Proinflammatory cytokine IL-1 beta promotes tumor growth of Lewis lung carcinoma by induction of angiogenic factors: in vivo analysis of tumor-stromal interaction.

Abstract

Inflammatory conditions are associated with tumor development. IL-1beta is a multifunctional and proinflammatory cytokine that affects nearly all types of cells. To investigate the role of IL-1beta in tumor growth in vivo, we transduced the retroviral vector coding human IL-1beta gene into mouse Lewis lung carcinoma (LLC) cells and subsequently inoculated the transformant (LLC/IL-1beta) to syngeneic C57BL/6 mice. Tumors derived from LLC/IL-1beta grew faster (240%, day 18, vs null-vector control LLC/neo; p < 0.01) and showed more abundant vasculature (250%, vs LLC/neo; p < 0.05), whereas LLC/IL-1beta cells, LLC/neo cells, and wild-type LLC cells did not show any significant difference in the growth rate in vitro. As compared with LLC/neo cells, LLC/IL-1beta cells secreted 2-fold the amount of vascular endothelial growth factor and >10-fold the amount of macrophage-inflammatory protein-2 (CXCL2), one of whose main functions is angiogenesis. Although LLC/IL-1beta itself did not secrete hepatocyte growth factor (HGF), the tumor derived from LLC/IL-1beta cells also contained a >4-fold higher concentration of HGF, another angiogenic factor. In situ hybridization of HGF mRNA in LLC/IL-1beta tumor sections demonstrated that stromal fibroblasts and infiltrating cells overexpressed HGF mRNA. Moreover, when cultured in the presence of HGF in vitro, LLC/IL-1beta cells secreted even larger amounts of vascular endothelial growth factor and macrophage-inflammatory protein-2. The antiangiogenic agent TNP-470 and anti-CXCR2 Ab inhibited the tumor growth of LLC/IL-1beta cells in vivo. These results indicated that secreting IL-1beta into the tumor milieu induces several angiogenic factors from tumor and stromal cells and thus promotes tumor growth through hyperneovascularization.

• Authors: Yasuo Saijo, Masashi Tanaka, Makoto Miki, Kazuhiro Usui, Takuji Suzuki, Makoto Maemondo, Xin Hong, Ryushi Tazawa, Toshiaki Kikuchi, Kouji Matsushima, Toshihiro Nukiwa
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 169 Issue 1 Pg. 469-75 (Jul 01 2002) ISSN: 0022-1767 [Print] United States
• PMID: 12077278 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Angiogenesis Inducing Agents
• Angiogenesis Inhibitors
• Antibodies
• Chemokine CXCL2
• Chemokines
• Cxcl2 protein, mouse
• Cyclohexanes
• Endothelial Growth Factors
• Interleukin-1
• Lymphokines
• Receptors, Interleukin-8B
• Sesquiterpenes
• Vascular Endothelial Growth Factor A
• Vascular Endothelial Growth Factors
• Hepatocyte Growth Factor
• O-(Chloroacetylcarbamoyl)fumagillol

Topics

• Angiogenesis Inducing Agents (biosynthesis)
• Angiogenesis Inhibitors (pharmacology)
• Animals
• Antibodies (pharmacology)
• Carcinoma, Lewis Lung (blood supply, immunology, metabolism, pathology)
• Cell Communication (genetics, immunology)
• Cell Division (immunology)
• Chemokine CXCL2
• Chemokines (biosynthesis, metabolism)
• Cyclohexanes
• Endothelial Growth Factors (biosynthesis, metabolism)
• Gene Transfer Techniques
• Hepatocyte Growth Factor (biosynthesis, genetics)
• Humans
• Immunohistochemistry
• Inflammation (immunology)
• Interleukin-1 (biosynthesis, genetics, physiology)
• Lymphokines (biosynthesis, metabolism)
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Mice, Nude
• O-(Chloroacetylcarbamoyl)fumagillol
• Receptors, Interleukin-8B (immunology)
• Sesquiterpenes (pharmacology)
• Species Specificity
• Stromal Cells (immunology, metabolism, pathology)
• Tumor Cells, Cultured
• Up-Regulation (genetics, immunology)
• Vascular Endothelial Growth Factor A
• Vascular Endothelial Growth Factors