶段促进抗肿瘤反应，并在晚期疾病中刺激新血管生成和转移。在许多人类癌症的微环境趋化因子中，MIF 和 VEGF 与 TAMs 的募集增加相关。此外，MIF 通过调节免疫反应和促进与 VEGF 相关的血管生成来增强肿瘤细胞的转移。相反，MIF 的抑制可导致细胞周期停滞和细胞凋亡。一些趋化因子（例如 CXCL12、CXCL11、CXCL8）及其受体，由于其调节迁移和增殖的能力，参与了血管生成过程。在这项研究中，我们比较了 MIF mRNA 的表达与 VEGF mRNA 的表达以及与新血管生成相关的其他趋化因子（如 CXCL12、CXCL11、CXCL8 和 CXCR4）的 mRNA 表达，这些趋化因子在人子宫内膜癌组织（EC）和正常子宫内膜（NE）中。从 15 名接受原发性手术的 FIGO Ⅰ-Ⅲ期的患者中提取新鲜的 EC 组织和 NE 样本。部分组织用于组织学检查，部分组织用 RNA 稳定剂处理并存放在-80°C。有 4 名患者退出。在所有 11 名患者中，EC 组织中的 MIF mRNA 明显上调（P=0.01），与 NE 样本相比。在 54%的患者中，MIF mRNA 的过表达与 VEGF mRNA 的过表达一致（P=NS）。MIF mRNA 与 CXCL12 mRNA 的表达呈负相关（P=0.01）。MIF 过表达与低分级 G1-2（P=0.01）、子宫内膜 I 型（P=0.05）、无血管淋巴管间隙浸润（P=0.01）和 3 年无病生存（DFS）（P=0.01）显著相关。正如之前对乳腺癌患者的研究报告的那样，我们的数据表明，子宫内膜癌患者中 MIF 的上调可能与远处和淋巴转移的抑制有关。
