Abstract
Angiogenesis is necessary for solid tumor growth and dissemination. In addition to angiogenesis, it has become increasingly clear that inflammation is a key component in cancer insurgence that can promote tumor angiogenesis. We noted that angiogenesis is a common and key target of most chemopreventive molecules, where they most likely suppress the angiogenic switch in premalignant tumors, a concept we termed angioprevention. We have shown that various molecules, such as flavonoids, antioxidants, and retinoids, act in the tumor microenvironment, inhibiting the recruitment and/or activation of endothelial cells and phagocytes of the innate immunity. N-acetyl-cysteine, and the green tea flavonoid epigallocatechin-3-gallate (EGCG) and the beer/hops-derived chalcone Xanthohumol all prevent angiogenesis in the Matrigel sponge angiogenic assay in vivo and inhibit the growth of the highly angiogenic Kaposi’s sarcoma tumor cells (KS-Imm) in nude mice. The synthetic retinoid 4-hydroxyfenretinide (4HPR) also shows antiangiogenic effects. We analyzed the regulation of gene expression they exert in primary human umbilical endothelial cells (HUVEC) in culture with functional genomics. Expression profiles obtained through Affymetrix GeneChip arrays identified overlapping sets of genes regulated by anti-oxidants. In contrast, the ROS-producing 4HPR induced members of the TGFβ-ligand superfamily, which, at least in part, explains its anti-angiogenic activity. NAC and the flavonoids all suppressed the IkB/NF-κB signaling pathway even in the presence of NF-κB stimulation by TNFα, and showed reduced expression of many NF-κB target genes. A selective apoptotic effect on transformed cells, but not on endothelial cells, of the anti-oxidants may be related to the reduced expression of the NF-κB-dependent survival factors Bcl2 and Birc5/surviving, which are selectively overexpressed in transformed cells by these factors. The repression of the NF- κB pathway suggests anti-inflammatory effects for the antioxidant compounds that may also represent an indirect role in angiogenesis inhibition. The green tea flavonoid EGCG does target inflammatory cells, mostly neutrophils, and inhibits inflammation-associated angiogenesis. The other angiopreventive molecules are turning out to be effective modulators of phagocyte recruitment and activation, further linking inflammation and vascularization to tumor onset and progression and providing a key target for cancer prevention.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
Aggarwal BB, Shishodia S (2004). Suppression of the nuclear factor-kappaB activation pathway by spice-derived phytochemicals: reasoning for seasoning. Ann N Y Acad Sci 1030:434–441
Albini A, Noonan DM (2005) Rescuing COX-2 Inhibitors From the Waste Bin. J Natl Cancer Inst 97:859–860
Albini A, Tosetti F, Benelli R, Noonan DM (2005) Tumor inflammatory angiogenesis and its chemoprevention. Cancer Res 65:10637–10641
Balkwill F, Mantovani A (2001) Inflammation and cancer: back to Virchow? Lancet 357:539–545
Balkwill F, Charles KA, Mantovani A (2005) Smoldering and polarized inflammation in the initiation and promotion of malignant disease. Cancer Cell 7:211–217
Benelli R, Morini M, Carrozzino F, Ferrari N, Minghelli S, Santi L, Cassatella M, Noonan DM, Albini A (2002) Neutrophils as a key cellular target for angiostatin: implications for regulation of angiogenesis and inflammation. FASEB J 16:267–269
Benelli R, Albini A, Noonan D (2003) Neutrophils and angiogenesis: potential initiators of the angiogenic cascade. In: The neutrophil: Cassatella MA (ed) An emerging regulator of inflammatory and immune response. Karger, Basel pp 167–181
