Abstract
Close to 38 500 new cases of squamous cell carcinoma of the head and neck (SCCHN) are diagnosed each year. Traditional therapy for SCCHN has involved a multimodality approach of radiotherapy, surgery, and chemotherapy. More recently, novel therapeutic targets for solid tumors, including SCCHN, have been subject to preclinical and clinical applications.
One of these newer approaches is antiangiogenic therapy. The mechanism of angiogenesis and the role it plays in tumor growth has been the subject of extensive investigation over the last 3 decades. As new antiangiogenic agents are being approved for the treatment of various solid tumors this critical review, using current preclinical and clinical evidence available thus far, examines the possible future role this new modality will have in the management of SCCHN. The different steps of angiogenesis and the corresponding targets are discussed, with a focus on vascular endothelial growth factor, as well as the preclinical and clinical evidence for the role of angiogenesis in SCCHN.
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References
Ferrara N, Hillan KJ, Gerber HP, et al. Discovery and development of bevacizumab: an anti-VEGF antibody for treating cancer. Nat Rev Drug Discov 2004; 3: 391–400
Folkman J. Clinical applications of research on angiogenesis. N Engl J Med 1995; 333: 1757–63
Kerbel R, Folkman J. Clinical translation of angiogenesis inhibitors. Nat Rev Cancer 2002; 2: 727–39
Holden SN, Morrow M, O’Bryant C, et al. Correlative biological assays used to guide dose-escalation in a phase I study of the antiangiogenic alphavbeta3 and alphavbeta5 intefrin antagonist EMD121974 (EMD) [abstract no. 110]. Proc Am Soc Clin Oncol 2002; 21: 28a
Rizvi NA, Humphrey JS, Ness EA, et al. A phase I study of oral BMS-27529: a novel nonhydroxamate sheldase-sparing matrix metalloproteinase inhibitor, in patients with advanced or metastatic cancer. Clin Cancer Res 2004; 10: 1963–70
Jemal A, Murray T, Ward E, et al. Cancer statistics. CA Cancer J Clin 2005; 55: 10–30
Greenlee RT, Murray T, Bolden S, et al. Cancer statistics 2000. CA Cancer J Clin 2000; 50: 7–33
Cohen EEW. Novel therapeutic targets in squamous cell carcinoma of the head and neck. Semin Oncol 2004; 31: 755–68
Asgari MM, Haggerty JG, McNiff JM, et al. Expression and localization of thymidine phosphorylase/platelet-derived endothelial cell growth factor in skin and cutaneous tumors. J Cutan Pathol 1999; 26: 287–94
Sauter ER, Coia LR, Eisenberg BL, et al. Radiation treatment decreases transforming growth factor alpha expression in squamous carcinoma of the tongue. Cancer Lett 1994; 78: 159–62
Reiss M, Munoz-Antonia T, Cowan JM, et al. Resistance of human squamous carcinoma cells to transforming growth factor beta 1 is a recessive trait. Proc Natl Acad Sci U S A 1993; 90: 6280–4
Janot F, el-Najjar AK, Morrison RS, et al. Expression of basic fibroblast growth factor in squamous cell carcinoma of the head and neck is associated with degree of histologic differentiation. Int J Cancer 1999; 64: 117–23
Cohen RF, Contrino J, Spiro JD, et al. Interleukin-8 expression by head and neck squamous cell carcinoma. Arch Otolaryngol Head Neck Surg 1995; 121: 202–9
Carmeliet P, Jain RK. Angiogenesis in cancer and other diseases. Nature 2000; 407: 249–57
Carmeliet P. Mechanisms of angiogenesis and arteriogenesis. Nat Med 2000; 6: 389–95
Jain RK. Normalizing tumor vasculature with anti-angiogenic therapy: a new paradigm for combination therapy. Nat Med 2001; 7: 987–9
Bottaro DP. Cancer: out of air is not out of action. Nature 2003; 423: 593–5
Scott PA, Harril AL. Current approaches to targeting cancer using anti-angi-ogenesis therapy. Cancer Treat Rev 1994; 20: 393–412
