The role of interleukin 1 in growth and metastasis of human cancer xenografts

• Published in: Clinical cancer research 2006-02, Vol.12 (4), p.1088-1096
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic agents; Biological and medical sciences; Cell Line, Tumor; Cell Membrane Permeability - drug effects; Cell Proliferation - drug effects; Cells, Cultured; Dose-Response Relationship, Drug; Endothelial Cells - drug effects; Endothelial Cells - physiology; Female; Gene Expression Regulation, Neoplastic; Humans; Interleukin 1 Receptor Antagonist Protein; Interleukin-1 - genetics; Interleukin-1 - pharmacology; Interleukin-1 - physiology; Interleukin-8 - biosynthesis; Medical sciences; Melanoma, Experimental - drug therapy; Melanoma, Experimental - genetics; Melanoma, Experimental - metabolism; Mice; Mice, Nude; Neoplasm Metastasis - prevention & control; Pharmacology. Drug treatments; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; RNA, Messenger - metabolism; Sialoglycoproteins - metabolism; Sialoglycoproteins - pharmacology; Time Factors; Vascular Endothelial Growth Factor A - biosynthesis; Xenograft Model Antitumor Assays
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-05-1603

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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