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

Abstract

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 with other agents in the treatment of human cancers.

• Authors: Dina M Elaraj, David M Weinreich, Sheelu Varghese, Markus Puhlmann, Stephen M Hewitt, Nancy M Carroll, Elizabeth D Feldman, Ewa M Turner, H Richard Alexander
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 12 Issue 4 Pg. 1088-96 (Feb 15 2006) ISSN: 1078-0432 [Print] United States
• PMID: 16489061 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)

Chemical References

• IL1RN protein, human
• Il1rn protein, mouse
• Interleukin 1 Receptor Antagonist Protein
• Interleukin-1
• Interleukin-8
• RNA, Messenger
• Sialoglycoproteins
• Vascular Endothelial Growth Factor A

Topics

• Animals
• Cell Line, Tumor
• Cell Membrane Permeability (drug effects)
• Cell Proliferation (drug effects)
• Cells, Cultured
• Dose-Response Relationship, Drug
• Endothelial Cells (drug effects, physiology)
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Interleukin 1 Receptor Antagonist Protein
• Interleukin-1 (genetics, pharmacology, physiology)
• Interleukin-8 (biosynthesis)
• Melanoma, Experimental (drug therapy, genetics, metabolism)
• Mice
• Mice, Nude
• Neoplasm Metastasis (prevention & control)
• RNA, Messenger (genetics, metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Sialoglycoproteins (metabolism, pharmacology)
• Time Factors
• Vascular Endothelial Growth Factor A (biosynthesis)
• Xenograft Model Antitumor Assays