Hobson B, Benekamp J. Endothelial proliferation in tumors and normal tissues: continuous labelling studies. Br J Cancer 1984; 49: 405–13
Sridhar SS, Shepherd FA. Targeting angiogenesis: a review of angiogenesis inhibitors in the treatment of lung cancer. Lung Cancer 2003; 42 Suppl. 1: S81–91
Bergers G, Song S, Meyer-Morse N, et al. Benefits of targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors. J Clin Invest 2003; 111: 1287–95
Seghezzi G, Patel S, Ren CJ, et al. Fibroblast growth factor-2 (FGF-2) induces vascular endothelial growth factor (VEGF) expression in the endothelial cells of forming capillaries: an autocrine mechanism contributing to angiogenesis. J Cell Biol 2000; 141: 1659–73
Laird AD, Vajcoczy P, Shawver LK, et al. SU6668 is a potent antiangiogenic and antitumor agent that induces regression of established tumors. Cancer Res 2000; 60(15): 4152–60
Garcia-Barros M, Paris F, Cordon-Cardo C, et al. Tumor response to radiotherapy regulated by endothelial cell apoptosis. Science 2003; 300: 1155–9
Suit HD, Willers H. Comment on tumor response by radiotherapy regulated by endothelial cell apoptosis. Science 2003Dec 12; 302(5652): 1894c
Brown M, Brislow R, Glazer P, et al. Comment on “Tumor response to radiotherapy regulated by endothelial cell apoptosis” (II). Science 2003; 302(5652): 1894
Moeller BJ, Dreher MR, Rabbani ZN, et al. Pleiotropic effects of HIF-1 blockade on tumor radiosensitivity. Cancer Cell 2005; 8: 99–110
Pasqualini R, Ruoslahti E. Organ targeting in vivo using phage display peptide libraries. Nature 1996; 380: 364–6
Curnis F, Sacchi A, Borgna L, et al. Enhancement of tumor necrosis factor alpha antitumor immunotherapeutic properties by targeted delivery to aminopep-tidase N (CD13). Nat Biotechnol 2000; 18: 1185–90
Curnis F, Sacchi A, Corti A. Improving chemotherapeutic drug penetration in tumors by vascular targeting and barrier alteration. J Clin Invest 2002; 110: 475–82
Herbst RS, Madden TL, Tran HT, et al. Safety and pharmacokinetic effects of TNP-470, an angiogenesis inhibitor, combined with paclitaxel in patients with solid tumors: evidence for activity in non-small cell lung cancer. J Clin Oncol 2002; 15: 4440–7
Yamaguchi M, Sugio K, Ondo K, et al. Reduced expression of thrombospondin-1 correlates with poor prognosis in patients with non-small cell lung cancer. Lung Cancer 2002May; 36(2): 143–50
Karameris A, Panagou P, Tsilalis T, et al. Association of expression of metal-loproteinases and their inhibitors with the metastatic potential of squamous cell lung carcinomas: a molecular and immunohistochemical study. Am J Respir Crit Care Med 1997; 156: 1930–6
Hidalgo M, Eckhardt SG. Development of matrix metalloproteinase inhibitors in cancer therapy. J Natl Cancer Inst 2001; 93: 178–93
Ozdemir E, Kakehi Y, Okuno H. Role of matrix metalloproteinase-9 in the basement membrane destruction of superficial urothelial carcinomas. J Urol 1999; 161: 1706–63
Shou Y, Hirano T, Gong Y. Influence of angiogenic factors and matrix metal-loproteinases upon tumor progression in non-small cell lung cancer. Br J Cancer 2001; 85: 1706–12
Khokha R, Benhardt DT. Matrix metalloproteinases and tissue inhibitors of metal-loproteinases: a review of their role in tumorigenesis and tissue invasion. Invasion Metastasis 1989; 9: 391–405
Douillard JY, Pexchel C, Shepherd F, et al. Randomized phase II feasibility study of combining the matrix metalloproteinase inhibitor BMS-27591 with paclitaxel plus carboplatin in advanced non-small cell lung cancer. Lung Cancer 2004; 46: 361–8
Giatromanolaki A, Koukourakis MI, Comley M, et al. Platelet derived endothelial cell growth factor (thymidine phosphorylase) expression in lung cancer. J Pathol 1997; 181: 196–9
Tannock IF, Hill RP. The basic science of oncology. 3rded. New York: McGraw-Hill, 1998
