Secreted Growth Factors as Therapeutic Targets

Part of the Cancer Drug Discovery and Development book series (CDD&D)


Secreted growth factors directed from malignant cell to malignant cell, malignant cell to stromal cells, vascular cells and immune system cells or from stromal cells, vascular cells and immune system cells to malignant cells are essential for the growth and progression of malignant disease. Proangiogenic factors including members of the vascular endothelial growth factor (VEGF)-A family, placental growth factor, members of the fibroblast growth factor family, semaphorins, ephrins, angiopoietins, stromal-cell derived factor-1, EG-VEGF, Bv8, transforming growth factor-βs (TGFβs), and others act on endothelial cells, endothelial precursor cells and endothelial progenitor cells from the bone marrow to promote tumor growth. Platelet-derived growth factors act on pericytes. The VEGF-C and VEGF-D family members stimulate lymphangiogenesis. TGFβ secreted by malignant cells and stromal cells acts on the tumor stromal cells and on immune system cells to promote growth of the malignancy. Urokinase plasminogen activator and tissue plasminogen activator stimulate malignant cell and vascular cell migration as do numerous secreted matrix metalloproteinases. Secreted protein acidic and rich in cysteine (SPARC) stimulates the growth of malignant cells and influences malignant cell invasion and metastasis. In the bone, RANK ligand secretion can be stimulated by malignant disease to stimulate osteoclast-mediated bone resorption and allow metastasis growth. The interleukin family of secreted proteins mediates immune system activity. Immune system damping interleukins are involved in tumor immune evasion as are the chemokines monocyte chemoattractant protein 1 (MCP1) and RANTES. The large epidermal growth factor family stimulates the proliferation of epithelial malignant cells. Similarly, insulin-like growth factors and hepatocyte growth factor increase the growth of malignant tumors. Recently, the Wnt family of secreted growth factors has been identified as deregulated in multiple epithelial tumors. Many secreted growth factors are potential therapeutic targets for neutralizing antibodies or soluble receptor constructs.




  1. Achen MG, Stacker SA (2008) Molecular control of lymphatic metastasis. Ann N Y Acad Sci 1131:225–234PubMedCrossRefGoogle Scholar
  2. Allegra CJ, Jessup M, Somerfield MR, Hamilton SR, Hammond EH, Hayes DF, McAllister PK, Morton RF, Schilsky RL (2009) American society of clinical oncology provisional clinical opinion: testing for KRAS gene mutations in patients with metastatic colorectal carcinoma to predict response to anti-epidermal growth factor receptor monoclonal antibody therapy. J Clin Oncol 27:2091–2096PubMedCrossRefGoogle Scholar
  3. Balkwill F (2004) Cancer and the chemokine network. Nat Rev Cancer 4:540–550PubMedCrossRefGoogle Scholar
  4. Beenken A, Mohammadi M (2009) The FGF family: biology, pathophysiology and therapy. Nat Rev Drug Discov 8:235–253PubMedCrossRefGoogle Scholar
  5. Bergers G, Hanahan D (2008) Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer 8:592–603PubMedCrossRefGoogle Scholar
  6. Bernet A, Fitamant J (2008) Netrin-1 and its receptors in tumor growth promotion. Expert Opin Ther Targets 12:995–1007PubMedCrossRefGoogle Scholar
  7. Cao Y, Cao R, Hedlund E-M (2008) Regulation of tumor angiogenesis and metastasis by FGF and PDGF signaling pathways. J Mol Med 86:785–789PubMedCrossRefGoogle Scholar
  8. Cheever MA (2008) Twelve immunotherapy drugs that could cure cancers. Immunol Rev 222:357–368PubMedCrossRefGoogle Scholar
  9. Chitnis MM, Yuen JSP, Protheroe AS, Pollack M, Macaulay VM (2008) The type 1 insulin-like growth factor receptor pathway. Clin Cancer Res 14:6364–6370PubMedCrossRefGoogle Scholar
  10. Ciardiello F, Caputo R, Bianco R, Damiano V, Fontanini G, Cuccato S, de Placido S, Bianco AR, Tortora G (2001) Inhibition of growth factor production and angiogenesis in human cancer cells by ZD1839 (Iressa), a selective epidermal growth factor receptor tyrosine kinase inhibitor. Clin Cancer Res 7:1459–1465PubMedGoogle Scholar
  11. Clark CJ, Sage EH (2008) A prototypic matricellular protein in the tumor microenvironment – where there’s SPARC, there’s fire. J Cell Biochem 104:721–732PubMedCrossRefGoogle Scholar
  12. Dvorak HF, Brown LF, Detmar M, Dvorak AM (1995) Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis. Am J Pathol 146:1029–1039PubMedGoogle Scholar
  13. Ellis LM, Hicklin DJ (2008) VEGF-targeted therapy: mechanisms of anti-tumor activity. Nat Rev Cancer 8:579–596PubMedCrossRefGoogle Scholar
  14. Ellis GK, Bone HG, Chlebowski R, Paul D, Spadafora S, Smith J, Fan M, Jun S (2008) Randomized trial of denosumab in patients receiving adjuvant aromatase inhibitors for nonmetastatic breast cancer. J Clin Oncol 26:4875–4882PubMedCrossRefGoogle Scholar
  15. Fischer C, Jonckx B, Mazzone M, Zacchigna S, Loges S, Pattarini L, Chorianopoulos E, Liesenborghs L, Koch M, De Mol M, Autiero M, Wyns S, Plaisance S, Moons L, van Rooijen N, Giacca M, Stassen JM, Dewerchin M, Collen D, Carmeliet P (2007) Anti-PlGF inhibits growth of VEGF(R)-inhibitor-resistant tumors without affecting healthy vessels. Cell 131:463–475PubMedCrossRefGoogle Scholar
  16. Fischer C, Mazzone M, Jonckx B, Carmeliet P (2008) FLT1 and its ligands VEGFB and PlGF: drug targets for anti-angiogenic therapy? Nat Rev Cancer 8:942–956PubMedCrossRefGoogle Scholar
  17. Fizazi K, Lipton A, Mariette X, Body JJ, Rahim Y, Gralow JR, Gao G, Wu L, Sohn W, Jun S (2009) Randomized phase II trial of denosumab in patients with bone metastases from prostate cancer, breast cancer or other neoplasms after intravenous bisphosphonates. J Clin Oncol 27:1564–1571PubMedCrossRefGoogle Scholar
  18. Folkman J (1995) Angiogenesis in cancer, vascular, rheumatoid and other diseases. Nat Med 1:27–31PubMedCrossRefGoogle Scholar
  19. Fong L, Hou Y, Rivas A, Benike C, Yuen A, Fisher GA, Davis MM, Engleman EG (2001) Altered peptide ligand vaccination with Flt3 ligand expanded dendritic cells for tumor immunotherapy. Proc Natl Acad Sci U S A 98:8809–8814PubMedCrossRefGoogle Scholar
  20. Giles RH, van Es JH, Clevers H (2003) Caught up in a Wnt storm: Wnt signaling in cancer. Biochim Biophys Acta 1653:1–24PubMedGoogle Scholar
  21. Grigorian M, Ambartssumian N, Lukanidin E (2008) Metastasis-inducing S100A4 protein: implication in non-malignant human pathologies. Curr Mol Med 8:492–496PubMedCrossRefGoogle Scholar
  22. Guleng B, Tateishi K, Ohta M, Kanai F, Jazag A, Ijichi H, Tanaka Y, Washida M, Morikane K, Fukushima Y, Yamori T, Tsuruo T, Kawabe T, Miyagishi M, Taira K, Sata M, Omata M (2005) Blockade of the stromal cell-derived factor-1/CXCR4 axis attenuates in vivo tumor growth by inhibiting angiogenesis in a vascular endothelial growth factor-independent manner. Cancer Res 65:5864–5871PubMedCrossRefGoogle Scholar
  23. Gusterson BA, Hunter KD (2009) Should we be surprised at the paucity of response to EGFR inhibitors? Lancet Oncol 10:522–527PubMedCrossRefGoogle Scholar
  24. Helfman DM, Kim EJ, Lukanidin E, Grigorian M (2005) The metastasis associated protein S100A4: role in tumor progression and metastasis. Br J Cancer 92:1955–1958PubMedCrossRefGoogle Scholar
  25. Heng DYC, Bukowski RM (2008) Anti-angiogenic targets in the treatment of advanced renal cell carcinoma. Curr Cancer Drug Targets 8:676–682PubMedCrossRefGoogle Scholar
  26. Herbst RS, Bunn PA (2003) Targeting the epidermal growth factor receptor in non-small cell lung cancer. Clin Cancer Res 9:5813–5824PubMedGoogle Scholar
  27. Hopfner M, Schuppan D, Scherubl H (2008) Targeted medical therapy of biliary tract cancer: recent advances and future perspectives. World J Gastroenterol 14:7021–7032PubMedCrossRefGoogle Scholar
  28. Jezierska A, Motyl T (2009) Matrix metalloproteinase-2 involvement in breast cancer progression: a mini-review. Med Sci Monit 15:RA32–RA40PubMedGoogle Scholar
  29. Jin T, Fantus IG, Sun J (2008) Wnt and beyond Wnt: multiple mechanisms control the transcriptional property of β-catenin. Cell Signal 20:1697–1704PubMedCrossRefGoogle Scholar
  30. Kawada M, Inoue H, Masuda T, Ikeda D (2006) Insulin-like growth factor I secreted from prostate stromal cells mediate tumor-stromal cell interactions of prostate cancer. Cancer Res 66:4419–4425PubMedCrossRefGoogle Scholar
  31. Kleinberg DL, Wood TL, Furth PA, Lee AV (2009) Growth hormone and insulin-like growth factor-I in the transition from normal mammary development to preneoplastic mammary lesions. Endocrine Rev 30:51–74CrossRefGoogle Scholar
  32. Konecny GE, Meng YG, Untch M, Wang HJ, Bauerfeind I, Epstein M, Stieber P, Vernes JM, Gutierrez J, Hong K, Beryt M, Hepp H, Slamon DJ, Pegram MD (2004) Association between HER-2/neu and vascular endothelial growth factor predicts clinical outcome in primary breast cancer patients. Clin Cancer Res 10:1706–1716PubMedCrossRefGoogle Scholar
  33. Kopetz S, Hoff PM, Eng C, Overman MJ, Glover KY, Chang DZ, Wolff RA, Abbruzzese JL, Ellis LM, Heymach JV (2009) Levels of angiogenic cytokines prior to disease progression in metastatic colorectal cancer patients treated with bevacizumab. Proceedings of the ASCO 2009; Gastrointestinal cancer symposium, Abstr 292Google Scholar
  34. Korn T, Bettelli E, Oukka M, Kuchroo VK (2009) IL-17 and Th17 cells. Annu Rev Immunol 27:485–517PubMedCrossRefGoogle Scholar
  35. Krieg C, Boyman O (2009) The role of chemokines in cancer immune surveillance by the adaptive immune system. Semin Cancer Biol 19:76–83PubMedCrossRefGoogle Scholar
  36. Ledda MF, Adris S, Bravo AI, Kairiyama C, Bover L, Chernajovsky Y, Mordoh J, Podhajcer OL (1997) Suppression of SPARC expression by antisense RNA abrogates the tumorigenicity of human melanoma cells. Nat Med 3:171–176PubMedCrossRefGoogle Scholar
  37. Lipton A, Steger GG, Figueroa J, Alvarado C, Solal-Celigny P, Body JJ, de Boer R, Berardi R, Gascon P, Tonkin KS, Coleman RE, Paterson AHG, Gao GM, Kinsey AC, Peterson MC, Jun S (2008) Extended efficacy and safety of denosumab in breast cancer patients with bone metastases not receiving prior bisphosphonate therapy. Clin Cancer Res 14:6690–6696PubMedCrossRefGoogle Scholar
  38. Loges S, Roncal C, Carmeliet P (2008) Development of targeted angiogenic medicine. J Thromb Haemost 7:21–33PubMedCrossRefGoogle Scholar
  39. Lopez-Otin C, Matrisian LM (2007) Emerging roles of proteases in tumor suppression. Nat Rev Cancer 7:800–808PubMedCrossRefGoogle Scholar
  40. Martin SK, Dewar AL, Farrugia AN, Horvath N, Gronthos S, To LB, Zannettino ACW (2006) Tumor angiogenesis is associated with plasma levels of stromal-derived factor-1a in patients with multiple myeloma. Clin Cancer Res12:6973–6977PubMedCrossRefGoogle Scholar
  41. McDonald SL, Silver A (2009) The opposing roles of Wnt5a in cancer. Br J Cancer 101:209–214PubMedCrossRefGoogle Scholar
  42. McMahon B, Kwaan HC (2007) The plasminogen activator system and cancer. Pathophysiol Haemost Thromb 36:184–194CrossRefGoogle Scholar
  43. Montero JC, Rodriguez-Barrueco R, Ocana A, Diaz-Rodriguez E, Esparis-Ogando A, Pandiella A (2008) Neuregulins and cancer. Clin Cancer Res 14:3237–3241PubMedCrossRefGoogle Scholar
  44. Motzer RJ, Michaelson MD, Redman BG, Hudes GR, Wilding G, Figlin RA, Ginsberg MS, Kim ST, Baum CM, DePrimo SE, Li JZ, Bello CL, Theuer CP, George DJ, Rini BI (2006) Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. J Clin Oncol 24:16–24PubMedCrossRefGoogle Scholar
  45. Moutsopoulos NM, Wen J, Wahl SM (2008) TGF-β and tumors – an ill-fated alliance. Curr Opin Immunol 20:234–240PubMedCrossRefGoogle Scholar
  46. Mueller MM, Fusenig, NE (2004) Friends or foes – bipolar effects of the tumour stroma in cancer. Nat Rev Cancer 4:839–849PubMedCrossRefGoogle Scholar
  47. Mullen P, Cameron DA, Hasmann M, Smyth JF, Langdon SP (2007) Sensitivity to pertuzumab (2C4) in ovarian cancer models: cross-talk with estrogen receptor signaling. Mol Cancer Ther 6:93–100PubMedCrossRefGoogle Scholar
  48. Musgrove EA (2004) Wnt signaling via the epidermal growth factor receptor: a role in breast cancer? Breast Cancer Res 6:65–68PubMedCrossRefGoogle Scholar
  49. Naber HPH, ten Dijke P, Pardali E (2008) Role of TGF-β in the tumor stroma. Curr Cancer Drug Targets 8:466–472PubMedCrossRefGoogle Scholar
  50. Norden AD, Drappatz J, Wen PY (2008) Novel anti-angiogenic therapies for malignant gliomas. Lancet Neurol 7:1152–1160PubMedCrossRefGoogle Scholar
  51. Onn A, Correa AM, Gilcrease M, Isobe T, Massarelli E, Bucana CD, O’Reilly MS, Hong WK, Fidler IJ, Putnam JB, Herbst RS (2004) Synchronous overexpression of epidermal growth factor receptor and HER2-neu protein is a predictor of poor outcome in patients with stage I non-small cell lung cancer. Clin Cancer Res 10: 136–143PubMedCrossRefGoogle Scholar
  52. Otrock ZK, Makarem JA, Shamseddine AI (2007) Vascular endothelial growth factor family of ligands and receptors: review. Blood Cells Mol Dis 38:258–268PubMedCrossRefGoogle Scholar
  53. Petit I, Jin D, Rafii S (2007) The SDF-1-CXCR4 signaling pathway: a molecular hub modulating neo-angiogenesis. Trends Immunol 28:300–307CrossRefGoogle Scholar
  54. Philippou A, Maridaki M, Koutsilieris M (2008) The role of urokinase-type plasminogen activator (uPA) and transforming growth factor beta 1 (TGFβ1) in muscle regeneration. In Vivo 22:735–750Google Scholar
