Skip to main content

Advertisement

Log in

Targeting platelet-derived growth factor (PDGF) signaling in gastrointestinal cancers: preclinical and clinical considerations

  • Review
  • Published:
Tumor Biology

Abstract

The prognosis of advanced gastrointestinal malignancies has been generally dreadful prompting robust search for better, more personalized, and more tailored treatments. In recent years, important signaling pathways leading to tumor progression and metastasis have been discovered with the subsequent development of targeted therapies to target these pathways. These include epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), mammalian target of rapamycin (mTOR), and mesenchymal epithelial transition (MET). In this review, we will revise the different biological and clinical aspects related to the use of PDGF pathway-targeted therapies in gastrointestinal cancers with particular focus on the future prospective in that regard.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Abdel-Rahman O. Targeting vascular endothelial growth factor (VEGF) pathway in gastric cancer: preclinical and clinical aspects. Crit Rev Oncol/Hematol. 2014. doi:10.1016/j.critrevonc.2014.05.012.

    Google Scholar 

  2. Venook AP, Papandreou C, Furuse J, de Guevara LL. The incidence and epidemiology of hepatocellular carcinoma: a global and regional perspective. Oncologist. 2010;15(Supplement 4):5–13.

    Article  PubMed  Google Scholar 

  3. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90.

    Article  PubMed  Google Scholar 

  4. Kordes S, Cats A, Meijer SL, van Laarhoven HW. Targeted therapy for advanced esophagogastric adenocarcinoma. Crit Rev Oncol Hematol. 2014;90:68–76.

    Article  CAS  PubMed  Google Scholar 

  5. Kasper S, Schuler M. Targeted therapies in gastroesophageal cancer. Eur J Cancer. 2014;50(7):1247–58. doi:10.1016/j.ejca.2014.01.009.

    Article  CAS  PubMed  Google Scholar 

  6. Alvarez RH, Kantarjian HM, & Cortes, JE. Biology of platelet-derived growth factor and its involvement in disease. In Mayo Clinic Proceedings. 2006; 81(9):1241–57. Elsevier.

  7. Fantl WJ, Johnson DE, Williams LT. Signalling by receptor tyrosine kinases. Annu Rev Biochem. 1993;62:453–81.

    Article  CAS  PubMed  Google Scholar 

  8. Terracio L, Ronnstrand L, Tingstrom A, et al. Induction of platelet derived growth factor receptor expression in smooth muscle cells and fibroblasts upon tissue culturing. J Cell Biol. 1988;107:1947–57.

    Article  CAS  PubMed  Google Scholar 

  9. Type III RTKs: PDGFR, CSFR, Kit, FLT3 receptor family. IUPHAR database (IUPHAR-DB). 2014. http://www.iuphar-db.org/DATABASE/FamilyMenuForward?familyId=322. Accessed on 27 Oct 2014.

  10. Huang F, Wang M, Yang T, Cai J, Zhang Q, Sun Z, et al. Gastric cancer-derived MSC-secreted PDGF-DD promotes gastric cancer progression. J Cancer Res Clin Oncol. 2014; 1–14

  11. Kodama M, Kitadai Y, Sumida T, Ohnishi M, Ohara E, Tanaka M, et al. Expression of platelet‐derived growth factor (PDGF)‐B and PDGF‐receptor β is associated with lymphatic metastasis in human gastric carcinoma. Cancer Sci. 2010;101(9):1984–9.

    Article  CAS  PubMed  Google Scholar 

  12. Drescher D, Moehler M, Gockel I, Frerichs K, Muller A, Dunschede F, et al. Coexpression of receptor-tyrosine-kinases in gastric adenocarcinoma-a rationale for a molecular targeting strategy? World J Gastroenterol. 2007;13(26):3605.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Gockel I, Moehler M, Frerichs K, Drescher D, Trinh TT, Duenschede F, et al. Co-expression of receptor tyrosine kinases in esophageal adenocarcinoma and squamous cell cancer. Oncol Rep. 2008;20(4):845.

