Advertisement

VEGFR and PDGFR Targeting in Pancreatic Cancer

  • Gowru Srivani
  • Shipra Reddy Bethi
  • Sheik Aliya
  • Afroz Alam
  • Ganji Purnachandra NagarajuEmail author
Chapter

Abstract

Numerous studies have confirmed that angiogenesis acts as a momentous process in pancreatic cancer (PC) developmental stages in tumor growth, proliferation, differentiation, and metastasis. Proangiogenic factor overexpression such as fibroblast growth factor (FGF), tumor necrosis factor (TNF), epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), and platelet-derived growth factor (PDGF) initiates progression of angiogenesis in the tumor cells. Among these VEGF and PDGFR have been confirmed as strong angiogenic factors. Overexpression of these factors has an imperative function in each step of angiogenesis development during tumor progression, recurrence, and fewer prognoses in pancreatic carcinomas. This chapter covers elementary biology of VEGF and PDGFR and their expression as prognostic biomarkers in pancreatic cancer. Overexpression of VEGF–PDGFR-mediated signaling pathways associated with pancreatic cancer metastasis and accumulating diverse therapeutic targets of VEGF and PDGFR complex are discussed.

Keywords

Pancreatic cancer Angiogenesis VEGF PDGF 

References

  1. 1.
    Siegel RL, Miller KD, Jemal A (2016) Cancer statistics, 2016. CA Cancer J Clin 66:7–30CrossRefGoogle Scholar
  2. 2.
    Herreros-Villanueva M, Bujanda L (2016) Non-invasive biomarkers in pancreatic cancer diagnosis: what we need versus what we have. Ann Transl Med 4:134CrossRefGoogle Scholar
  3. 3.
    Malhotra L, Ahn D, Bloomston M (2015) The pathogenesis, diagnosis, and management of pancreatic cancer. J Gastrointest Dig Syst 4:295Google Scholar
  4. 4.
    Yachida S, Jones S, Bozic I, Antal T, Leary R, Fu B, Kamiyama M, Hruban RH, Eshleman JR, Nowak MA (2010) Distant metastasis occurs late during the genetic evolution of pancreatic cancer. Nature 467:1114CrossRefGoogle Scholar
  5. 5.
    Klöppel G, Basturk O, Schlitter AM, Konukiewitz B, Esposito I (2014) Intraductal neoplasms of the pancreas. Semin Diagn Pathol, Elsevier:452–466Google Scholar
  6. 6.
    Riess HB, Goerke A, Oettle H (2008) Pancreatic cancer. Springer, BerlinGoogle Scholar
  7. 7.
    Sohn TA, Yeo CJ, Cameron JL, Hruban RH, Fukushima N, Campbell KA, Lillemoe KD (2004) Intraductal papillary mucinous neoplasms of the pancreas: an updated experience. Ann Surg 239:788CrossRefGoogle Scholar
  8. 8.
    Ghaneh P, Kawesha A, Evans JD, Neoptolemos JP (2002) Molecular prognostic markers in pancreatic cancer. J Hepatobiliary Pancreat Sci 9:1–11CrossRefGoogle Scholar
  9. 9.
    Garcea G, Neal C, Pattenden C, Steward W, Berry D (2005) Molecular prognostic markers in pancreatic cancer: a systematic review. Eur J Cancer 41:2213–2236CrossRefGoogle Scholar
  10. 10.
    Shi Q, Le X, Wang B, Abbruzzese JL, Xiong Q, He Y, Xie K (2001) Regulation of vascular endothelial growth factor expression by acidosis in human cancer cells. Oncogene 20:3751CrossRefGoogle Scholar
  11. 11.
    Hoeben A, Landuyt B, Highley MS, Wildiers H, Van Oosterom AT, De Bruijn EA (2004) Vascular endothelial growth factor and angiogenesis. Pharmacol Rev 56:549–580CrossRefGoogle Scholar
  12. 12.
    Karar J, Maity A (2011) PI3K/AKT/mTOR pathway in angiogenesis. Front Mol Neurosci 4:51CrossRefGoogle Scholar
  13. 13.
