Skip to main content

Stromal PDGF Receptors as Prognostic and Predictive Biomarkers

  • Chapter
  • First Online:
Book cover Biomarkers of the Tumor Microenvironment
  • 1192 Accesses

Abstract

The PDGF family of growth factors exerts important regulatory functions on mesenchymal cells such as fibroblasts, vascular smooth muscle cells, and pericytes. Through activation of the tyrosine kinase PDGF alpha- and beta-receptors, these growth factors stimulate proliferation and migration of target cells and regulate their contractile capacity. PDGF receptors play major roles during development in settings of paracrine interactions between mesenchymal cells and epithelial or endothelial cells.

The focus of this review is a discussion of experimental and correlative studies which have explored the biological mechanisms and clinical significance of PDGF receptors in mesenchymal cells of the tumor microenvironment. Collectively these studies identify the PDGF system as critical regulators of tumor growth, metastasis, and drug efficacy.

Continued efforts in this field have the potential to advance stromal PDGF receptors to a state of clinically implemented biomarkers and therapeutic targets in selected patient populations.

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

Access this chapter

Institutional subscriptions

References

  1. Doolittle RF, Hunkapiller MW, Hood LE, Devare SG, Robbins KC, Aaronson SA, et al. Simian sarcoma virus onc gene, v-sis, is derived from the gene (or genes) encoding a platelet-derived growth factor. Science. 1983;221(4607):275–7.

    Article  CAS  PubMed  Google Scholar 

  2. Ehnman M, Ostman A. Therapeutic targeting of platelet-derived growth factor receptors in solid tumors. Expert Opin Investig Drugs. 2013;23(2):211–26.

    Article  PubMed  Google Scholar 

  3. Heldin CH. Targeting the PDGF signaling pathway in tumor treatment. Cell Commun Sign. 2013;11:97.

    Article  Google Scholar 

  4. Heldin CH, Ostman A, Ronnstrand L. Signal transduction via platelet-derived growth factor receptors. Biochim Biophys Acta. 1998;1378(1):F79–113.

    CAS  PubMed  Google Scholar 

  5. Andrae J, Gallini R, Betsholtz C. Role of platelet-derived growth factors in physiology and medicine. Genes Dev. 2008;22(10):1276–312.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Hoch RV, Soriano P. Roles of PDGF in animal development. Development. 2003;130(20):4769–84.

    Article  CAS  PubMed  Google Scholar 

  7. Betsholtz C, Johnsson A, Heldin CH, Westermark B, Lind P, Urdea MS, et al. cDNA sequence and chromosomal localization of human platelet-derived growth factor A-chain and its expression in tumour cell lines. Nature. 1986;320(6064):695–9.

    Article  CAS  PubMed  Google Scholar 

  8. Fredriksson L, Li H, Eriksson U. The PDGF family: four gene products form five dimeric isoforms. Cytokine Growth Factor Rev. 2004;15(4):197–204.

    Article  CAS  PubMed  Google Scholar 

  9. Ostman A, Andersson M, Backstrom G, Heldin CH. Assignment of intrachain disulfide bonds in platelet-derived growth factor B-chain. J Biol Chem. 1993;268(18):13372–7.

    CAS  PubMed  Google Scholar 

  10. Betsholtz C, Rorsman F, Westermark B, Ostman A, Heldin CH. Analogous alternative splicing. Nature. 1990;344(6264):299.

    Article  CAS  PubMed  Google Scholar 

  11. Ostman A, Andersson M, Betsholtz C, Westermark B, Heldin CH. Identification of a cell retention signal in the B-chain of platelet-derived growth factor and in the long splice version of the A-chain. Cell Regul. 1991;2(7):503–12.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Klinghoffer RA, Mueting-Nelsen PF, Faerman A, Shani M, Soriano P. The two PDGF receptors maintain conserved signaling in vivo despite divergent embryological functions. Mol Cell. 2001;7(2):343–54.

    Article  CAS  PubMed  Google Scholar 

  13. Bostrom H, Willetts K, Pekny M, Leveen P, Lindahl P, Hedstrand H, et al. PDGF-A signaling is a critical event in lung alveolar myofibroblast development and alveogenesis. Cell. 1996;85(6):863–73.

    Article  CAS  PubMed  Google Scholar 

  14. Li J, Hoyle GW. Overexpression of PDGF-A in the lung epithelium of transgenic mice produces a lethal phenotype associated with hyperplasia of mesenchymal cells. Dev Biol. 2001;239(2):338–49.

    Article  CAS  PubMed  Google Scholar 

  15. Karlsson L, Lindahl P, Heath JK, Betsholtz C. Abnormal gastrointestinal development in PDGF-A and PDGFR-(alpha) deficient mice implicates a novel mesenchymal structure with putative instructive properties in villus morphogenesis. Development. 2000;127(16):3457–66.