    CAS  PubMed  Google Scholar 

  14. Liu YC, Chen SC, Chang C, Leu CM, Hu CP. Platelet-derived growth factor is an autocrine stimulator for the growth and survival of human esophageal carcinoma cell lines. Exp Cell Res. 1996;228(2):206–11.

    Article  CAS  PubMed  Google Scholar 

  15. Zhang JB, Sun HC, Jia WD, Zhuang PY, Qian YB, Zhu XD, et al. Up-regulation of platelet-derived growth factor-A is responsible for the failure of re-initiated interferon alpha treatment in hepatocellular carcinoma. BMC Cancer. 2012;12(1):439.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Maass T, Thieringer FR, Mann A, Longerich T, Schirmacher P, Strand D, et al. Liver specific overexpression of platelet‐derived growth factor‐B accelerates liver cancer development in chemically induced liver carcinogenesis. Int J Cancer. 2011;128(6):1259–68.

    Article  CAS  PubMed  Google Scholar 

  17. Sillars-Hardebol AH, Carvalho B, de Wit M, Postma C, Delis-van Diemen PM, Mongera S, et al. Identification of key genes for carcinogenic pathways associated with colorectal adenoma-to-carcinoma progression. Tumor Biol. 2010;31(2):89–96.

    Article  CAS  Google Scholar 

  18. Sihto H, Franssila K, Tanner M, Vasama-Nolvi C, Sarlomo-Rikala M, Nupponen NN, et al. Platelet-derived growth factor receptor family mutations in gastrointestinal stromal tumours. Scand J Gastroenterol. 2006;41(7):805–11.

    Article  PubMed  Google Scholar 

  19. Haller F, Happel N, Schulten HJ, von Heydebreck A, Schwager S, Armbrust T, et al. Site-dependent differential KIT and PDGFRA expression in gastric and intestinal gastrointestinal stromal tumors. Mod Pathol. 2007;20(10):1103–11.

    Article  CAS  PubMed  Google Scholar 

  20. Du CY, Shi YQ, Zhou YE, Fu H, Zhao G. The analysis of status and clinical implication of KIT and PDGFRA mutations in gastrointestinal stromal tumor (GIST). J Surg Oncol. 2008;98(3):175–8.

    Article  PubMed  Google Scholar 

  21. Miettinen M, Sobin LH, Lasota J. Gastrointestinal stromal tumors of the stomach: a clinicopathologic, immunohistochemical, and molecular genetic study of 1765 cases with long-term follow-up. Am J Surg Pathol. 2005;29(1):52–68.

    Article  PubMed  Google Scholar 

  22. Guo Y, Yin J, Zha L, Wang Z. Clinicopathological significance of platelet-derived growth factor B, platelet-derived growth factor receptor-β, and E-cadherin expression in gastric carcinoma. Contemp Oncol (Pozn). 2013;17(2):150–5.

    CAS  Google Scholar 

  23. Kurokawa Y, Matsuura N, Kawabata R, Nishikawa K, Ebisui C, Yokoyama Y, et al. Prognostic impact of major receptor tyrosine kinase expression in gastric cancer. Ann of Surg Oncol. 2014; 1–7.

  24. Suzuki S, Dobashi Y, Hatakeyama Y, Tajiri R, Fujimura T, Heldin CH, et al. Clinicopathological significance of platelet-derived growth factor (PDGF)-B and vascular endothelial growth factor-A expression, PDGF receptor-β phosphorylation, and microvessel density in gastric cancer. BMC Cancer. 2010;10(1):659.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Yuzawa S, Kano MR, Einama T, Nishihara H. PDGFRβ expression in tumor stroma of pancreatic adenocarcinoma as a reliable prognostic marker. Med Oncol. 2012;29(4):2824–30.

    Article  CAS  PubMed  Google Scholar 

  26. Chu JS, Ge FJ, Zhang B, Wang Y, Silvestris N, Liu LJ, et al. Expression and prognostic value of VEGFR-2, PDGFR-β, and c-Met in advanced hepatocellular carcinoma. J Exp Clin Cancer Res. 2013;32(16):234–56.

