Etoh T, Shibuta K, Barnard G F, Kitano S, Mori M
Department of Surgery, Medical Institute of Bioregulation, Kyushu University, Beppu, Japan.
Clin Cancer Res. 2000 Sep;6(9):3545-51.
Tumor angiogenesis is essential for tumor growth and tumor metastasis, and it depends on angiogenic factors produced by tumor cells and/or infiltrating cells in tumor tissue. In this study, we evaluated the clinical significance of the expression of angiogenin, which is a potent angiogenic protein, and the relationship between its mRNA expression and focal macrophage infiltration in colorectal cancer. Furthermore, we investigated the induction of angiogenin mRNA expression by proinflammatory cytokines mainly produced by inflammatory cells in tumor tissues. When we examined the relationship between the mRNA expression of angiogenin, by semiquantitative reverse transcription-PCR, and clinicopathological features in 65 patients with colorectal cancer, there was a significant difference in the vascular involvement, lymph node metastasis, liver metastasis, and advanced stage in patients with high-expression of angiogenin compared with low expression (P < 0.05). With regard to prognosis, the survival time for subjects in the high angiogenin mRNA group (tumor:normal ratio >1.9) was significantly worse (P < 0.05). When we examined the localization of angiogenin in colorectal cancer, immunohistochemical analysis in 65 patients with colorectal cancer revealed that angiogenin was predominantly expressed in cancer cells compared with stromal cells or normal tissues. The intensity of staining of angiogenin was significantly correlated with microvessel counts and focal macrophage infiltration counts (P < 0.05). In an in vitro study, interleukin-1beta and tumor necrosis factor-alpha induced angiogenin mRNA expression in colon cancer cells in a dose- and time-dependent manner, and these cytokines significantly upregulated the expression of angiogenin mRNA, especially in colon cancer cells rather than in other cells in the stroma of tumor tissues (fibroblasts, tumor infiltrating lymphocytes, macrophages). These results suggest that tumor angiogenesis in colorectal cancer may be advanced, at least in part, by angiogenin induced by proinflammatory cytokines derived from infiltrating macrophages.
肿瘤血管生成对于肿瘤生长和转移至关重要，它依赖于肿瘤细胞和/或肿瘤组织中浸润细胞产生的血管生成因子。在本研究中，我们评估了血管生成素（一种强效血管生成蛋白）表达的临床意义，以及其mRNA表达与结直肠癌中局灶性巨噬细胞浸润之间的关系。此外，我们研究了肿瘤组织中炎症细胞主要产生的促炎细胞因子对血管生成素mRNA表达的诱导作用。当我们通过半定量逆转录 - PCR检测65例结直肠癌患者血管生成素的mRNA表达与临床病理特征之间的关系时，血管生成素高表达患者与低表达患者相比，在血管侵犯、淋巴结转移、肝转移和晚期阶段存在显著差异（P < 0.05）。关于预后，血管生成素mRNA高表达组（肿瘤：正常比值>1.9）患者的生存时间明显更差（P < 0.05）。当我们检测结直肠癌中血管生成素的定位时，对65例结直肠癌患者的免疫组织化学分析显示，与基质细胞或正常组织相比，血管生成素主要在癌细胞中表达。血管生成素的染色强度与微血管计数和局灶性巨噬细胞浸润计数显著相关（P < 0.05）。在一项体外研究中，白细胞介素 - 1β和肿瘤坏死因子 - α以剂量和时间依赖性方式诱导结肠癌细胞中血管生成素mRNA的表达，并且这些细胞因子显著上调血管生成素mRNA的表达，尤其是在结肠癌细胞中，而不是在肿瘤组织基质中的其他细胞（成纤维细胞、肿瘤浸润淋巴细胞、巨噬细胞）中。这些结果表明，结直肠癌中的肿瘤血管生成可能至少部分是由浸润巨噬细胞衍生的促炎细胞因子诱导的血管生成素所促进的。
