Elaraj Dina M, Weinreich David M, Varghese Sheelu, Puhlmann Markus, Hewitt Stephen M, Carroll Nancy M, Feldman Elizabeth D, Turner Ewa M, Alexander H Richard
Surgical Metabolism Section, Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892-1201, USA.
Clin Cancer Res. 2006 Feb 15;12(4):1088-96. doi: 10.1158/1078-0432.CCR-05-1603.
Interleukin 1 (IL-1) is a pluripotent cytokine that promotes angiogenesis, tumor growth, and metastasis in experimental models; its presence in some human cancers is associated with aggressive tumor biology. The purpose of these studies was to characterize the role of IL-1 in human cancers and determine if inhibition of IL-1 via its receptor antagonist, IL-1Ra, alters tumor growth and metastatic potential.
IL-1 mRNA or protein levels were determined in clinical tumor samples, cancer cell lines, and xenografts using quantitative reverse transcription-PCR or ELISA. Biological activity of tumor-derived IL-1 protein was shown via induction of permeability across endothelial cell monolayers. The effects of recombinant IL-1Ra on tumor lines in culture (cell proliferation and IL-8 secretion) and in xenograft models (tumor growth, metastatic potential, and intratumoral levels of IL-8 and VEGF) were characterized. The effects of IL-1Ra-mediated regression of xenograft growth on angiogenic proteins (IL-8 and VEGF) were evaluated in an IL-1-producing melanoma (SMEL) xenograft model.
IL-1 mRNA was highly expressed in more than half of all tested metastatic human tumor specimens including non-small-cell lung carcinoma, colorectal adenocarcinoma, and melanoma tumor samples. Constitutive IL-1 mRNA expression was identified in several cancer cell lines; tumor supernatant from these cell lines produced a significant increase in endothelial cell monolayer permeability, a hallmark event in early angiogenesis, in an IL-1-dependent manner. Moreover, systemic recombinant IL-1Ra resulted in significant inhibition of xenograft growth and neovessel density of IL-1-producing, but not non-IL-1-producing, tumor cell lines. Subsequent analysis of SMEL, a melanoma cell line with constitutive IL-1 production, showed that neither exogenous IL-1 nor IL-1Ra altered tumor cell proliferation rates in vitro. Gene expression analyses of IL-1Ra-treated SMEL xenografts showed a >3-fold down-regulation of 100 genes compared with control including a marked down-regulation of IL-8 and VEGF.
These data show that the IL-1 gene is frequently expressed in metastases from patients with several types of human cancers. IL-1Ra inhibits xenograft growth in IL-1-producing tumors but has no direct antiproliferative effects in vitro; decreased tumor levels of IL-8 and VEGF may be an early surrogate of IL-1Ra-mediated antitumor activity. IL-1Ra may have a role alone or with other agents in the treatment of human cancers.
白细胞介素1（IL-1）是一种多能细胞因子，在实验模型中可促进血管生成、肿瘤生长和转移；在某些人类癌症中其存在与侵袭性肿瘤生物学特性相关。这些研究的目的是明确IL-1在人类癌症中的作用，并确定通过其受体拮抗剂IL-1Ra抑制IL-1是否会改变肿瘤生长和转移潜能。
使用定量逆转录PCR或ELISA法测定临床肿瘤样本、癌细胞系和异种移植瘤中的IL-1 mRNA或蛋白水平。通过诱导内皮细胞单层通透性来显示肿瘤来源的IL-1蛋白的生物学活性。对重组IL-1Ra在培养的肿瘤细胞系（细胞增殖和IL-8分泌）和异种移植模型（肿瘤生长、转移潜能以及肿瘤内IL-8和VEGF水平）中的作用进行了表征。在产生IL-1的黑色素瘤（SMEL）异种移植模型中评估了IL-1Ra介导的异种移植瘤生长消退对血管生成蛋白（IL-8和VEGF）的影响。
IL-1 mRNA在超过一半的所有测试转移性人类肿瘤标本中高表达，包括非小细胞肺癌、结肠腺癌和黑色素瘤肿瘤样本。在几种癌细胞系中鉴定出组成型IL-1 mRNA表达；这些细胞系的肿瘤上清液以IL-1依赖的方式使内皮细胞单层通透性显著增加，这是早期血管生成中的一个标志性事件。此外，全身性重组IL-1Ra可显著抑制产生IL-1的肿瘤细胞系（而非不产生IL-1的肿瘤细胞系）的异种移植瘤生长和新生血管密度。随后对组成型产生IL-1的黑色素瘤细胞系SMEL的分析表明，外源性IL-1和IL-1Ra在体外均未改变肿瘤细胞增殖率。对经IL-1Ra处理的SMEL异种移植瘤的基因表达分析显示，与对照相比，100个基因下调了3倍以上，包括IL-8和VEGF的显著下调。
这些数据表明，IL-1基因在几种类型人类癌症患者的转移灶中经常表达。IL-1Ra可抑制产生IL-1的肿瘤的异种移植瘤生长，但在体外没有直接的抗增殖作用；肿瘤中IL-8和VEGF水平的降低可能是IL-1Ra介导的抗肿瘤活性的早期替代指标。IL-1Ra可能单独或与其他药物联合用于人类癌症的治疗。
