Proinflammatory Cytokine IL-1β Promotes Tumor Growth of Lewis Lung Carcinoma by Induction of Angiogenic Factors: In Vivo Analysis of Tumor-Stromal Interaction1

Inflammatory conditions are associated with tumor development. IL-1β is a multifunctional and proinflammatory cytokine that affects nearly all types of cells. To investigate the role of IL-1β in tumor growth in vivo, we transduced the retroviral vector coding human IL-1β gene into mouse Lewis lung carcinoma (LLC) cells and subsequently inoculated the transformant (LLC/IL-1β) to syngeneic C57BL/6 mice. Tumors derived from LLC/IL-1β 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-1β 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-1β 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-1β itself did not secrete hepatocyte growth factor (HGF), the tumor derived from LLC/IL-1β cells also contained a >4-fold higher concentration of HGF, another angiogenic factor. In situ hybridization of HGF mRNA in LLC/IL-1β tumor sections demonstrated that stromal fibroblasts and infiltrating cells overexpressed HGF mRNA. Moreover, when cultured in the presence of HGF in vitro, LLC/IL-1β 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-1β cells in vivo. These results indicated that secreting IL-1β into the tumor milieu induces several angiogenic factors from tumor and stromal cells and thus promotes tumor growth through hyperneovascularization.

[1]  C. Van Waes,et al.  Hepatocyte growth factor/scatter factor-induced activation of MEK and PI3K signal pathways contributes to expression of proangiogenic cytokines interleukin-8 and vascular endothelial growth factor in head and neck squamous cell carcinoma. , 2001, Cancer research.

[2]  S. Matsufuji,et al.  Antiproliferative effect of IL-1 is mediated by p38 mitogen-activated protein kinase in human melanoma cell A375. , 1999, Journal of immunology.

[3]  Y. Konishi,et al.  Inhibitory effects of combined administration of antibiotics and anti-inflammatory drugs on lung tumor development initiated by N-nitrosobis(2-hydroxypropyl)amine in rats. , 2000, Carcinogenesis.

[4]  A. Bell,et al.  The five amino acid-deleted isoform of hepatocyte growth factor promotes carcinogenesis in transgenic mice , 1999, Oncogene.

[5]  E Medico,et al.  Expression of the Met/HGF receptor in normal and neoplastic human tissues. , 1991, Oncogene.

[6]  E. Scanziani,et al.  Effect of interleukin-1-beta on metastasis formation in different tumor systems. , 1991, Journal of the National Cancer Institute.

[7]  P. Lomedico,et al.  Interleukin 1 alpha and interleukin 1 beta bind to the same receptor on T cells. , 1986, Journal of immunology.

[8]  A. C. Webb,et al.  Multiple biological activities of human recombinant interleukin 1. , 1986, The Journal of clinical investigation.

[9]  D. Hanahan,et al.  Tumor-derived expression of vascular endothelial growth factor is a critical factor in tumor expansion and vascular function. , 1999, Cancer research.

[10]  T. Abe,et al.  Expression of the 37-kDa laminin binding protein in murine lung tumor cell correlates with tumor angiogenesis. , 2000, Cancer letters.

[11]  K. Matsushima,et al.  Physiologic regulation of postovulatory neutrophil migration into vagina in mice by a C-X-C chemokine(s). , 1998, Journal of immunology.

[12]  G. Hedlund,et al.  Gene transfer of a hybrid interleukin-1β gene to B16 mouse melanoma recruits leucocyte subsets and reduces tumour growth in vivo , 1997, Cancer Immunology, Immunotherapy.

[13]  W. Gong,et al.  Chemokines and their role in tumor growth and metastasis. , 1998, Journal of immunological methods.

[14]  O. Takikawa,et al.  Synergism between IFN-y and ILla / p in Growth Inhibition of an Allografted Tumor ' , 2001 .

[15]  P. Ghezzi,et al.  IL-1 induces IL-1. III. Specific inhibition of IL-1 production by IFN-gamma. , 1988, Journal of immunology.

[16]  H. Yoshiji,et al.  Protein kinase C lies on the signaling pathway for vascular endothelial growth factor-mediated tumor development and angiogenesis. , 1999, Cancer research.

[17]  M. Hoque,et al.  Role of HGF/c‐met system in invasion and metastasis of oral squamous cell carcinoma cells in vitro and its clinical significance , 2001, International journal of cancer.

[18]  P. Ghezzi,et al.  Hypoxia increases production of interleukin-1 and tumor necrosis factor by human mononuclear cells. , 1991, Cytokine.

[19]  C. Dinney,et al.  Interleukin 8 expression regulates tumorigenicity and metastases in androgen-independent prostate cancer. , 2000, Clinical cancer research : an official journal of the American Association for Cancer Research.

[20]  P. Comoglio,et al.  Interleukin 1 induces an autocrine loop hepatocyte growth factor/c-Met in murine Kaposi-like spindle cells. , 1996, Oncogene.

[21]  T. Shono,et al.  Involvement of interleukin-8, vascular endothelial growth factor, and basic fibroblast growth factor in tumor necrosis factor alpha-dependent angiogenesis , 1997, Molecular and cellular biology.

[22]  C. Dinarello,et al.  Biologic basis for interleukin-1 in disease. , 1996, Blood.

[23]  H. Saito,et al.  IL-1 Induced Chemokine Production Through the Association of Syk with TNF Receptor-Associated Factor-6 in Nasal Fibroblast Lines1 , 2001, The Journal of Immunology.

[24]  Toshikazu Nakamura,et al.  Targeting angiogenesis and HGF function using an adenoviral vector expressing the HGF antagonist NK4 for cancer therapy. , 2002, Molecular therapy : the journal of the American Society of Gene Therapy.

