Proinflammatory cytokine IL-1 beta promotes tumor growth of Lewis lung carcinoma by induction of angiogenic factors: in vivo analysis of tumor-stromal interaction.
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.
Saijo
Yasuo
Y
Department of Respiratory Oncology and Molecular Medicine, Institute of Development, Aging, and Cancer, Tohoku University, Sendai, Japan. yasosj@idac.tohoku.ac.jp
Tanaka
Masashi
M
Miki
Makoto
M
Usui
Kazuhiro
K
Suzuki
Takuji
T
Maemondo
Makoto
M
Hong
Xin
X
Tazawa
Ryushi
R
Kikuchi
Toshiaki
T
Matsushima
Kouji
K
Nukiwa
Toshihiro
T
D043925:Angiogenesis Inducing Agents / Q000096:biosynthesis*; D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D018827:Carcinoma, Lewis Lung / Q000098:blood supply / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D002450:Cell Communication / Q000235:genetics / Q000276:immunology; D002455:Cell Division / Q000276:immunology; D054426:Chemokine CXCL2; D018925:Chemokines / Q000096:biosynthesis / Q000378:metabolism; D003510:Cyclohexanes; D016228:Endothelial Growth Factors / Q000096:biosynthesis / Q000378:metabolism; D018014:Gene Transfer Techniques; D017228:Hepatocyte Growth Factor / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation / Q000276:immunology; D007375:Interleukin-1 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D008222:Lymphokines / Q000096:biosynthesis / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D000077609:O-(Chloroacetylcarbamoyl)fumagillol; D023063:Receptors, Interleukin-8B / Q000276:immunology; D012717:Sesquiterpenes / Q000494:pharmacology; D013045:Species Specificity; D017154:Stromal Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D043925:Angiogenesis Inducing Agents; D020533:Angiogenesis Inhibitors; D000906:Antibodies; D054426:Chemokine CXCL2; D018925:Chemokines; C404915:Cxcl2 protein, mouse; D003510:Cyclohexanes; D016228:Endothelial Growth Factors; D007375:Interleukin-1; D008222:Lymphokines; D023063:Receptors, Interleukin-8B; D012717:Sesquiterpenes; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D017228:Hepatocyte Growth Factor; D000077609:O-(Chloroacetylcarbamoyl)fumagillol