    Ferrara N, Houck K, Jakeman L, Leung DW (1992) Molecular and biological properties of the vascular endothelial growth factor family of proteins. Endocr Rev 13:18–32CrossRefGoogle Scholar
  14. 14.
    Verheul H, Hoekman K, Luykx-de Bakker S, Eekman CA, Folman CC, Broxterman HJ, Pinedo HM (1997) Platelet: transporter of vascular endothelial growth factor. Clin Cancer Res 3:2187–2190PubMedGoogle Scholar
  15. 15.
    Sunderkötter C, Steinbrink K, Goebeler M, Bhardwaj R, Sorg C (1994) Macrophages and angiogenesis. J Leukoc Biol 55:410–422CrossRefGoogle Scholar
  16. 16.
    Neufeld G, Cohen T, Gengrinovitch S, Poltorak Z (1999) Vascular endothelial growth factor (VEGF) and its receptors. FASEB J 13:9–22CrossRefGoogle Scholar
  17. 17.
    Niu G, Chen X (2010) Vascular endothelial growth factor as an anti-angiogenic target for cancer therapy. Curr Drug Targets 11:1000–1017CrossRefGoogle Scholar
  18. 18.
    Holmes DI, Zachary I (2005) The vascular endothelial growth factor (VEGF) family: angiogenic factors in health and disease. Genome Biol 6:209CrossRefGoogle Scholar
  19. 19.
    Brissova M, Aamodt K, Brahmachary P, Prasad N, Hong J-Y, Dai C, Mellati M, Shostak A, Poffenberger G, Aramandla R (2014) Islet microenvironment, modulated by vascular endothelial growth factor-A signaling, promotes β cell regeneration. Cell Metab 19:498–511CrossRefGoogle Scholar
  20. 20.
    Shibuya M, Claesson-Welsh L (2006) Signal transduction by VEGF receptors in regulation of angiogenesis and lymphangiogenesis. Exp Cell Res 312:549–560CrossRefGoogle Scholar
  21. 21.
    Shibuya M (2011) Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) signaling in angiogenesis: a crucial target for anti-and pro-angiogenic therapies. Genes Cancer 2:1097–1105CrossRefGoogle Scholar
  22. 22.
    Poesen K, Lambrechts D, Van Damme P, Dhondt J, Bender F, Frank N, Bogaert E, Claes B, Heylen L, Verheyen A (2008) Novel role for vascular endothelial growth factor (VEGF) receptor-1 and its ligand VEGF-B in motor neuron degeneration. J Neurosci 28:10451–10459CrossRefGoogle Scholar
  23. 23.
    Salven P, Lymboussaki A, Heikkilä P, Jääskela-Saari H, Enholm B, Aase K, von Euler G, Eriksson U, Alitalo K, Joensuu H (1998) Vascular endothelial growth factors VEGF-B and VEGF-C are expressed in human tumors. Am J Pathol 153:103–108CrossRefGoogle Scholar
  24. 24.
    Muoio DM (2010) Metabolism and vascular fatty acid transport. N Engl J Med 363:291–293CrossRefGoogle Scholar
  25. 25.
    Zafar MI, Zheng J, Kong W, Ye X, Gou L, Regmi A, Chen L-L (2017) The role of vascular endothelial growth factor-B in metabolic homoeostasis: current evidence. Biosci Rep 37:BSR20171089CrossRefGoogle Scholar
  26. 26.
    Zhang F, Tang Z, Hou X, Lennartsson J, Li Y, Koch AW, Scotney P, Lee C, Arjunan P, Dong L (2009) VEGF-B is dispensable for blood vessel growth but critical for their survival, and VEGF-B targeting inhibits pathological angiogenesis. Proc Natl Acad Sci 106:6152–6157CrossRefGoogle Scholar
  27. 27.
    Paavonen K, Horelli-Kuitunen N, Chilov D, Kukk E, Pennanen S, Kallioniemi O-P, Pajusola K, Olofsson B, Eriksson U, Joukov V (1996) Novel human vascular endothelial growth factor genes VEGF-B and VEGF-C localize to chromosomes 11q13 and 4q34, respectively. Circulation 93:1079–1082CrossRefGoogle Scholar
  28. 28.
    Jha SK, Rauniyar K, Karpanen T, Leppänen V-M, Brouillard P, Vikkula M, Alitalo K, Jeltsch M (2017) Efficient activation of the lymphangiogenic growth factor VEGF-C requires the C-terminal domain of VEGF-C and the N-terminal domain of CCBE1. Sci Rep 7:4916CrossRefGoogle Scholar
  29. 29.
    Marconcini L, Marchiò S, Morbidelli L, Cartocci E, Albini A, Ziche M, Bussolino F, Oliviero S (1999) c-fos-induced growth factor/vascular endothelial growth factor D induces angiogenesis in vivo and in vitro. Proc Natl Acad Sci 96:9671–9676CrossRefGoogle Scholar
  30. 30.
    El-Chemaly S, Pacheco-Rodriguez G, Malide D, Meza-Carmen V, Kato J, Cui Y, Padilla PI, Samidurai A, Gochuico BR, Moss J (2014) Nuclear localization of vascular endothelial growth factor-D and regulation of c-Myc–dependent transcripts in human lung fibroblasts. Am J Respir Cell Mol Biol 51:34–42CrossRefGoogle Scholar
  31. 31.
    Achen MG, Jeltsch M, Kukk E, Mäkinen T, Vitali A, Wilks AF, Alitalo K, Stacker SA (1998) Vascular endothelial growth factor D (VEGF-D) is a ligand for the tyrosine kinases VEGF receptor 2 (Flk1) and VEGF receptor 3 (Flt4). Proc Natl Acad Sci 95:548–553CrossRefGoogle Scholar
  32. 32.
    Lyttle DJ, Fraser KM, Fleming SB, Mercer AA, Robinson AJ (1994) Homologs of vascular endothelial growth factor are encoded by the poxvirus Orf virus. J Virol 68:84–92PubMedPubMedCentralGoogle Scholar
  33. 33.
    Meyer M, Clauss M, Lepple-Wienhues A, Waltenberger J, Augustin HG, Ziche M, Lanz C, Büttner M, Rziha HJ, Dehio C (1999) A novel vascular endothelial growth factor encoded by Orf Virus, VEGF-E, mediates angiogenesis via signalling through VEGFR-2 (KDR) but not VEGFR-1 (Flt-1) receptor tyrosine kinases. EMBO J 18(2):363–374CrossRefGoogle Scholar
  34. 34.
    Wise LM, Inder MK, Real NC, Stuart GS, Fleming SB, Mercer AA (2012) The vascular endothelial growth factor (VEGF)-E encoded by Orf virus regulates keratinocyte proliferation and migration and promotes epidermal regeneration. Cell Microbiol 14:1376–1390CrossRefGoogle Scholar
  35. 35.
    Ogawa S, Oku A, Sawano A, Yamaguchi S, Yazaki Y, Shibuya M (1998) A novel type of vascular endothelial growth factor, VEGF-E (NZ-7 VEGF), preferentially utilizes KDR/Flk-1 receptor and carries a potent mitotic activity without heparin-binding domain. J Biol Chem 273:31273–31282CrossRefGoogle Scholar
  36. 36.
    Jenkinson DM, McEwan PE, Moss VA, Elder HY (1990) Location and spread of Orf virus antigen in infected ovine skin. Vet Dermatol 1:189–195CrossRefGoogle Scholar
  37. 37.
    Yamazaki Y, Matsunaga Y, Tokunaga Y, Obayashi S, Saito M, Morita T (2009) Snake venom vascular endothelial growth factors (VEGF-Fs) exclusively vary their structures and functions among species. J Biol Chem 284:9885–9891CrossRefGoogle Scholar
  38. 38.
    Takahashi H, Hattori S, Iwamatsu A, Takizawa H, Shibuya M (2004) A novel snake venom vascular endothelial growth factor (VEGF) predominantly induces vascular permeability through preferential signaling via VEGF receptor-1. J Biol Chem 279:46304–46314CrossRefGoogle Scholar
  39. 39.
    Maglione D, Guerriero V, Viglietto G, Ferraro MG, Aprelikova O, Alitalo K, Del SV, Lei K, Chou JY, Persico M (1993) Two alternative mRNAs coding for the angiogenic factor, placenta growth factor (PlGF), are transcribed from a single gene of chromosome 14. Oncogene 8:925–931PubMedGoogle Scholar
  40. 40.
    Loges S, Schmidt T, Carmeliet P (2009) “Antimyeloangiogenic” therapy for cancer by inhibiting PlGF. Clin Cancer Res 15:3648–3653CrossRefGoogle Scholar
  41. 41.
    Korc M (2003) Pathways for aberrant angiogenesis in pancreatic cancer. Mol Cancer 2:8CrossRefGoogle Scholar
  42. 42.
    Stuttfeld E, Ballmer-Hofer K (2009) Structure and function of VEGF receptors. IUBMB Life 61:915–922CrossRefGoogle Scholar
  43. 43.
    Sipos B, Klapper W, Kruse M-L, Kalthoff H, Kerjaschki D, Klöppel G (2004) Expression of lymphangiogenic factors and evidence of intratumoral lymphangiogenesis in pancreatic endocrine tumors. Am J Pathol 165:1187–1197CrossRefGoogle Scholar
  44. 44.
    Hansel DE, Rahman A, Hermans J, De Krijger RR, Ashfaq R, Yeo CJ, Cameron JL, Maitra A (2003) Liver metastases arising from well-differentiated pancreatic endocrine neoplasms demonstrate increased VEGF-C expression. Mod Pathol 16:652CrossRefGoogle Scholar
  45. 45.
    Büchler P, Reber HA, Büchler MW, Friess H, Hines OJ (2002) VEGF-RII influences the prognosis of pancreatic cancer. Ann Surg 236:738CrossRefGoogle Scholar
  46. 46.
    Costache M, Ioana M, Iordache S, Ene D, Costache CA, Săftoiu A (2015) VEGF expression in pancreatic cancer and other malignancies: a review of the literature. Rom J Intern Med 53:199–208CrossRefGoogle Scholar
  47. 47.
    Wei D, Le X, Zheng L, Wang L, Frey JA, Gao AC, Peng Z, Huang S, Xiong HQ, Abbruzzese JL (2003) Stat3 activation regulates the expression of vascular endothelial growth factor and human pancreatic cancer angiogenesis and metastasis. Oncogene 22:319–329CrossRefGoogle Scholar
  48. 48.
    Thomas RM, Jaquish DV, French RP, Lowy AM (2010) The RON tyrosine kinase receptor regulates VEGF production in pancreatic cancer cells. Pancreas 39:301CrossRefGoogle Scholar
  49. 49.
    Raica M, Cimpean AM (2010) Platelet-derived growth factor (PDGF)/PDGF receptors (PDGFR) axis as target for antitumor and antiangiogenic therapy. Pharmaceuticals 3:572–599CrossRefGoogle Scholar
  50. 50.
    Heldin C-H, Westermark B (1999) Mechanism of action and in vivo role of platelet-derived growth factor. Physiol Rev 79:1283–1316CrossRefGoogle Scholar
  51. 51.
    Shim AH-R, Liu H, Focia PJ, Chen X, Lin PC, He X (2010) Structures of a platelet-derived growth factor/propeptide complex and a platelet-derived growth factor/receptor complex. Proc Natl Acad Sci 107:11307–11312CrossRefGoogle Scholar
  52. 52.
    Bafico A, Aaronson S (2003) Classification of growth factors and their receptors, Holland-Frei Cancer Medicine, 6th edn. BC Decker, HamiltonGoogle Scholar
  53. 53.
    Heldin C-H, Lennartsson J (2013) Structural and functional properties of platelet-derived growth factor and stem cell factor receptors. Cold Spring Harb Perspect Biol 5:a009100CrossRefGoogle Scholar
  54. 54.
    Spritz R, Strunk K, Lee S-T, Lu-Kuo J, Ward D, Le Paslier D, Altherr M, Dorman T, Moir D (1994) A YAC contig spanning a cluster of human type III receptor protein tyrosine kinase genes (PDGFRA-KIT-KDR) in chromosome segment 4q12. Genomics 22:431–436CrossRefGoogle Scholar
  55. 55.
    Weissmueller S, Manchado E, Saborowski M, Morris JP, Wagenblast E, Davis CA, Moon S-H, Pfister NT, Tschaharganeh DF, Kitzing T (2014) Mutant p53 drives pancreatic cancer metastasis through cell-autonomous PDGF receptor β signaling. Cell 157:382–394CrossRefGoogle Scholar
  56. 56.
    Wang Y, Qiu H, Hu W, Li S, Yu J (2014) Over-expression of platelet-derived growth factor-D promotes tumor growth and invasion in endometrial cancer. Int J Mol Sci 15:4780–4794CrossRefGoogle Scholar
  57. 57.
    Wang Z, Kong D, Banerjee S, Li Y, Adsay NV, Abbruzzese J, Sarkar FH (2007) Down-regulation of platelet-derived growth factor-D inhibits cell growth and angiogenesis through inactivation of Notch-1 and nuclear factor-κB signaling. Cancer Res 67:11377–11385CrossRefGoogle Scholar