    CAS  PubMed  Google Scholar 

  16. Iwayama T, Steele C, Yao L, Dozmorov MG, Karamichos D, Wren JD, et al. PDGFRalpha signaling drives adipose tissue fibrosis by targeting progenitor cell plasticity. Genes Dev. 2015;29(11):1106–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Hellstrom M, Gerhardt H, Kalen M, Li X, Eriksson U, Wolburg H, et al. Lack of pericytes leads to endothelial hyperplasia and abnormal vascular morphogenesis. J Cell Biol. 2001;153(3):543–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Lindahl P, Johansson BR, Leveen P, Betsholtz C. Pericyte loss and microaneurysm formation in PDGF-B-deficient mice. Science. 1997;277(5323):242–5.

    Article  CAS  PubMed  Google Scholar 

  19. Soriano P. Abnormal kidney development and hematological disorders in PDGF beta-receptor mutant mice. Genes Dev. 1994;8(16):1888–96.

    Article  CAS  PubMed  Google Scholar 

  20. Betsholtz C, Keller A. PDGF, pericytes and the pathogenesis of idiopathic basal ganglia calcification (IBGC). Brain Pathol. 2014;24(4):387–95.

    Article  CAS  PubMed  Google Scholar 

  21. Robson MC, Phillips LG, Thomason A, Robson LE, Pierce GF. Platelet-derived growth factor BB for the treatment of chronic pressure ulcers. Lancet. 1992;339(8784):23–5.

    Article  CAS  PubMed  Google Scholar 

  22. Reed RK, Rubin K. Transcapillary exchange: role and importance of the interstitial fluid pressure and the extracellular matrix. Cardiovasc Res. 2010;87(2):211–7.

    Article  CAS  PubMed  Google Scholar 

  23. Forsberg K, Valyi-Nagy I, Heldin CH, Herlyn M, Westermark B. Platelet-derived growth factor (PDGF) in oncogenesis: development of a vascular connective tissue stroma in xenotransplanted human melanoma producing PDGF-BB. Proc Natl Acad Sci U S A. 1993;90(2):393–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Skobe M, Fusenig NE. Tumorigenic conversion of immortal human keratinocytes through stromal cell activation. Proc Natl Acad Sci U S A. 1998;95(3):1050–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Shao ZM, Nguyen M, Barsky SH. Human breast carcinoma desmoplasia is PDGF initiated. Oncogene. 2000;19(38):4337–45.

    Article  CAS  PubMed  Google Scholar 

  26. Tejada ML, Yu L, Dong J, Jung K, Meng G, Peale FV, et al. Tumor-driven paracrine platelet-derived growth factor receptor alpha signaling is a key determinant of stromal cell recruitment in a model of human lung carcinoma. Clin Cancer Res. 2006;12(9):2676–88.

    Article  CAS  PubMed  Google Scholar 

  27. Campbell JS, Hughes SD, Gilbertson DG, Palmer TE, Holdren MS, Haran AC, et al. Platelet-derived growth factor C induces liver fibrosis, steatosis, and hepatocellular carcinoma. Proc Natl Acad Sci U S A. 2005;102(9):3389–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Anderberg C, Li H, Fredriksson L, Andrae J, Betsholtz C, Li X, et al. Paracrine signaling by platelet-derived growth factor-CC promotes tumor growth by recruitment of cancer-associated fibroblasts. Cancer Res. 2009;69(1):369–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Pietras K, Pahler J, Bergers G, Hanahan D. Functions of paracrine PDGF signaling in the proangiogenic tumor stroma revealed by pharmacological targeting. PLoS Med. 2008;5(1):e19.

    Article  PubMed  PubMed Central  Google Scholar 

  30. 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. International journal of cancer Journal international du cancer. 2013;132(4):813–23.

    Article  CAS  PubMed  Google Scholar 

  31. Pena C, Cespedes MV, Lindh MB, Kiflemariam S, Mezheyeuski A, Edqvist PH, et al. STC1 expression by cancer-associated fibroblasts drives metastasis of colorectal cancer. Cancer Res. 2013;73(4):1287–97.

    Article  CAS  PubMed  Google Scholar 

  32. Baranowska-Kortylewicz J, Abe M, Pietras K, Kortylewicz ZP, Kurizaki T, Nearman J, et al. Effect of platelet-derived growth factor receptor-beta inhibition with STI571 on radioimmunotherapy. Cancer Res. 2005;65(17):7824–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Pietras K, Stumm M, Hubert M, Buchdunger E, Rubin K, Heldin CH, et al. STI571 enhances the therapeutic index of epothilone B by a tumor-selective increase of drug uptake. Clin Cancer Res. 2003;9(10 Pt 1):3779–87.