    Google Scholar 

  27. Chen L, Shi Y, Jiang CY, Wei LX, Lv YL, Wang YL, et al. Coexpression of PDGFR-alpha, PDGFR-beta and VEGF as a prognostic factor in patients with hepatocellular carcinoma. Int J Biol Markers. 2010;26(2):108–16.

    Article  Google Scholar 

  28. Kitadai Y, Sasaki T, Kuwai T, Nakamura T, Bucana CD, Hamilton SR, et al. Expression of activated platelet‐derived growth factor receptor in stromal cells of human colon carcinomas is associated with metastatic potential. Int J Cancer. 2006;119(11):2567–74.

    Article  CAS  PubMed  Google Scholar 

  29. Søreide K, Sandvik OM, Søreide JA, Gudlaugsson E, Mangseth K, Haugland HK. Tyrosine-kinase mutations in c-KIT and PDGFR-alpha genes of imatinib naïve adult patients with gastrointestinal stromal tumours (GISTs) of the stomach and small intestine: relation to tumour-biological risk-profile and long-term outcome. Clin Transl Oncol. 2012;14(8):619–29.

    Article  PubMed  Google Scholar 

  30. Cassier PA, Fumagalli E, Rutkowski P, Schöffski P, Van Glabbeke M, Debiec-Rychter M, et al. Outcome of patients with platelet-derived growth factor receptor alpha-mutated gastrointestinal stromal tumors in the tyrosine kinase inhibitor era. Clin Cancer Res. 2012;18(16):4458–64.

    Article  CAS  PubMed  Google Scholar 

  31. Emile JF, Brahimi S, Coindre JM, Bringuier PP, Monges G, Samb P, et al. Frequencies of KIT and PDGFRA mutations in the MolecGIST prospective population-based study differ from those of advanced GISTs. Med Oncol. 2012;29(3):1765–72.

    Article  CAS  PubMed  Google Scholar 

  32. Heldin CH. Targeting the PDGF signaling pathway in tumor treatment. Cell Commun Signal. 2013;11(1):97.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Abdel-Rahman O, Fouad M. Risk of cardiovascular toxicities in patients with solid tumors treated with sunitinib, axitinib, cediranib or regorafenib: an updated systematic review and comparative meta-analysis. Crit Rev Oncol Hematol. 2014. doi:10.1016/j.critrevonc.2014.06.003.

  34. Abdel-Rahman O, Fouad M. Risk of thyroid dysfunction in patients with solid tumors treated with VEGF receptor tyrosine kinase inhibitors: a critical literature review and meta analysis. Expert Rev Anticancer Ther. 2014;14(9):1063–73. doi:10.1586/14737140.2014.929501.

    Article  CAS  PubMed  Google Scholar 

  35. Peng, Y., Guo, J. J., Liu, Y. M., & Wu, X. L. MicroRNA-34a inhibits the growth, invasion and metastasis of gastric cancer by targeting PDGFR and MET expression. Biosci Rep. 2014;34(3). doi:10.1042/BSR20140020.

  36. Rajkumar VS, Boxer G, Robson M, Muddle J, Papastavrou Y, Pedley RB. A comparative study of PDGFR inhibition with imatinib on radiolabeled antibody targeting and clearance in two pathologically distinct models of colon adenocarcinoma. Tumor Biol. 2012;33(6):2019–29.

    Article  CAS  Google Scholar 

  37. Yamamoto M, Kikuchi H, Ohta M, Kawabata T, Hiramatsu Y, Kondo K, et al. TSU68 prevents liver metastasis of colon cancer xenografts by modulating the premetastatic niche. Cancer Res. 2008;68(23):9754–62.

    Article  CAS  PubMed  Google Scholar 

  38. Kitadai Y, Sasaki T, Kuwai T, Nakamura T, Bucana CD, Fidler IJ. Targeting the expression of platelet-derived growth factor receptor by reactive stroma inhibits growth and metastasis of human colon carcinoma. Am J Pathol. 2006;169(6):2054–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Shinagawa K, Kitadai Y, Tanaka M, Sumida T, Onoyama M, Ohnishi M, et al. Stroma‐directed imatinib therapy impairs the tumor‐promoting effect of bone marrow‐derived mesenchymal stem cells in an orthotopic transplantation model of colon cancer. Int J Cancer. 2013;132(4):813–23.

    Article  CAS  PubMed  Google Scholar 

  40. Yoon YK, Im SA, Min A, Kim HP, Hur HS, Lee KH, et al. Sunitinib synergizes the antitumor effect of cisplatin via modulation of ERCC1 expression in models of gastric cancer. Cancer Lett. 2012;321(2):128–36.

    Article  CAS  PubMed  Google Scholar 

  41. Taeger J, Moser C, Hellerbrand C, Mycielska ME, Glockzin G, Schlitt HJ, et al. Targeting FGFR/PDGFR/VEGFR impairs tumor growth, angiogenesis, and metastasis by effects on tumor cells, endothelial cells, and pericytes in pancreatic cancer. Mol Cancer Ther. 2011;10(11):2157–67.

    Article  CAS  PubMed  Google Scholar 

  42. Huynh H, Chow PKH, Tai WM, Choo SP, Chung AYF, Ong HS, et al. Dovitinib demonstrates antitumor and antimetastatic activities in xenograft models of hepatocellular carcinoma. J Hepatol. 2012;56(3):595–601.

    Article  CAS  PubMed  Google Scholar 

  43. Ohta M, Kawabata T, Yamamoto M, Tanaka T, Kikuchi H, Hiramatsu Y, et al. TSU68, an antiangiogenic receptor tyrosine kinase inhibitor, induces tumor vascular normalization in a human cancer xenograft nude mouse model. Surg Today. 2009;39(12):1046–53.

    Article  CAS  PubMed  Google Scholar 

  44. Garner, AP, Gozgit JM, Anjum R, Vodala S, Schrock A, Zhou T, et al. Ponatinib inhibits polyclonal drug-resistant KIT oncoproteins and shows therapeutic potential in heavily pretreated gastrointestinal stromal tumor (GIST) patients. Clin Cancer Res. 2014.doi:10.1158/1078-0432.

  45. Sako H, Fukuda K, Saikawa Y, Nakamura R, Takahashi T, Wada N, et al. Antitumor effect of the tyrosine kinase inhibitor nilotinib on gastrointestinal stromal tumor (GIST) and imatinib-resistant GIST cells. PLoS One. 2014;9(9):e107613.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Mayr M, Becker K, Schulte N, Belle S, Hofheinz R, Krause A, et al. Phase I study of imatinib, cisplatin and 5-fluoruracil or capecitabine in advanced esophageal and gastric adenocarcinoma. BMC Cancer. 2012;12(1):587.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Kang YK, Ryu MH, Yoo C, Ryoo BY, Kim HJ, Lee JJ, et al. Resumption of imatinib to control metastatic or unresectable gastrointestinal stromal tumours after failure of imatinib and sunitinib (RIGHT): a randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2013;14(12):1175–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Moehler M, Mueller A, Hartmann JT, et al. An open-label, multicentre biomarker-oriented AIO phase II trial of sunitinib for patients with chemo-refractory advanced gastric cancer. Eur J Cancer. 2011;10:1511–20.

    Article  Google Scholar 

  49. Yi JH, Lee J, Lee J, et al. Randomised phase II trial of docetaxel and sunitinib in patients with metastatic gastric cancer who were previously treated with fluoropyrimidine and platinum. Br J Cancer. 2012;106(9):1469–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Dragovich T, Laheru D, Dayyani F, Bolejack V, Smith L, Seng J, et al. Phase II trial of vatalanib in patients with advanced or metastatic pancreatic adenocarcinoma after first-line gemcitabine therapy (PCRT O4-001). Cancer Chemother Pharmacol. 2014;74(2):379–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Bruix J, Tak WY, Gasbarrini A, Santoro A, Colombo M, Lim HY, et al. Regorafenib as second-line therapy for intermediate or advanced hepatocellular carcinoma: multicentre, open-label, phase II safety study. Eur J Cancer. 2013;49(16):3412–9.