  58. 58.
    Chen H-M, Tsai C-H, Hung W-C (2015) Foretinib inhibits angiogenesis, lymphangiogenesis and tumor growth of pancreatic cancer in vivo by decreasing VEGFR-2/3 and TIE-2 signaling. Oncotarget 6:14940PubMedPubMedCentralGoogle Scholar
  59. 59.
    Yokoi K, Sasaki T, Bucana CD, Fan D, Baker CH, Kitadai Y, Kuwai T, Abbruzzese JL, Fidler IJ (2005) Simultaneous inhibition of EGFR, VEGFR and PDGFR signaling combined with gemcitabine produces therapy of human pancreatic carcinoma and prolongs survival in an orthotopic nude mouse model. Cancer Res 65:10371CrossRefGoogle Scholar
  60. 60.
    El-Rayes B, Zalupski M, Shields A, Vaishampayan U, Heilbrun L, Jain V, Adsay V, Day J, Philip P (2003) Phase II study of gemcitabine, cisplatin, and infusional fluorouracil in advanced pancreatic cancer. J Clin Oncol 21:2920–2925CrossRefGoogle Scholar
  61. 61.
    Kindler HL, Friberg G, Singh DA, Locker G, Nattam S, Kozloff M, Taber DA, Karrison T, Dachman A, Stadler WM (2005) Phase II trial of bevacizumab plus gemcitabine in patients with advanced pancreatic cancer. J Clin Oncol 23:8033–8040CrossRefGoogle Scholar
  62. 62.
    Kindler H, Friberg G, Stadler W, Singh D, Locker G, Nattam S, Kozloff M, Kasza K, Vokes E (2004) Bevacizumab (B) plus gemcitabine (G) in patient (pts) with advanced pancreatic cancer (PC): updated results of a multi-center phase II trial. J Clin Oncol 22:4009–4009CrossRefGoogle Scholar
  63. 63.
    Javle M, Yu J, Garrett C, Pande A, Kuvshinoff B, Litwin A, Phelan J III, Gibbs J, Iyer R (2009) Bevacizumab combined with gemcitabine and capecitabine for advanced pancreatic cancer: a phase II study. Br J Cancer 100:1842CrossRefGoogle Scholar
  64. 64.
    Bao B, Ali S, Ahmad A, Azmi AS, Li Y, Banerjee S, Kong D, Sethi S, Aboukameel A, Padhye SB (2012) Hypoxia-induced aggressiveness of pancreatic cancer cells is due to increased expression of VEGF, IL-6 and miR-21, which can be attenuated by CDF treatment. PLoS One 7:e50165CrossRefGoogle Scholar
  65. 65.
    Bimonte S, Barbieri A, Leongito M, Piccirillo M, Giudice A, Pivonello C, De Angelis C, Granata V, Palaia R, Izzo F (2016) Curcumin anticancer studies in pancreatic cancer. Nutrients 8:433CrossRefGoogle Scholar
  66. 66.
    Shankar S, Nall D, Tang S-N, Meeker D, Passarini J, Sharma J, Srivastava RK (2011) Resveratrol inhibits pancreatic cancer stem cell characteristics in human and KrasG12D transgenic mice by inhibiting pluripotency maintaining factors and epithelial-mesenchymal transition. PLoS One 6:e16530CrossRefGoogle Scholar
  67. 67.
    Widakowich C, de Castro G, De Azambuja E, Dinh P, Awada A (2007) Side effects of approved molecular targeted therapies in solid cancers. Oncologist 12:1443–1455CrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

  • Gowru Srivani
    • 1
  • Shipra Reddy Bethi
    • 2
  • Sheik Aliya
    • 3
  • Afroz Alam
    • 1
  • Ganji Purnachandra Nagaraju
    • 4
    Email author
  1. 1.Department of Bioscience and BiotechnologyBanasthali UniversityBanasthaliIndia
  2. 2.Department of Hematology and Medical Oncology, Winship Cancer InstituteEmory UniversityAtlantaUSA
  3. 3.Department of BiotechnologyJawaharlal Nehru Technical UniversityHyderabadIndia
  4. 4.Department of Hematology and Medical Oncology, School of Medicine, Winship Cancer InstituteEmory UniversityAtlantaUSA

Personalised recommendations