    CAS  PubMed  Google Scholar 

  34. Pietras K, Rubin K, Sjoblom T, Buchdunger E, Sjoquist M, Heldin CH, et al. Inhibition of PDGF receptor signaling in tumor stroma enhances antitumor effect of chemotherapy. Cancer Res. 2002;62(19):5476–84.

    CAS  PubMed  Google Scholar 

  35. Pietras K, Ostman A, Sjoquist M, Buchdunger E, Reed RK, Heldin CH, et al. Inhibition of platelet-derived growth factor receptors reduces interstitial hypertension and increases transcapillary transport in tumors. Cancer Res. 2001;61(7):2929–34.

    CAS  PubMed  Google Scholar 

  36. Abramsson A, Berlin O, Papayan H, Paulin D, Shani M, Betsholtz C. Analysis of mural cell recruitment to tumor vessels. Circulation. 2002;105(1):112–7.

    Article  CAS  PubMed  Google Scholar 

  37. Furuhashi M, Sjoblom T, Abramsson A, Ellingsen J, Micke P, Li H, et al. Platelet-derived growth factor production by B16 melanoma cells leads to increased pericyte abundance in tumors and an associated increase in tumor growth rate. Cancer Res. 2004;64(8):2725–33.

    Article  CAS  PubMed  Google Scholar 

  38. Pietras K, Hanahan D. A multitargeted, metronomic, and maximum-tolerated dose “chemo-switch” regimen is antiangiogenic, producing objective responses and survival benefit in a mouse model of cancer. J Clin Oncol. 2005;23(5):939–52.

    Article  CAS  PubMed  Google Scholar 

  39. Hosaka K, Yang Y, Seki T, Nakamura M, Andersson P, Rouhi P, et al. Tumour PDGF-BB expression levels determine dual effects of anti-PDGF drugs on vascular remodelling and metastasis. Nat Commun. 2013;4:2129.

    Article  PubMed  Google Scholar 

  40. McCarty MF, Somcio RJ, Stoeltzing O, Wey J, Fan F, Liu W, et al. Overexpression of PDGF-BB decreases colorectal and pancreatic cancer growth by increasing tumor pericyte content. J Clin Invest. 2007;117(8):2114–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Cooke VG, LeBleu VS, Keskin D, Khan Z, O’Connell JT, Teng Y, et al. Pericyte depletion results in hypoxia-associated epithelial-to-mesenchymal transition and metastasis mediated by met signaling pathway. Cancer Cell. 2012;21(1):66–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Keskin D, Kim J, Cooke VG, CC W, Sugimoto H, Gu C, et al. Targeting vascular pericytes in hypoxic tumors increases lung metastasis via angiopoietin-2. Cell Rep. 2015;10(7):1066–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Hong J, Tobin NP, Rundqvist H, Li T, Lavergne M, Garcia-Ibanez Y, et al. Role of tumor pericytes in the recruitment of myeloid-derived suppressor cells. J Natl Cancer Inst. 2015;107(10) doi:10.1093/jnci/djv209.

  44. Nisancioglu MH, Betsholtz C, Genove G. The absence of pericytes does not increase the sensitivity of tumor vasculature to vascular endothelial growth factor-a blockade. Cancer Res. 2010;70(12):5109–15.

    Article  CAS  PubMed  Google Scholar 

  45. Corvigno S, Wisman GB, Mezheyeuski A, van der Zee AG, Nijman HW, Avall-Lundqvist E, et al. Markers of fibroblast-rich tumor stroma and perivascular cells in serous ovarian cancer: inter- and intra-patient heterogeneity and impact on survival. Oncotarget. 2016;7(14):18573–84.

    Article  PubMed  PubMed Central  Google Scholar 

  46. 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-beta phosphorylation, and microvessel density in gastric cancer. BMC Cancer. 2010;10:659.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Jarvius M, Paulsson J, Weibrecht I, Leuchowius KJ, Andersson AC, Wahlby C, et al. In situ detection of phosphorylated platelet-derived growth factor receptor beta using a generalized proximity ligation method. Mol Cell Proteomics. 2007;6(9):1500–9.

    Article  CAS  PubMed  Google Scholar 

  48. Koos B, Paulsson J, Jarvius M, Sanchez BC, Wrede B, Mertsch S, et al. Platelet-derived growth factor receptor expression and activation in choroid plexus tumors. Am J Pathol. 2009;175(4):1631–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Paulsson J, Lindh MB, Jarvius M, Puputti M, Nister M, Nupponen NN, et al. Prognostic but not predictive role of platelet-derived growth factor receptors in patients with recurrent glioblastoma. International journal of cancer Journal international du cancer. 2011;128(8):1981–8.

