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Angiogenic Signaling Pathways and Anti-angiogenic Therapies in Human Cancer

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Predictive Biomarkers in Oncology

Abstract

Vascular endothelial growth factor (VEGF) is the principal regulator of tumor angiogenesis and is overexpressed in the majority of solid tumors. Therapeutic inhibition of VEGF and its main receptor (VEGFR2) has shown significant clinical efficacy in several human cancers. However, in unselected patient populations, often these agents have not offered sustainable clinical benefit. Some of the challenges with the clinical efficacy of anti-VEGF/VEGFR therapies may be explained by the heterogeneity of human tumor vessels and variation in their sensitivity to VEGF/VEGFR inhibition. However, the process of tumor angiogenesis is far more complex with frequent cross talk between VEGF/VEGFR and other signaling pathways. In addition to anti-angiogenic effects, anti-VEGF/VEGFR agents also cause “normalization” of tumor vessels and “pruning” of normal vessels. In order to achieve significant improvement in clinical efficacy of anti-VEGF/VEGFR therapies in the near future, it will be important to (1) better understand the complex biology of VEGF/VEGFR and non-VEGF/VEGFR signaling pathways in the context of pathologic (aberrant) angiogenesis in human cancer tissues, (2) translate such biologic concepts into a more comprehensive molecular profiling and pathologic disease state characterization, and (3) advance the much needed predictive biomarker science to drive rational patient-tailoring and combinatorial therapeutic strategies in next-generation clinical trials of anti-angiogenic therapies. It will also be critical to identify and address other clinical and scientific challenges, including various primary and acquired mechanisms of resistance to anti-angiogenic therapies.

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Abbreviations

BRC:

Breast carcinoma

CIN:

Chromosomal instability

CRC:

Colorectal carcinoma

DV:

Draining vein

ECOG:

Eastern Cooperative Oncology Group

EGFR:

Epidermal growth factor receptor

FA:

Feeder artery

FDA:

Food and Drug Administration

FGFR:

Fibroblast growth factor receptor

FISH:

Fluorescent in situ hybridization

FLK1:

Fetal liver kinase 1

FOLFIRI:

Folinic acid, 5-fluorouracil, and irinotecan

GEJ:

Gastroesophageal junction

GIST:

Gastrointestinal stromal tumor

GMP:

Glomeruloid microvascular proliferation

HCC:

Hepatocellular carcinoma

HER2:

Human epidermal growth factor receptor 2

HGF:

Hepatocyte growth factor

IgG:

Immunoglobulin G

IHC:

Immunohistochemistry

ILF:

Irinotecan, bolus fluorouracil, and leucovorin

INF:

α Interferon-α

MC:

Mast cell

MDSCs:

Myeloid-derived suppressor cells

MET:

Mesenchymal epithelial transition factor

MTC:

Medullary thyroid carcinoma

MVD:

Microvascular density

NGS:

Next-generation sequencing

NRP1:

Neuropilin 1

NRP2:

Neuropilin 2

NSCLC:

Non-small cell lung carcinoma

OC:

Ovarian cancer

OS:

Overall survival

PACA:

Pancreatic cancer

PDGFR:

Platelet-derived growth factor

PDGF-Rb:

Platelet-derived growth factor receptor-beta

PFS:

Progression-free survival

PlGF:

Placental growth factor

RCC:

Renal cell carcinoma

RNA:

Ribonucleic acid

TAM:

Tumor associated macrophage

TAMs:

Tumor-associated macrophages

TCGA:

The Cancer Genome Atlas

TGF-b:

Transforming growth factor-beta

TKIs:

Tyrosine kinase inhibitors

Treg:

Regulatory T cells

VEGF:

Vascular endothelial growth factor

VEGFR:

Vascular endothelial growth factor receptor

VPF:

Vascular permeability factor

References

  1. Jain RK. Antiangiogenesis strategies revisited: from starving tumors to alleviating hypoxia. Cancer Cell. 2014;26(5):605–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350(23):2335–42.

    Article  CAS  PubMed  Google Scholar 

  3. Jang HJ, Kim BJ, Kim JH, Kim HS. The addition of bevacizumab in the first-line treatment for metastatic colorectal cancer: an updated meta-analysis of randomized trials. Oncotarget. 2017;8(42):73009–16.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Hayes DF. Bevacizumab treatment for solid tumors: boon or bust? JAMA. 2011;305(5):506–8.

    Article  CAS  PubMed  Google Scholar 

  5. Jain RK. Lessons from multidisciplinary translational trials on anti-angiogenic therapy of cancer. Nat Rev Cancer. 2008;8(4):309–16.

    Article  CAS  PubMed  Google Scholar 

  6. Carmeliet P, Jain RK. Molecular mechanisms and clinical applications of angiogenesis. Nature. 2011;473(7347):298–307. https://doi.org/10.1038/nature10144.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med. 1971;285(21):1182–6.

    Article  CAS  PubMed  Google Scholar 

  8. Jain RK. Normalizing tumor microenvironment to treat cancer: bench to bedside to biomarkers. J Clin Oncol. 2013;31(17):2205–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Ferrara N. Vascular endothelial growth factor. Arterioscler Thromb Vasc Biol. 2009;29(6):789–91.

    Article  CAS  PubMed  Google Scholar 

  10. Sitohy B, Nagy JA, Dvorak HF. Anti-VEGF/VEGFR therapy for cancer: reassessing the target. Cancer Res. 2012;72(8):1909–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Sitohy B, Chang S, Sciuto TE, Masse E, Shen M, Kang PM, et al. Early actions of anti-vascular endothelial growth factor/vascular endothelial growth factor receptor drugs on angiogenic blood vessels. Am J Pathol. 2017;187(10):2337–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Fischer C, Mazzone M, Jonckx B, Carmeliet P. FLT1 and its ligands VEGFB and PlGF: drug targets for anti-angiogenic therapy? Nat Rev Cancer. 2008;8(12):942–56.

    Article  CAS  PubMed  Google Scholar 

  13. Rolny C, Mazzone M, Tugues S, Laoui D, Johansson I, Coulon C, et al. HRG inhibits tumor growth and metastasis by inducing macrophage polarization and vessel normalization through downregulation of PlGF. Cancer Cell. 2011;19(1):31–44.

    Article  CAS  PubMed  Google Scholar 

  14. Gacche RN, Assaraf YG. Redundant angiogenic signaling and tumor drug resistance. Drug Resist Updat. 2018;36:47–76.

    Article  PubMed  Google Scholar 

  15. Neufeld G, Kessler O. The semaphorins: versatile regulators of tumour progression and tumour angiogenesis. Nat Rev Cancer. 2008;8(8):632–45.

    Article  CAS  PubMed  Google Scholar 

  16. Stockmann C, Doedens A, Weidemann A, Zhang N, Takeda N, Greenberg JI, et al. Deletion of vascular endothelial growth factor in myeloid cells accelerates tumorigenesis. Nature. 2008;456(7223):814–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Lee S, Chen TT, Barber CL, Jordan MC, Murdock J, Desai S, et al. Autocrine VEGF signaling is required for vascular homeostasis. Cell. 2007;130(4):691–703.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Lanahan AA, Hermans K, Claes F, Kerley-Hamilton JS, Zhuang ZW, Giordano FJ, et al. VEGF receptor 2 endocytic trafficking regulates arterial morphogenesis. Dev Cell. 2010;18(5):713–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Vasudev NS, Reynolds AR. Anti-angiogenic therapy for cancer: current progress, unresolved questions and future directions. Angiogenesis. 2014;17(3):471–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Fan F, Wey JS, McCarty MF, Belcheva A, Liu W, Bauer TW, et al. Expression and function of vascular endothelial growth factor receptor-1 on human colorectal cancer cells. Oncogene. 2005;24(16):2647–53.

    Article  CAS  PubMed  Google Scholar 

  21. Dales JP, Garcia S, Bonnier P, Duffaud F, Carpentier S, Djemli A, et al. Prognostic significance of VEGF receptors, VEGFR-1 (Flt-1) and VEGFR-2 (KDR/Flk-1) in breast carcinoma. Ann Pathol. 2003;23(4):297–305.

    PubMed  Google Scholar 

  22. Guo P, Fang Q, Tao HQ, Schafer CA, Fenton BM, Ding I, et al. Overexpression of vascular endothelial growth factor by MCF-7 breast cancer cells promotes estrogen-independent tumor growth in vivo. Cancer Res. 2003;63(15):4684–91.

    CAS  PubMed  Google Scholar 

  23. Spannuth WA, Nick AM, Jennings NB, Armaiz-Pena GN, Mangala LS, Danes CG, et al. Functional significance of VEGFR-2 on ovarian cancer cells. Int J Cancer. 2009;124(5):1045–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Ellis LM, Hicklin DJ. VEGF-targeted therapy: mechanisms of anti-tumour activity. Nat Rev Cancer. 2008;8(8):579–91.

    Article  CAS  PubMed  Google Scholar 

  25. Lu KV, Chang JP, Parachoniak CA, Pandika MM, Aghi MK, Meyronet D, et al. VEGF inhibits tumor cell invasion and mesenchymal transition through a MET/VEGFR2 complex. Cancer Cell. 2012;22(1):21–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Fan F, Samuel S, Gaur P, Lu J, Dallas NA, Xia L, et al. Chronic exposure of colorectal cancer cells to bevacizumab promotes compensatory pathways that mediate tumour cell migration. Br J Cancer. 2011;104(8):1270–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Ronca R, Benkheil M, Mitola S, Struyf S, Liekens S. Tumor angiogenesis revisited: regulators and clinical implications. Med Res Rev. 2017;37(6):1231–74.

    Article  PubMed  Google Scholar 

  28. Welti JC, Gourlaouen M, Powles T, Kudahetti SC, Wilson P, Berney DM, et al. Fibroblast growth factor 2 regulates endothelial cell sensitivity to sunitinib. Oncogene. 2011;30(10):1183–93.

    Article  CAS  PubMed  Google Scholar 

  29. Shojaei F, Lee JH, Simmons BH, Wong A, Esparza CO, Plumlee PA, et al. HGF/c-Met acts as an alternative angiogenic pathway in sunitinib-resistant tumors. Cancer Res. 2010;70(24):10090–100.

    Article  CAS  PubMed  Google Scholar 

  30. Eklund L, Saharinen P. Angiopoietin signaling in the vasculature. Exp Cell Res. 2013;319(9):1271–80.

    Article  CAS  PubMed  Google Scholar 

  31. Li JL, Sainson RC, Oon CE, Turley H, Leek R, Sheldon H, et al. DLL4-Notch signaling mediates tumor resistance to anti-VEGF therapy in vivo. Cancer Res. 2011;71(18):6073–83.

    Article  CAS  PubMed  Google Scholar 

  32. Crawford Y, Kasman I, Yu L, Zhong C, Wu X, Modrusan Z, et al. PDGF-C mediates the angiogenic and tumorigenic properties of fibroblasts associated with tumors refractory to anti-VEGF treatment. Cancer Cell. 2009;15(1):21–34.

    Article  CAS  PubMed  Google Scholar 

  33. di Tomaso E, London N, Fuja D, Logie J, Tyrrell JA, Kamoun W, et al. PDGF-C induces maturation of blood vessels in a model of glioblastoma and attenuates the response to anti-VEGF treatment. PLoS One. 2009;4(4):e5123.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Huang D, Ding Y, Zhou M, Rini BI, Petillo D, Qian CN, et al. Interleukin-8 mediates resistance to antiangiogenic agent sunitinib in renal cell carcinoma. Cancer Res. 2010;70(3):1063–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Salvucci O, Tosato G. Essential roles of EphB receptors and EphrinB ligands in endothelial cell function and angiogenesis. Adv Cancer Res. 2012;114:21–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Cascone T, Herynk MH, Xu L, Du Z, Kadara H, Nilsson MB, et al. Upregulated stromal EGFR and vascular remodeling in mouse xenograft models of angiogenesis inhibitor-resistant human lung adenocarcinoma. J Clin Invest. 2011;121(4):1313–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Greenberg JI, Shields DJ, Barillas SG, Acevedo LM, Murphy E, Huang J, et al. A role for VEGF as a negative regulator of pericyte function and vessel maturation. Nature. 2008;456(7223):809–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Carmeliet P, Jain RK. Principles and mechanisms of vessel normalization for cancer and other angiogenic diseases. Nat Rev Drug Discov. 2011;10(6):417–27.

    Article  CAS  PubMed  Google Scholar 

  39. Nasir A, Holzer TR, Chen M, Man MZ, Schade AE. Differential expression of VEGFR2 protein in HER2 positive primary human breast cancer: potential relevance to anti-angiogenic therapies. Cancer Cell Int. 2017;17:56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Nagy JA, Dvorak HF. Heterogeneity of the tumor vasculature: the need for new tumor blood vessel type-specific targets. Clin Exp Metastasis. 2012;29(7):657–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Goel S, Duda DG, Xu L, Munn LL, Boucher Y, Fukumura D, et al. Normalization of the vasculature for treatment of cancer and other diseases. Physiol Rev. 2011;91(3):1071–121.

    Article  CAS  PubMed  Google Scholar 

  42. Smith NR, Baker D, James NH, Ratcliffe K, Jenkins M, Ashton SE, et al. Vascular endothelial growth factor receptors VEGFR-2 and VEGFR-3 are localized primarily to the vasculature in human primary solid cancers. Clin Cancer Res. 2010;16(14):3548–61.

    Article  CAS  PubMed  Google Scholar 

  43. Holzer TR, Fulford AD, Nedderman DM, Umberger TS, Hozak RR, Joshi A, et al. Tumor cell expression of vascular endothelial growth factor receptor 2 is an adverse prognostic factor in patients with squamous cell carcinoma of the lung. PLoS One. 2013;8(11):e80292.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Sitohy B, Nagy JA, Jaminet SC, Dvorak HF. Tumor-surrogate blood vessel subtypes exhibit differential susceptibility to anti-VEGF therapy. Cancer Res. 2011;71(22):7021–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Nasir A, Reising LO, Nedderman DM, Fulford AD, Uhlik MT, Benjamin LE, et al. Heterogeneity of vascular endothelial growth factor receptors 1, 2, 3 in primary human colorectal carcinoma. Anticancer Res. 2016;36(6):2683–96.

    CAS  PubMed  Google Scholar 

  46. Nasir A, Falcon B, Wang D, et al. Vascular and tumor cell expression of VEGFR2 and molecular subtyping: an innovative biomarker approach in bladder cancer. ASCO-GU Cancers Symposium. San Francisco; 2018.

    Google Scholar 

  47. Tolaney SM, Boucher Y, Duda DG, Martin JD, Seano G, Ancukiewicz M, et al. Role of vascular density and normalization in response to neoadjuvant bevacizumab and chemotherapy in breast cancer patients. Proc Natl Acad Sci U S A. 2015;112(46):14325–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Jeong HS, Jones D, Liao S, Wattson DA, Cui CH, Duda DG, et al. Investigation of the lack of angiogenesis in the formation of lymph node metastases. J Natl Cancer Inst. 2015;107(9):699.

    Article  CAS  Google Scholar 

  49. Wehland M, Bauer J, Magnusson NE, Infanger M, Grimm D. Biomarkers for anti-angiogenic therapy in cancer. Int J Mol Sci. 2013;14(5):9338–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Pilotto S, Bonomi M, Massari F, Milella M, Ciuffreda L, Brunelli M, et al. Anti-angiogenic drugs and biomarkers in non-small-cell lung cancer: a ‘hard days night’. Curr Pharm Des. 2014;20(24):3958–72.