Vicacqua RJ, Lebedda J, Wa K. Phase I/II study of sequential interferon alpha-2b (IFN-alpha-2b) and weekly topotecan/vinorelbine in advanced non-small cell lung cancer (NSCLC) [abstract no. 2721]. Proc Am Soc Clin Oncol 2002May; 21: 226b
Cenni E, Perut F, Zuntini M, et al. Inhibition of angiogenic activity of renal carcinoma by an antisense oligonucleotide targeting fibroblast growth factor-2. Anticancer Res 2005; 25(2A): 1109–13
O’Reilly MS, Boehm T, Shing Y. Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastasis by a Lewis lung carcinoma. Cell 1994; 79: 315–28
Sugarbaker EV, Thornwaite J, Ketcham A. Inhibitory effect of a primary tumor on metastasis. In: Day S, Myers WPL, Stanley P, et al, editors. Progress in cancer research and therapy. New York: Raven Press, 1977: 227–40
Sim BK, O’Reilly MS, Liang H. A recombinant human angiostatin inhibits experimental primary and metastatic cancer. Cancer Res 1997; 57: 1329–34
Mauceri HJ, Hanna N, Beckett MA. Combined effects of angiostatin and ionizing radiation in antitumor therapy. Nature 1998; 394: 287–91
O’Reilly MS, Boehm T, Shing Y. Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell 1997; 88: 277–85
Boehm T, Folkman J, Shing Y. Antiangiogenic therapy of experimental cancer does not induce acquired drug resistance. Nature 1997; 390: 404–7
Black WR, Agner RC. Tumor regression after endostatin therapy. Nature 1998; 391: 450
Hanna NH, Estes D, Cress A, et al. Recombinant human angiostatin (rhAngiostatin) in combination with paclitaxel and carboplatin in patients (pts) with advanced NSCLC: preliminary results of a phase II trial [abstract no. 7105]. Proc Am Soc Clin Oncol 2004; 23: 639
Beerepoot LV, Witteveen EO, Groenewegen G, et al. Recombinant human angiostatin by twice daily subcutaneous injection in advanced cancer: a pharmacokinetic and long term safety study. Clin Cancer Res 2003; 9: 4025–33
Farhadi MR, Capelle HH, Erber R, et al. Combined inhibition of vascular endothelial growth factor and platelet-derived growth factor signaling: effects on the angiogenesis, microcirculation, and growth of orthotopic malignant gliomas. J Neurosurg 2005; 103: 363–70
Ferrara N. The role of vascular endothelial growth factor in pathological angiogenesis. Breast Cancer Res Treat 1995; 36: 127–37
Houck KA, Ferrara N, Winer J, et al. The vascular endothelial growth factor family: identification of a fourth molecular species and characterization of alternative splicing of RNA. Mol Endocrinol 1991; 12: 1806–14
Keck PJ, Hauser SD, Krivi G, et al. Vascular permeability factor, an endothelial cell mitogen related to PDGF. Science 1989; 246: 1309–12
Zhang L, Chen QR, Mixson AJ. Antiangiogenic gene therapy in cancer. Curr Genomics 2000; 1: 117–33
Riedel F, Gotte K, Hormann K, et al. Antiangiogenic therapy of head and neck squamous cell carcinoma by vascular endothelial growth factor antisense therapy. Adv Otorhinolaryngol 2005; 62: 103–20
Kim KJ, Li B, Winer J, et al. Inhibition of vascular endothelial growth factor induced angiogenesis suppresses tumor growth in vivo. Nature 1993; 362: 841–4
Saleh M, Stacker SA, Wilks AF. Inhibition of growth of C6 glioma cells in vivo by expression of anti-sense vascular endothelial growth factor sequence. Cancer Res 1996; 59: 895–900
Ke LD, Fueyo J, Chen X, et al. A novel approach to glioma gene therapy: down-regulation of the vascular endothelial growth factor in glioma cells using ribozymes. Int J Oncol 1998; 12: 1391–6
Takahashi Y, Tucker SL, Kitadai Y, et al. Vessel count and expression of vascular endothelial growth factor as prognostic factors in node negative colon cancer. Arch Surg 1997; 132: 541–6
Giantonio BJ, Catalono PJ, Meropol NJ, et al. High-dose bevacizumab in combination with FOLFOX4 improves survival in patients with previously treated advanced colorectal cancer: results from the Eastern Cooperative Oncology Group (ECOG) study E3200 [abstract no. 169a]}. 2005 Gastrointestinal Cancers Symposium; 2005 Jan 27-9; Hollywood (FL)
Sandler AB, Gray R, Brahmer J, et al. Randomized phase II/III trial of paclitaxel (P) plus carboplatin (C) with or without bevacizumab (NSC #704865) in patients with advanced non-squamous non-small cell lung cancer (NSCLC). An Eastern Cooperative Oncology Group (ECOG) trial — E4599 [abstract no. LBA4]. J Clin Oncol 2005Jun 1; 23: 16S
Johnson DH, Fehrenbacher L, Novotny WF, et al. Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic nonsmall cell lung cancer. J Clin Oncol 2004; 22: 2184–91
Hanahan D, Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 1996; 86: 353–64
Risau W. Mechanisms of angiogenesis. Nature 1997; 386: 671–4
Vailhe B, Vittet D, Feige JJ. In vitro models of vasculogenesis and angiogenesis. Lab Invest 2001; 81: 439–52
Bell SWE, Mavila A, Salazar R, et al. Differential gene expression during capillary morphogenesis in 3D collagen matrices: regulated expression of genes involved in basement membrane matrix assembly, cell cycle progression, cellular differentiation and G-protein signaling. J Cell Sci 2001; 114: 2755–73
Gerritsen ME, Soriano R, Yang S, et al. In silico data filtering to identify new angiogenesis targets from a large in vitro gene profiling data set. Physiol Genomics 2002; 10: 13–20
Grove AD, Prabhu VV, Young BL, et al. Both protein activation and gene expression are involved in early vascular tube formation in vitro. Clin Cancer Res 2002; 8: 3019–26
Hahn CN, Su ZJ, Drogemuller CJ, et al. Expression profiling reveals functionally important genes and coordinately regulated signaling pathway genes during in vitro angiogenesis. Physiol Genomics 2005; 22: 57–69
Godl K, Gruss OJ, Eickoff J, et al. Proteomic characterization of the angiogenesis inhibitor SU6668 reveals multiple impacts on cellular kinase signaling. Cancer Res 2005; 65: 6919–26
Shim JS, Kwon HJ. Chemical genetics for therapeutic target mining. Expert Opin Ther Targets 2004; 8: 653–61
Nanda A, St Croix B. Tumor endothelial markers: new targets for cancer therapy. Curr Opin Oncol 2004Jan; 16: 44–9
Halin C, Rondini S, Nilsson F, et al. Enhancement of antitumor activity of interleukin-12 by targeted delivery to neovasculature. Nat Biotechnol 2002Mar; 20(3): 264–9
Mineta H, Miura R, Ogino T, et al. Prognostic value of vascular endothelial growth factor in patients with head and neck squamous cell carcinomas. Br J Cancer 2000; 83: 775–81
Riedel F, Gotte K, Li M, et al. Abrogation of VEGF expression in human head and neck squamous cell carcinoma decreases angiogenic activity in vitro and in vivo. Int J Oncol 2003; 23: 577–83
Dray TG, Hardin NJ, Sofferman RA. Angiogenesis as a prognostic marker in early head and neck cancer. Ann Otol Rhinol Laryngol 1995; 104: 724–9
Tae K, El-Naggar A, Yoo E, et al. Expression of vascular endothelial growth factor and microvessel density in head and neck tumorigenesis. Clin Cancer Res 2000; 6: 2821–8
Mirabelli CK, Bennett CF, Anderson K, et al. In vitro and in vivo pharmacologic activities of anti-sense oligonucleotides. Anti Cancer Des 1991; 6: 647–61
Nakashima T, Hudson M, Clayman GL. Antisense inhibition of vascular endothelial growth factor in human head and neck squamous cell carcinoma. Head Neck 2000; 22(5): 483–8
Neuchrist C, Bohan M, Erovic MD. Vascular endothelial growth factor C and vascular endothelial growth factor receptor 3 expression in squamous cell carcinomas of the head and neck. Head Neck 2003Jun; 25(6): 464–73
Li M, Ye C, Feng C, et al. Enhanced antiangiogenic therapy of squamous cell carcinoma by combined endostatin and epidermal growth factor receptor-antisense therapy. Clin Cancer Res 2002; 8: 3570–8
Petruzzelli GJ, Benefield J, Taitz AD, et al. Heparin-binding growth factor(s) derived from head and neck squamous cell carcinomas induce endothelial cell proliferation. Head Neck 1997Oct; 19(7): 576–82
Pammer J, Weninger W, Mildner M, et al. Vascular endothelial growth factor is constitutively expressed in normal human salivary glands and is secreted in the saliva of healthy individuals. J Pathol 1998; 186: 186–91
Riedel F, Gotte K, Schwalb J, et al. Serum levels of vascular endothelial growth factor in patients with head and neck cancer. Eur Arch Otorhinolaryngol 2000; 257(6): 332–6
Riedel F, Gotte K, Shwalb J. Expression of vascular endothelial growth factor correlates with angiogenesis and p53 mutations in head and neck squamous cell carcinoma. Acta Otolaryngol 2000; 120: 105–11
Wolf GT, Fisher SG. Effectiveness of salvage neck dissection for advanced regional metastases when induction chemotherapy and radiation are used for organ preservation. Laryngoscope 1992Aug; 102(8): 934–9
Teknos TN, Cox C, Yoo S, et al. Elevated serum vascular endothelial growth factor and decreased survival in advanced laryngeal carcinoma. Head Neck 2002Nov; 24(11): 1004–11
Dietz A, Rudat V, Conradt C, et al. Prognostic relevance of serum levels of the angiogenic peptide b FGF in advanced carcinoma of the head and neck treated by primary radiochemotherapy. Head Neck 2000Oct; 22(7): 666–73
Tseng JE, Glisson BS, Khuri FR, et al. Phase II study of antiangiogenic agent thalidomide in recurrent or metastatic squamous cell carcinoma of the head and neck. Cancer 2001; 92: 2364–73
Vokes EE, Cohen EEW, Mauer AM, et al. A phase I study of erlotinib and bevacizumab for recurrent or metastatic squamous cell carcinoma of the head and neck [abstract no. 5504]. Proc Am Soc Clin Oncol 2005; 24: 23
Klos KS, Zhou X, Lee S, et al. Combined transtuzumab and paclitaxel treatment better inhibits ErbB-2 mediated angiogenesis in breast carcinoma through a more effective inhibition of Akt than either treatment alone. Cancer 2003; 98: 1377–85
Asakuma J, Sumitomo M, Asano T, et al. Modulation of tumor growth and tumor induced angiogenesis after epidermal growth factor receptor inhibition by ZD1839 in renal cell carcinoma. J Urol 2004; 171: 897–902
Petit AM, Rak J, Hung MC, et al. Neutralizing antibodies against epidermal growth factor and Erb-2/neu receptor tyrosine kinases down-regulate vascular endothelial growth factor production by tumor cells in vitro and in vivo: angiogenic implications for signal transduction therapy of solid tumors. Am J Pathol 1997; 151: 1523–30
Viloria-Petit A, Crombet T, Jothy S, et al. Acquired resistance to the antitumor effect of epidermal growth factor receptor-blocking antibodies in vivo: a role for altered tumor angiogenesis. Cancer Res 2001; 61: 5090–101
Dannenberg AJ, Lippman SM, Mann JR, et al. Cyclooxygenase-2 and epidermal growth factor receptor: pharmacologic targets for chemoprevention. J Clin Oncol 2005; 23: 254–66
Choe MS, Zhang X, Shin HJ, et al. Interaction between EGFR and COX-2 mediated pathways and its implication in chemoprevention of head and neck cancer. Mol Cancer Ther 2005Sep; 4(9): 1448–55
Lenz HJ. Antiangiogenic agents in cancer therapy. Oncology (Williston Park) 2005Apr; 19(4 Suppl. 3): 17–25
Ratain MJ. Advances in drug development. Clin Adv Hematol Oncology 2005; 3: 371–2
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Saba, N.F., Chen, Z.(. & Shin, D.M. Vascular Targeting and Therapeutics for Squamous Cell Carcinoma of the Head and Neck. Am J Cancer 5, 7–18 (2006). https://doi.org/10.2165/00024669-200605010-00002
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DOI: https://doi.org/10.2165/00024669-200605010-00002