    Article  CAS  PubMed  Google Scholar 

  52. Starling N, Hawkes EA, Chau I, Watkins D, Thomas J, Webb J, et al. A dose escalation study of gemcitabine plus oxaliplatin in combination with imatinib for gemcitabine-refractory advanced pancreatic adenocarcinoma. Ann Oncol. 2012;23(4):942–7. doi:10.1093/annonc/mdr317.

    Article  CAS  PubMed  Google Scholar 

  53. Cainap C, Qin S, Huang WT, Chung IJ, Pan H, Cheng Y, et al. (2013). Phase III trial of linifanib versus sorafenib in patients with advanced hepatocellular carcinoma (HCC). In J Clin Oncol 31(4).

  54. Shin SJ, Jung M, Jeung HC, Kim HR, Rha SY, Roh JK, et al. A phase I pharmacokinetic study of TSU-68 (a multiple tyrosine kinase inhibitor of VEGFR-2, FGF and PDFG) in combination with S-1 and oxaliplatin in metastatic colorectal cancer patients previously treated with chemotherapy. Invest New Drugs. 2012;30(4):1501–10.

    Article  CAS  PubMed  Google Scholar 

  55. Grothey A, Cutsem EV, Sobrero A, Siena S, Falcone A, Ychou M, et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013;381(9863):303–12.

    Article  CAS  PubMed  Google Scholar 

  56. Joensuu H, Eriksson M, Hall KS, Hartmann JT, Pink D, Schütte J, et al. One vs three years of adjuvant imatinib for operable gastrointestinal stromal tumor: a randomized trial. Jama. 2012;307(12):1265–72.

    Article  CAS  PubMed  Google Scholar 

  57. Blay JY, Le Cesne A, Ray-Coquard I, Bui B, Duffaud F, Delbaldo C, et al. Prospective multicentric randomized phase III study of imatinib in patients with advanced gastrointestinal stromal tumors comparing interruption versus continuation of treatment beyond 1 year: the French Sarcoma Group. J Clin Oncol. 2007;25(9):1107–13.

    Article  CAS  PubMed  Google Scholar 

  58. Demetri GD, van Oosterom AT, Garrett CR, Blackstein ME, Shah MH, Verweij J, et al. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet. 2006;368(9544):1329–38.

    Article  CAS  PubMed  Google Scholar 

  59. Ganjoo KN, Villalobos VM, Kamaya A, Fisher GA, Butrynski JE, Morgan JA, et al. A multicenter phase II study of pazopanib in patients with advanced gastrointestinal stromal tumors (GIST) following failure of at least imatinib and sunitinib. Ann Oncol. 2014;25(1):236–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Demetri GD, Reichardt P, Kang YK, Blay JY, Rutkowski P, Gelderblom H, et al. Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013;381(9863):295–302.

    Article  CAS  PubMed  Google Scholar 

  61. Kang YK, Yoo C, Ryoo BY, Lee JJ, Tan E, Park I, et al. Phase II study of dovitinib in patients with metastatic and/or unresectable gastrointestinal stromal tumours after failure of imatinib and sunitinib. Br J Cancer. 2013;109(9):2309–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Conflicts of interest

None.

Funding

This work has not been funded.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Omar Abdel-Rahman.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Abdel-Rahman, O. Targeting platelet-derived growth factor (PDGF) signaling in gastrointestinal cancers: preclinical and clinical considerations. Tumor Biol. 36, 21–31 (2015). https://doi.org/10.1007/s13277-014-2797-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-014-2797-9

Keywords

Navigation