  55. Pinkas J, Teicher BA (2006) TGF-β in cancer and as a therapeutic target. Biochem Pharmacol 72: 523–529PubMedCrossRefGoogle Scholar
  56. Pollack M (2008) Insulin and insulin-like growth factor signaling in neoplasia. Nat Rev Cancer 8:915–928CrossRefGoogle Scholar
  57. Potiron VA, Roche J, Drabkin HA (2009) Semaphorins and their receptors in lung cancer. Cancer Lett 273:1–14PubMedCrossRefGoogle Scholar
  58. Riely GJ, Miller VA (2007) Vascular endothelial growth factor trap in non-small cell lung cancer. Clin Cancer Res 13(15 suppl):4623s–4627sCrossRefGoogle Scholar
  59. Riely GJ, Politi KA, Miller VA, Pao W (2006) Update on epidermal growth factor receptor mutations in non-small cell lung cancer. Clin Cancer Res 12:7232–7241PubMedCrossRefGoogle Scholar
  60. Rodon J, DeSantos V, Ferry RJ Jr, Kurzrock R (2008) Early drug development of inhibitors of the insulin-like growth factor-I receptor pathway: lessons from the first clinical trials. Mol Cancer Ther 7:2575–2588PubMedCrossRefGoogle Scholar
  61. Roodman GD (2009) Pathogenesis of myeloma bone disease. Leukemia 23:435–441PubMedCrossRefGoogle Scholar
  62. Roorda BD, ter Elst A, Kamps WA, de Bont ESJM (2009) Bone marrow-derived cells and tumor growth: contribution of bone marrow-derived cells to tumor micro-environments with focus on mesenchymal stem cells. Crit Rev Oncol Hematol 69:187–198PubMedCrossRefGoogle Scholar
  63. Rosenberg SA, Sportes C, Ahmadzadeh M, et al (2006) IL-7 administration to humans leads to expansion of CD8 and CD4 cells but a relative decrease of CD4T-regulatory cells. J Immunother 29:313–319PubMedCrossRefGoogle Scholar
  64. Rosen LS, Kurzrock R, Mulay M, Van Vugt A, Purdom M, Ng C, Silverman J, Koutsoukos A, Sun YN, Bass MB, Xu RY, Polverino A, Wiezorek JS, Chang DD, Benjamin R, Herbst RS (2007) Safety, pharmacokinetics and efficacy of AMG 706, an oral multikinase inhibitor, in patients with advanced solid tumors. J Clin Oncol 25:2369–2376PubMedCrossRefGoogle Scholar
  65. Roskoski R Jr (2008) VEGF receptor protein-tyrosine kinases: structure and regulation. Biochem Biophys Res Commun 375:287–291PubMedCrossRefGoogle Scholar
  66. Rowlands MA, Gunnell D, Harris R, Vatten LJ, Holly JMP, Martin RM (2009) Circulating insulin-like growth factor peptides and prostate cancer risk: a systematic review and meta-analysis. Int J Cancer 124:2416–2429PubMedCrossRefGoogle Scholar
  67. Royston D, Jackson DG (2009) Mechanisms of lymphatic metastasis in human colorectal adenocarcinoma. J Pathol 217:608–619PubMedCrossRefGoogle Scholar
  68. Schwartz GG (2008) prostate cancer, serum parathyroid hormone and the progression of skeletal metastases. Cancer Epidemiol Biomarkers Prev 17:478–483PubMedCrossRefGoogle Scholar
  69. Sergina NV, Rausch M, Wang D, Blair J, Hann B, Shokat KM, Moasser MM (2007) Escape from HER-family tyrosine kinase inhibitor therapy by the kinase-inactive HER3. Nature 445:437–441PubMedCrossRefGoogle Scholar
  70. Shojaei F, Wu X, Zhong C, Yu L, Liang XH, Yao J, Blanchard D, Bais C, Peale FV, van Bruggen N, Ho C, Ross J, Tan M, Carano RAD, Meng YG, Ferrara N (2007) Bv8 regulates myeloid-cell-dependent tumor angiogenesis. Nature 450:825–834PubMedCrossRefGoogle Scholar
  71. Shukla V, Coumoul X, Vassilopoulos A, Deng CX (2008) IGF signaling pathway as a selective target of familial breast cancer therapy. Curr Mol Med 8:727–740PubMedCrossRefGoogle Scholar
  72. Sica A, Allavena P, Mantovani A (2008) Cancer related inflammation: the macrophage connection. Cancer Lett 264:204–215CrossRefGoogle Scholar
  73. Sipkins DA, Wei X, Wu JW, Runnels JM, Cote D, Means TK, Luster AD, Scadden DT, Lin CP (2005) In vivo imaging of specialized bone marrow endothelial microdomains for tumor engraftment. Nature 435:969–973PubMedCrossRefGoogle Scholar
  74. Sirica AE (2008) Role of ErbB family receptor tyrosine kinases in intrahepatic cholangiocarcinoma. World J Gastroenterol 14:7033–7058PubMedCrossRefGoogle Scholar
  75. Smith LS, Drengler RL, Wood TE, Laheru DA, Hidalgo M, Borad MJ, Trieu V, Knauer D, Desai N, Von Hoff DD (2008) SPARC and CA19-9 as biomarkers in patients with advanced pancreatic cancer treated with nab paclitaxel plus gemcitabine. J Clin Oncol 26 (Abstr 15592)Google Scholar
  76. So WK, Cheng JC, Poon SL, Leung PCK (2008) Gonadotropin-releasing hormone and ovarian cancer: a functional and mechanistic overview. FEBS J 275:5496–5511PubMedCrossRefGoogle Scholar
  77. Stacker SA, Achen MG (2008) From anti-angiogenesis to anti-lymphangiogenesis: emerging trends in cancer therapy. Lymphatic Res Biol 6: 165–172CrossRefGoogle Scholar
  78. Stolina M, Kostenuik PJ, Dougall WC, Fitzpatrick LA, Zack DJ (2007) RANKL inhibition: from mice to men (and women). In: Choi Y (ed.) Osteoimmunology. Springer, NY, pp 143–150CrossRefGoogle Scholar
  79. Sung B, Murakami A, Oyajobi BO, Aggarwal BB (2009) Zerumbone abolishes RANKL-induced NF-kB activation, inhibits osteoclastogenesis, and suppresses human breast cancer-induced bone loss in athymic nude mice. Cancer Res 69:1477–1484PubMedCrossRefGoogle Scholar
  80. Teicher BA (2007) Transforming growth factor-β and the immune response to malignant disease. Clin Cancer Res 13:6247–6251PubMedCrossRefGoogle Scholar
  81. Toschi L, Janne PA (2008) Single-agent and combination therapeutic strategies to inhibit hepatocyte growth factor/MET signaling in cancer. Clin Cancer Res 14:5941–5946PubMedCrossRefGoogle Scholar
  82. Yarden Y (2001) The EGFR family and its ligands in human cancer: signaling mechanisms and therapeutic opportunities. Eur J Cancer 37:3–8CrossRefGoogle Scholar
  83. You WK, McDonald DM (2008) The hepatocyte growth factor/c-Met signaling pathway as a therapeutic target to inhibit angiogenesis. BMB Rep 41:833–839PubMedCrossRefGoogle Scholar
  84. Younces A, Pro B, Robertson MJ, Flinn IW, Romaguera JE, Hagemeister F, Dang NH, Fiumara P, Loyer EM, Cabanillas FF, McLaughlin PW, Rodriguez MA, Samaniego F (2004) Phase II clinical trial of interleukin-12 in patients with relapsed and refractory non-Hodgkin’s lymphoma and Hodgkin’s disease. Clin Cancer Res 10:5432–5438CrossRefGoogle Scholar
  85. Zannettino ACW, Farrugia AN, Kortesidis A, Mannavis J, To LB, Martin SK, Diamond P, Tamamura H, Lapidot T, Fujii N, Gronthos S (2005) Elevated serum levels of stromal-derived factor-1a are associated with increased osteoclast activity and osteolytic bone disease in multiple myeloma patients. Cancer Res 65:1700–1709PubMedCrossRefGoogle Scholar
  86. Zeisberg EM, Potenta S, Xie L, Zeisberg M, Kalluri R (2007) Discovery of endothelial to mesenchymal transition as a source for carcinoma-associated fibroblasts. Cancer Res 67:10123–10128PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Genzyme CorporationFraminghamUSA

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