    Article  CAS  PubMed  Google Scholar 

  50. Frings O, Augsten M, Tobin NP, Carlson J, Paulsson J, Pena C, et al. Prognostic significance in breast cancer of a gene signature capturing stromal PDGF signaling. Am J Pathol. 2013;182(6):2037–47.

    Article  CAS  PubMed  Google Scholar 

  51. Paulsson J, Sjoblom T, Micke P, Ponten F, Landberg G, Heldin CH, et al. Prognostic significance of stromal platelet-derived growth factor beta-receptor expression in human breast cancer. Am J Pathol. 2009;175(1):334–41.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Hagglof C, Hammarsten P, Josefsson A, Stattin P, Paulsson J, Bergh A, et al. Stromal PDGFRbeta expression in prostate tumors and non-malignant prostate tissue predicts prostate cancer survival. PLoS One. 2010;5(5):e10747.

    Article  PubMed  PubMed Central  Google Scholar 

  53. 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 beta is associated with lymphatic metastasis in human gastric carcinoma. Cancer Sci. 2010;101(9):1984–9.

    Article  CAS  PubMed  Google Scholar 

  54. 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 

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

    Article  CAS  PubMed  Google Scholar 

  56. Ehnman M, Missiaglia E, Folestad E, Selfe J, Strell C, Thway K, et al. Distinct effects of ligand-induced PDGFRalpha and PDGFRbeta signaling in the human rhabdomyosarcoma tumor cell and stroma cell compartments. Cancer Res. 2013;73(7):2139–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Frödin M, Mezheyeuski A, Corvigno S, Harmenberg U, Sandström P, Egevad L Johansson M, Östman A. Perivascular PDGFR-β is an independent marker for prognosis in renal cell carcinoma. Br J Cancer. 2017;116(2):195–201.

    Google Scholar 

  58. Paulsson J, Ehnman M, Ostman A. PDGF receptors in tumor biology: prognostic and predictive potential. Future Oncol. 2014;10(9):1695–708.

    Article  CAS  PubMed  Google Scholar 

  59. Crowley MR, Bowtell D, Serra R. TGF-beta, c-Cbl, and PDGFR-alpha the in mammary stroma. Dev Biol. 2005;279(1):58–72.

    Article  CAS  PubMed  Google Scholar 

  60. Mezheyeuski A, Bradic Lindh M, Guren TK, Dragomir A, Pfeiffer P, Kure EH, Ikdahl T, Skovlund E, Corvigno S, Strell C, Pietras K, Ponten F, Mulder J, Qvortrup C, Portyanko A, Tveit KM, Glimelius B, Sorbye H, Östman A. Survival-associated heterogeneity of marker-defined perivascular cells in colorectal cancer. Oncotarget. 2016;7(27):41948–58.

    Google Scholar 

  61. Paulsson J, Rydén L, Strell C, Frings O, Tobin NP, Fornander T, Bergh J, Landberg G, Stål O, Östman A. High expression of stromal PDGFRβ is associated with reduced benefit of tamoxifen in breast cancer. J Pathol Clin Res. 2016;3(1):38–43.

    Google Scholar 

  62. Ryden L, Jonsson PE, Chebil G, Dufmats M, Ferno M, Jirstrom K, et al. Two years of adjuvant tamoxifen in premenopausal patients with breast cancer: a randomised, controlled trial with long-term follow-up. Eur J Cancer. 2005;41(2):256–64.

    Article  CAS  PubMed  Google Scholar 

  63. Rutqvist LE, Johansson H, Stockholm Breast Cancer Study G. Long-term follow-up of the randomized Stockholm trial on adjuvant tamoxifen among postmenopausal patients with early stage breast cancer. Acta Oncol. 2007;46(2):133–45.

    Article  CAS  PubMed  Google Scholar 

  64. Lindborg M, Cortez E, Hoiden-Guthenberg I, Gunneriusson E, von Hage E, Syud F, et al. Engineered high-affinity affibody molecules targeting platelet-derived growth factor receptor beta in vivo. J Mol Biol. 2011;407(2):298–315.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Arne Östman .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Östman, A. (2017). Stromal PDGF Receptors as Prognostic and Predictive Biomarkers. In: Akslen, L., Watnick, R. (eds) Biomarkers of the Tumor Microenvironment. Springer, Cham. https://doi.org/10.1007/978-3-319-39147-2_5

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-39147-2_5

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-39145-8

  • Online ISBN: 978-3-319-39147-2

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics