Molecular links between tumor angiogenesis and inflammation: inflammatory stimuli of macrophages and cancer cells as targets for therapeutic strategy

Abstract

Both inflammation and angiogenesis are exacerbated by increased production of chemokines/cytokines, growth factors, proteolytic enzymes, proteoglycans, lipid mediators and prostaglandins. It has been reported that approximately 15-20% of all malignancies are initiated or exacerbated by inflammation. Initiation and progression of cancer are also closely linked to angiogenesis. Infiltration of macrophages is a dramatic and common feature of inflammation, angiogenesis and cancer, and has been recently highlighted in an attempt to develop novel strategies for treating cancer. The recruitment and infiltration of macrophages in the tumor microenvironment activates them to support the malignant progression of cancer cells, and these macrophages are called tumor-associated macrophages. In a model of experimental angiogenesis using mouse corneas, macrophages infiltrated tissue in response to inflammatory cytokines and produced chemokines and angiogenesis-promoting factors, such as vascular endothelial growth factor-A, interleukin-8, matrix metalloproteinases, prostanoids and reactive oxygen species. Moreover, in a cancer xenograft model, inflammatory stimuli by a representative inflammatory cytokine, interleukin-1beta, enhanced tumor growth and angiogenesis with infiltration and activation of macrophages. Co-culture of cancer cells with macrophages synergistically stimulated production of various angiogenesis-related factors when stimulated by the inflammatory cytokine. This inflammatory angiogenesis in both mouse cornea and a tumor model was mediated, in part, by activation of nuclear factor kappaB and activator protein 1 (Jun/Fos). Administration of either nuclear factor kappaB-targeting drugs or cyclooxygenase 2 inhibitors or depletion of macrophages could block both inflammatory angiogenesis and tumor angiogenesis. Thus, both inflammatory and angiogenic responses in tumor stroma could be targets for development of anticancer therapeutic drugs.

Figure 1

Growth factors, cytokines, adhesion molecules, proteases and other factors promote angiogenesis and inflammation in common and uncommon diseases. Ang, angiopoietin; COX2, cyclooxygenase 2; ECM, extracellular matrix; EGF, epidermal growth factor; FGF, fibroblast growth factor; HGF, hepatocyte growth factor; ICAM, intercellular adhesion molecule; IFN, interferon; IL, interleukin; MCP, monocyte chemoattractant protein; MMP, matrix metallopeptidase; Ox‐LDL, oxidised low density lipoprotein; PA, plasminogen activator; PDGF, platelet‐derived growth factor; SDF, stromal cell derived factor; TGF, transforming growth factor; TNF, tumor necrosis factor; VCAM, vascular cell adhesion molecule; VEGF, vascular endothelial growth factor; VLDL, very low density lipoprotein.

Figure 2

Monocytes/macrophages are educated to support malignant progression of cancer cells. Among the various inflammatory cell types and fibroblasts in tumor stroma, tumor‐associated macrophages (TAM) are thought to play a critical role in supporting the progression of cancer. Monocytes/macrophages are recruited to the tumor, become TAM, and help creation of a microenvironment that favors angiogenesis, migration and growth of malignant cells. CSF‐1, colony stimulating growth factor‐1; MCP‐1, monocyte chemoattractant protein‐1; MIP‐1, macrophage inhibitor protein‐1; VEGF, vascular endothelial growth factor.

Figure 3

IL‐1β is a potent angiogenic factor and the effect of selective cyclooxygenase 2 (COX 2) inhibitors on IL‐1β‐induced angiogenesis in mouse corneas. (a) IL‐1β‐ or VEGF‐induced angiogenesis on day 4 and 6 are shown. (b) Effect of two COX 2 selective inhibitors, DFU (50 mg/kg) or JTE522 (50 mg/kg), on IL‐1β‐induced angiogenesis in mouse corneas.

Figure 4

Administration of bisphosphonate encapsulated in a liposome (CI₂MDP‐LIP) inhibits IL‐1β‐induced tumor growth, angiogenesis and macrophage infiltration in tumors. (a) Growth of lung tumors (LLC/neo and LLC/IL‐1β), (b) number of infiltrating macrophage in tumors, and (c) microvascular density (MVD) in tumors are inhibited by administration of Cl₂MDP‐LIP.

Figure 5

Targeting activated macrophages including TAMs modulates angiogenesis, tumor growth and invasion by cancer cells. In this system for TAMs‐mediated tumor angiogenesis, inhibitors of macrophages infiltration/activation, and inflammatory mediators (e.g., COX2 activity and NF‐κB) are expected to suppress angiogenesis at various sites.