    Article  CAS  PubMed  Google Scholar 

  51. Duda DG, Willett CG, Ancukiewicz M, di Tomaso E, Shah M, Czito BG, et al. Plasma soluble VEGFR-1 is a potential dual biomarker of response and toxicity for bevacizumab with chemoradiation in locally advanced rectal cancer. Oncologist. 2010;15(6):577–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Meyerhardt JA, Ancukiewicz M, Abrams TA, Schrag D, Enzinger PC, Chan JA, et al. Phase I study of cetuximab, irinotecan, and vandetanib (ZD6474) as therapy for patients with previously treated metastastic colorectal cancer. PLoS One. 2012;7(6):e38231.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Willett CG, Duda DG, di Tomaso E, Boucher Y, Ancukiewicz M, Sahani DV, et al. Efficacy, safety, and biomarkers of neoadjuvant bevacizumab, radiation therapy, and fluorouracil in rectal cancer: a multidisciplinary phase II study. J Clin Oncol. 2009;27(18):3020–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Zhu AX, Ancukiewicz M, Supko JG, Sahani DV, Blaszkowsky LS, Meyerhardt JA, et al. Efficacy, safety, pharmacokinetics, and biomarkers of cediranib monotherapy in advanced hepatocellular carcinoma: a phase II study. Clin Cancer Res. 2013;19(6):1557–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Lambrechts D, Claes B, Delmar P, Reumers J, Mazzone M, Yesilyurt BT, et al. VEGF pathway genetic variants as biomarkers of treatment outcome with bevacizumab: an analysis of data from the AViTA and AVOREN randomised trials. Lancet Oncol. 2012;13(7):724–33.

    Article  CAS  PubMed  Google Scholar 

  56. Lambrechts D, Lenz HJ, de Haas S, Carmeliet P, Scherer SJ. Markers of response for the antiangiogenic agent bevacizumab. J Clin Oncol. 2013;31(9):1219–30.

    Article  CAS  PubMed  Google Scholar 

  57. Holzer TR, Fulford AD, Reising LO, Nedderman DM, Zhang X, Benjamin LE, et al. Profiling of vascular endothelial growth factor receptor heterogeneity identifies protein expression-defined subclasses of human non-small cell lung carcinoma. Anticancer Res. 2016;36(7):3277–88.

    CAS  PubMed  Google Scholar 

  58. Kankeu Fonkoua L, Yee NS. Molecular characterization of gastric carcinoma: therapeutic implications for biomarkers and targets. Biomedicines. 2018;6(1).

    Article  PubMed Central  Google Scholar 

  59. Cancer Genome Atlas Research Network. Comprehensive molecular characterization of gastric adenocarcinoma. Nature. 2014;513(7517):202–9.

    Google Scholar 

  60. Uhlik MT, Liu J, Falcon BL, Iyer S, Stewart J, Celikkaya H, et al. Stromal-based signatures for the classification of gastric cancer. Cancer Res. 2016;76(9):2573–86.

    Article  CAS  PubMed  Google Scholar 

  61. Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006;355(24):2542–50.

    Article  CAS  PubMed  Google Scholar 

  62. Reck M, von Pawel J, Zatloukal P, Ramlau R, Gorbounova V, Hirsh V, et al. Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAil. J Clin Oncol. 2009;27(8):1227–34.

    Article  CAS  PubMed  Google Scholar 

  63. Reck M, von Pawel J, Zatloukal P, Ramlau R, Gorbounova V, Hirsh V, et al. Overall survival with cisplatin-gemcitabine and bevacizumab or placebo as first-line therapy for nonsquamous non-small-cell lung cancer: results from a randomised phase III trial (AVAiL). Ann Oncol. 2010;21(9):1804–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Schneider BP, Li L, Shen F, Miller KD, Radovich M, O’Neill A, et al. Genetic variant predicts bevacizumab-induced hypertension in ECOG-5103 and ECOG-2100. Br J Cancer. 2014;111(6):1241–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Poveda AM, Selle F, Hilpert F, Reuss A, Savarese A, Vergote I, et al. Bevacizumab combined with weekly paclitaxel, pegylated liposomal doxorubicin, or topotecan in platinum-resistant recurrent ovarian cancer: analysis by chemotherapy cohort of the randomized phase III AURELIA trial. J Clin Oncol. 2015;33(32):3836–8.

    Article  CAS  PubMed  Google Scholar 

  66. Liu JF, Matulonis UA. Bevacizumab in newly diagnosed ovarian cancer. Lancet Oncol. 2015;16(8):876–8.

    Article  CAS  PubMed  Google Scholar 

  67. Krill LS, Tewari KS. Integration of bevacizumab with chemotherapy doublets for advanced cervical cancer. Expert Opin Pharmacother. 2015;16(5):675–83.

    Article  CAS  PubMed  Google Scholar 

  68. Crafton SM, Salani R. Beyond chemotherapy: an overview and review of targeted therapy in cervical cancer. Clin Ther. 2016;38(3):449–58.

    Article  CAS  PubMed  Google Scholar 

  69. Ciombor KK, Berlin J. Aflibercept – a decoy VEGF receptor. Curr Oncol Rep. 2014;16(2):368.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Aprile G, Rijavec E, Fontanella C, Rihawi K, Grossi F. Ramucirumab: preclinical research and clinical development. Oncol Targets Ther. 2014;7:1997–2006.

    Article  CAS  Google Scholar 

  71. Ramucirumab TP. Boon or bane. J Egypt Natl Canc Inst. 2016;28(3):133–40.

    Article  Google Scholar 

  72. Wu P, Nielsen TE, Clausen MH. FDA-approved small-molecule kinase inhibitors. Trends Pharmacol Sci. 2015;36(7):422–39.

    Article  CAS  PubMed  Google Scholar 

  73. Wu P, Nielsen TE, Clausen MH. Small-molecule kinase inhibitors: an analysis of FDA-approved drugs. Drug Discov Today. 2016;21(1):5–10.

    Article  CAS  PubMed  Google Scholar 

  74. Zhu Y, Choi SH, Shah K. Multifunctional receptor-targeting antibodies for cancer therapy. Lancet Oncol. 2015;16(15):e543–e54.

    Article  CAS  PubMed  Google Scholar 

  75. Yokoi K, Thaker PH, Yazici S, Rebhun RR, Nam DH, He J, et al. Dual inhibition of epidermal growth factor receptor and vascular endothelial growth factor receptor phosphorylation by AEE788 reduces growth and metastasis of human colon carcinoma in an orthotopic nude mouse model. Cancer Res. 2005;65(9):3716–25.

    Article  CAS  PubMed  Google Scholar 

  76. Amin DN, Hida K, Bielenberg DR, Klagsbrun M. Tumor endothelial cells express epidermal growth factor receptor (EGFR) but not ErbB3 and are responsive to EGF and to EGFR kinase inhibitors. Cancer Res. 2006;66(4):2173–80.

    Article  CAS  PubMed  Google Scholar 

  77. Erber R, Thurnher A, Katsen AD, Groth G, Kerger H, Hammes HP, et al. Combined inhibition of VEGF and PDGF signaling enforces tumor vessel regression by interfering with pericyte-mediated endothelial cell survival mechanisms. FASEB J. 2004;18(2):338–40.

    Article  CAS  PubMed  Google Scholar 

  78. Hojjat-Farsangi M. Small-molecule inhibitors of the receptor tyrosine kinases: promising tools for targeted cancer therapies. Int J Mol Sci. 2014;15(8):13768–801.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Mabry R, Gilbertson DG, Frank A, Vu T, Ardourel D, Ostrander C, et al. A dual-targeting PDGFRbeta/VEGF-A molecule assembled from stable antibody fragments demonstrates anti-angiogenic activity in vitro and in vivo. MAbs. 2010;2(1):20–34.

    Article  PubMed  PubMed Central  Google Scholar 

  80. Kienast Y, Klein C, Scheuer W, Raemsch R, Lorenzon E, Bernicke D, et al. Ang-2-VEGF-A CrossMab, a novel bispecific human IgG1 antibody blocking VEGF-A and Ang-2 functions simultaneously, mediates potent antitumor, antiangiogenic, and antimetastatic efficacy. Clin Cancer Res. 2013;19(24):6730–40.

    Article  CAS  PubMed  Google Scholar 

  81. Tol J, Koopman M, Cats A, Rodenburg CJ, Creemers GJ, Schrama JG, et al. Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer. N Engl J Med. 2009;360(6):563–72.

    Article  CAS  PubMed  Google Scholar 

  82. Gianni L, Romieu GH, Lichinitser M, Serrano SV, Mansutti M, Pivot X, et al. AVEREL: a randomized phase III trial evaluating bevacizumab in combination with docetaxel and trastuzumab as first-line therapy for HER2-positive locally recurrent/metastatic breast cancer. J Clin Oncol. 2013;31(14):1719–25.

    Article  CAS  PubMed  Google Scholar 

  83. Chauhan VP, Stylianopoulos T, Martin JD, Popovic Z, Chen O, Kamoun WS, et al. Normalization of tumour blood vessels improves the delivery of nanomedicines in a size-dependent manner. Nat Nanotechnol. 2012;7(6):383–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Seto T, Kato T, Nishio M, Goto K, Atagi S, Hosomi Y, et al. Erlotinib alone or with bevacizumab as first-line therapy in patients with advanced non-squamous non-small-cell lung cancer harbouring EGFR mutations (JO25567): an open-label, randomised, multicentre, phase 2 study. Lancet Oncol. 2014;15(11):1236–44.

    Article  CAS  PubMed  Google Scholar 

  85. Izumi Y, Xu L, di Tomaso E, Fukumura D, Jain RK. Tumour biology: herceptin acts as an anti-angiogenic cocktail. Nature. 2002;416(6878):279–80.

    Article  CAS  PubMed  Google Scholar 

  86. Kodack DP, Chung E, Yamashita H, Incio J, Duyverman AM, Song Y, et al. Combined targeting of HER2 and VEGFR2 for effective treatment of HER2-amplified breast cancer brain metastases. Proc Natl Acad Sci U S A. 2012;109(45):E3119–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Falchook GS, Moulder SL, Wheler JJ, Jiang Y, Bastida CC, Kurzrock R. Dual HER2 inhibition in combination with anti-VEGF treatment is active in heavily pretreated HER2-positive breast cancer. Ann Oncol. 2013;24(12):3004–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Huang Y, Goel S, Duda DG, Fukumura D, Jain RK. Vascular normalization as an emerging strategy to enhance cancer immunotherapy. Cancer Res. 2013;73(10):2943–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

The author would like to acknowledge the dedication and hard work of Timothy Holzer, Angie Fulford, Beverly Falcon, Drew Nedderman, Leslie O’Neal Reising, James Alston, and Mia Chen in the lab in developing and optimizing technically robust immunohistochemical and bright-field in situ hybridization technologies for VEGFR2, VEGFR3, and VEGFR1 for archival human tissues. Thanks to Jeff Hanson for supporting pathologic angiogenesis and oncologic disease state characterization analyses. Thanks also to Andrew Schade, Kelly Credille, Aafia Chaudhry, Katherine Marie Bell-McGuinn, Mayukh Das, Richard Walgren, Laura Benjamin, Bronislaw Pytowsky, Mark Uhlik, and Jeremy Graff for great scientific and clinical collaboration on tumor angiogenesis and anti-angiogenesis projects over the years.

Disclaimer Expert scientific and clinical views expressed in this chapter are those of the author.

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Authors and Affiliations

  1. Diagnostic & Experimental Pathology, Tailored Therapeutics, Eli Lilly & Co., Indianapolis, IN, USA

    Aejaz Nasir

  2. BJ’s Diagnostic & Precision Oncology, Tampa, FL, USA

    Aejaz Nasir

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  1. Department of Pathology and Lab Medicine, Indiana University School of Medicine, Indianapolis, IN, USA

    Sunil Badve

  2. Targos Inc., Issaquah, WA, USA

    George Louis Kumar

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Nasir, A. (2019). Angiogenic Signaling Pathways and Anti-angiogenic Therapies in Human Cancer. In: Badve, S., Kumar, G. (eds) Predictive Biomarkers in Oncology. Springer, Cham. https://doi.org/10.1007/978-3-319-95228-4_19

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  • DOI: https://doi.org/10.1007/978-3-319-95228-4_19

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  • Online ISBN: 978-3-319-95228-4

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