[25]  T. Yoshida,et al.  Suppression of hepatoma growth and angiogenesis by a fumagillin derivative TNP470: possible involvement of nitric oxide synthase. , 1998, Cancer research.

[26]  A. Krüger,et al.  Promotion of experimental liver metastasis by tumor necrosis factor , 1995, International journal of cancer.

[27]  J. Siegfried,et al.  Hepatocyte growth factor promotes tumor growth in a novel in vivo model of human lung cancer. , 2001, American journal of respiratory cell and molecular biology.

[28]  W. Berdel,et al.  Vascular endothelial growth factor and interleukin-6 in paracrine tumor-stromal cell interactions in multiple myeloma. , 2000, Blood.

[29]  T. Iwanaga,et al.  Absence of endothelial cells, central necrosis, and fibrosis are associated with aggressive inflammatory breast cancer. , 2001, Cancer research.

[30]  M. Burdick,et al.  Inhibition of interleukin-8 reduces tumorigenesis of human non-small cell lung cancer in SCID mice. , 1996, The Journal of clinical investigation.

[31]  S. Merajver,et al.  Molecular biology of breast cancer metastasis: Inflammatory breast cancer: clinical syndrome and molecular determinants , 2000, Breast Cancer Research.

[32]  T. Oku,et al.  Synergism between IFN-gamma and IL-1 alpha/beta in growth inhibition of an allografted tumor. , 1993, Journal of immunology.

[33]  C. Dinarello,et al.  Staphylococcus epidermidis induces complement activation, tumor necrosis factor and interleukin-1, a shock-like state and tissue injury in rabbits without endotoxemia. Comparison to Escherichia coli. , 1991, The Journal of clinical investigation.

[34]  G. Kollias,et al.  Mice deficient in tumor necrosis factor-α are resistant to skin carcinogenesis , 1999, Nature Medicine.

[35]  J. Roth,et al.  Autocrine interleukin-1beta production in leukemia: evidence for the involvement of mutated RAS. , 1999, Cancer research.

[36]  A. Harris,et al.  Association of macrophage infiltration with angiogenesis and prognosis in invasive breast carcinoma. , 1996, Cancer research.

[37]  W. Brown,et al.  Effect of ultraviolet-inducible cytokines on melanoma growth in vivo: stimulation of melanoma growth by interleukin-1 and -6. , 1994, Photodermatology, photoimmunology & photomedicine.

[38]  M. Kaghad,et al.  Human interleukin 1 beta fused to the human growth hormone signal peptide is N-glycosylated and secreted by Chinese hamster ovary cells. , 1991, Gene.

[39]  S. Spechler.  The role of gastric carditis in metaplasia and neoplasia at the gastroesophageal junction. , 1999, Gastroenterology.

[40]  C. Patterson,et al.  Induction of Vascular Endothelial Growth Factor Gene Expression by Interleukin-1 in Rat Aortic Smooth Muscle Cells (*) , 1995, The Journal of Biological Chemistry.

[41]  J. Norton,et al.  In vivo gene therapy of a murine pancreas tumor with recombinant vaccinia virus encoding human interleukin-1 beta. , 1995, Surgery.

[42]  P. Cameron,et al.  Identification of a monocyte specific pre-interleukin 1 beta convertase activity. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[43]  R. Strieter,et al.  Interleukin-8 as a macrophage-derived mediator of angiogenesis. , 1992, Science.

[44]  Elise C. Kohn,et al.  The microenvironment of the tumour–host interface , 2001, Nature.

[45]  C. Tsai,et al.  Profile of cytokine expression in nasopharyngeal carcinomas: a distinct expression of interleukin 1 in tumor and CD4+ T cells. , 1999, Cancer research.

[46]  L. Ellis,et al.  Regulation of vascular endothelial growth factor expression in human colon cancer by interleukin-1β , 1999, British Journal of Cancer.

[47]  K. Matsumoto,et al.  HGF/NK4, a four-kringle antagonist of hepatocyte growth factor, is an angiogenesis inhibitor that suppresses tumor growth and metastasis in mice. , 2000, Cancer research.

[48]  B. Aggarwal,et al.  Human interleukin 1 is a cytocidal factor for several tumor cell lines. , 1985, Journal of immunology.

[49]  K. Alitalo,et al.  Proinflammatory Cytokines Regulate Expression of the Lymphatic Endothelial Mitogen Vascular Endothelial Growth Factor-C* , 1998, The Journal of Biological Chemistry.

[50]  M. Tamura,et al.  Enhancement of human hepatocyte growth factor production by interleukin-1 alpha and -1 beta and tumor necrosis factor-alpha by fibroblasts in culture. , 1993, The Journal of biological chemistry.

[51]  L. Rangell,et al.  Hepatocyte growth factor enhances vascular endothelial growth factor-induced angiogenesis in vitro and in vivo. , 2001, The American journal of pathology.

[52]  I. Takanami,et al.  Tumor-Associated Macrophage Infiltration in Pulmonary Adenocarcinoma: Association with Angiogenesis and Poor Prognosis , 1999, Oncology.

[53]  R. Hasina,et al.  Paracrine angiogenic loop between head‐and‐neck squamous‐cell carcinomas and macrophages , 2001, International journal of cancer.

[54]  C. Smith,et al.  Expression of proinflammatory and proangiogenic cytokines in patients with head and neck cancer. , 1999, Clinical cancer research : an official journal of the American Association for Cancer Research.

[55]  T. Nakamura,et al.  Paracrine effects of hepatocyte growth factor/scatter factor on non-small-cell lung carcinoma cell lines. , 1998, British Journal of Cancer.