Benelli R, Frumento G, Albini A, Noonan DM (2006a) Models of inflammatory processes in cancer. In: Marshall LA, Stevenson CS, Morgan DW (eds) In vivo models of inflammation. Birkhäuser, Basel, pp 83–102
Benelli R, Lorusso G, Albini A, Noonan DM (2006b) Cytokines and Chemokines as regulators of angiogenesis in health and disease. Curr Pharm Des 12:3101–3115
Brigati C, Noonan DM, Albini A, Benelli R (2002) Tumors and inflammatory infiltrates: friends or foes? Clin Exp Metastasis 19:247–258
Brown JR, DuBois RN (2005) COX-2: a molecular target for colorectal cancer prevention. J Clin Oncol 23:2840–2855
Carmeliet P (2005) Angiogenesis in life, disease and medicine. Nature 438:932–936
Coussens LM, Werb Z (2001) Inflammatory cells and cancer: think different! J Exp Med 193:F23–F26
Coussens LM, Werb Z (2002) Inflammation and cancer. Nature 420:860–867
Dell’Eva R, Ambrosini C, Minghelli S, Noonan DM, Albini A, Ferrari N (2006) The Akt inhibitor deguelin, is an angiopreventive agent also acting on the NF-{kappa} B pathway. Carciogenesis, in press
Dorai T, Aggarwal BB (2004) Role of chemopreventive agents in cancer therapy. Cancer Lett 215:129–140
Dvorak HF (2005) Angiogenesis: update 2005. J Thromb Haemost 3:1835–1842
Ferrara N, Kerbel RS (2005) Angiogenesis as a therapeutic target. Nature 438:967–974
Ferrari N, Pfeffer U, Dell’Eva R, Ambrosini C, Noonan DM, Albini A (2005) The transforming growth factor-beta family members bone morphogenetic protein-2 and macrophage inhibitory cytokine-1 as mediators of the antiangiogenic activity of N-(4-hydroxyphenyl) retinamide. Clin Cancer Res 11:4610–4619
Folkman J (1971) Tumor angiogenesis: therapeutic implications. N Engl J Med 285:1182–1186
Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100:57–70
Jain RK (2005) Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307:58–62
Karin M (2005) Inflammation and cancer: the long reach of Ras. Nat Med 11:20–21
Karin M, Greten FR (2005) NF-kappaB: linking in-flammation and immunity to cancer development and progression. Nat Rev Immunol 5:749–759
Kerbel R, Folkman J (2002) Clinical translation of angiogenesis inhibitors. Nat Rev Cancer 2:727–739
Pfeffer U, Ferrari N, Dell’eva R, Indraccolo S, Morini M, Noonan DM, Albini A (2005) Molecular mechanisms of action of angiopreventive anti-oxidants on endothelial cells: Microarray gene expression analyses. Mutat Res 591:198–211
Pollard JW (2004) Tumour-educated macrophages promote tumour progression and metastasis. Nat Rev Cancer 4:71–78
Rafii S, Lyden D, Benezra R, Hattori K, Heissig B (2002) Vascular and haematopoietic stem cells: novel targets for anti-angiogenesis therapy? Nat Rev Cancer 2:826–835
Scapini P, Morini M, Tecchio C, Minghelli S, Carlo ED, Tanghetti E, Albini A, Lowell C, Berton G, Noonan DM, Cassatella MA (2004) CXCL1/Macrophage Inflammatory Protein-2-Induced Angiogenesis in Vivo is Mediated by Neutrophil-Derived Vascular Endothelial Growth Factor-A1. J Immunol 172:5032–5040
Sparmann A, Bar-Sagi D (2004) Ras-induced interleukin-8 expression plays a critical role in tumor growth and angiogenesis. Cancer Cell 6:447–458
Tosetti F, Ferrari N, De Flora S, Albini A (2002) Angioprevention: angiogenesis is a common and key target for cancer chemopreventive agents. FASEB J 16:2–14
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2007 Springer-Verlag Berlin Heidelberg
About this paper
Cite this paper
Noonan, D.M., Benelli, R., Albini, A. (2007). Angiogenesis and Cancer Prevention: A Vision. In: Senn, HJ., Kapp, U. (eds) Cancer Prevention. Recent Results in Cancer Research, vol 174. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-540-37696-5_19
Download citation
DOI: https://doi.org/10.1007/978-3-540-37696-5_19
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-540-37695-8
Online ISBN: 978-3-540-37696-5
eBook Packages: MedicineMedicine (R0)