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Tumor-Associated Fibroblasts and their Matrix pp 257–265Cite as

Role of PDGF in Tumor-Stroma Interactions

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Part of the book series: The Tumor Microenvironment ((TTME,volume 4))

Abstract

Growth factors belonging to the platelet-derived growth factor (PDGF) family are major mitogens for fibroblasts and smooth muscle cells. In tumors, PDGF signaling participate both in the recruitment of fibroblasts and in extracellular matrix deposition and remodeling. Activation of PDGF receptors contributes to the increased interstitial fluid pressure observed in tumors, presumably through promotion of fibroblast contraction. Inhibition of PDGF signaling has been shown to decrease the interstitial fluid pressure in tumors, leading to enhanced drug uptake and improved treatment effect. In addition, PDGF promotes angiogenesis through the recruitment of pericytes to capillaries, which improves tumor vessel function and also protects endothelial cells from anti-angiogenic therapy targeting the vascular endothelial growth factor (VEGF) signaling pathway. Thus, inhibition of the PDGF receptor kinase has been shown to improve the anti-angiogenic effect of VEGF receptor kinase inhibitors in tumor models.

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Abbreviations

EGF:

Epidermal growth factor

IFP:

Interstitial fluid pressure

LMW-PTP:

Low molecular weight protein tyrosine phosphatase

PI-3 kinase:

Phosphatidylinositol-3 kinase

PLC:

Phospholipase C

PDGF:

Platelet derived growth factor

PKC:

Protein kinase C

PTP:

Protein tyrosine phosphatase

TC-PTP:

T-cell protein tyrosine phosphatase

TGFβ:

Transforming growth factor β

VEGF:

Vascular endothelial growth factor

References

  • Andrae J, Gallini R, Betsholtz C (2008) Role of platelet-derived growth factors in physiology and medicine. Genes Dev 22:1276–1312

    Article  PubMed  CAS  Google Scholar 

  • Aukland K, Reed RK (1993) Interstitial-lymphatic mechanisms in the control of extracellular fluid volume. Physiol Rev 73:1–78

    PubMed  CAS  Google Scholar 

  • Baluk P, Hashizume H, McDonald DM (2005) Cellular abnormalities of blood vessels as targets in cancer. Curr Opin Genet Dev 15:102–111

    Article  PubMed  CAS  Google Scholar 

  • Bergers G, Song S (2005) The role of pericytes in blood-vessel formation and maintenance. Neuro-oncol 7:452–464

    Article  PubMed  CAS  Google Scholar 

  • Bergers G, Song S, Meyer-Morse N, Bergsland E, Hanahan D (2003) Benefits of targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors. J Clin Invest 111:1287–1295

    PubMed  CAS  Google Scholar 

  • Betsholtz C (2004) Insight into the physiological functions of PDGF through genetic studies in mice. Cytokine Growth Factor Rev 15:215–228

    Article  PubMed  CAS  Google Scholar 

  • Chiara F, Bishayee S, Heldin CH, Demoulin JB (2004) Autoinhibition of the platelet-derived growth factor beta-receptor tyrosine kinase by its C-terminal tail. J Biol Chem 279:19732–19738

    Article  PubMed  CAS  Google Scholar 

  • Chiarugi P, Cirri P, Raugei G, Camici G, Dolfi F, Berti A, Ramponi G (1995) PDGF receptor as a specific in vivo target for low M(r) phosphotyrosine protein phosphatase. FEBS Lett 372:49–53

    Article  PubMed  CAS  Google Scholar 

  • Cools J, DeAngelo DJ, Gotlib J, Stover EH, Legare RD, Cortes J, Kutok J, Clark J, Galinsky I, Griffin JD, Cross NC, Tefferi A, Malone J, Alam R, Schrier SL, Schmid J, Rose M, Vandenberghe P, Verhoef G, Boogaerts M, Wlodarska I, Kantarjian H, Marynen P, Coutre SE, Stone R, Gilliland DG (2003) A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome. N Engl J Med 348:1201–1214

    Article  PubMed  CAS  Google Scholar 

  • Fleming TP, Saxena A, Clark WC, Robertson JT, Oldfield EH, Aaronson SA, Ali IU (1992) Amplification and/or overexpression of platelet-derived growth factor receptors and epidermal growth factor receptor in human glial tumors. Cancer Res 52:4550–4553

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Fukumura D, Jain RK (2007) Tumor microvasculature and microenvironment: targets for anti-angiogenesis and normalization. Microvasc Res 74:72–84

    Article  PubMed  CAS  Google Scholar 

  • Furuhashi M, Sjoblom T, Abramsson A, Ellingsen J, Micke P, Li H, Bergsten-Folestad E, Eriksson U, Heuchel R, Betsholtz C, Heldin CH, Ostman A (2004) 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 64:2725–2733

    Article  PubMed  CAS  Google Scholar 

  • Haj FG, Markova B, Klaman LD, Bohmer FD, Neel BG (2003) Regulation of receptor tyrosine kinase signaling by protein tyrosine phosphatase-1B. J Biol Chem 278:739–744

    Article  PubMed  CAS  Google Scholar 

  • Hasumi Y, Klosowska-Wardega A, Furuhashi M, Ostman A, Heldin CH, Hellberg C (2007) Identification of a subset of pericytes that respond to combination therapy targeting PDGF and VEGF signaling. Int J Cancer 121:2606–2614

    Article  PubMed  CAS  Google Scholar 

  • Heinrich MC, Corless CL, Duensing A, McGreevey L, Chen CJ, Joseph N, Singer S, Griffith DJ, Haley A, Town A, Demetri GD, Fletcher CD, Fletcher JA (2003) PDGFRA activating mutations in gastrointestinal stromal tumors. Science 299:708–710

    Article  PubMed  CAS  Google Scholar 

  • Heldin CH, Westermark B (1999) Mechanism of action and in vivo role of platelet-derived growth factor. Physiol Rev 79:1283–1316

    PubMed  CAS  Google Scholar 

  • Heldin CH, Östman A, Rönnstrand L (1998) Signal transduction via platelet-derived growth factor receptors. Biochim Biophys Acta 1378:F79–F113

    PubMed  CAS  Google Scholar 

  • Heldin CH, Rubin K, Pietras K, Ostman A (2004) High interstitial fluid pressure—an obstacle in cancer therapy. Nat Rev Cancer 4:806–813

    Article  PubMed  CAS  Google Scholar 

  • Hellberg C, Schmees C, Karlsson S, Ahgren A, Heldin CH (2009) Activation of protein kinase C alpha is necessary for sorting the PDGF beta-receptor to Rab4a-dependent recycling. Mol Biol Cell 20:2856–2863

    Article  PubMed  CAS  Google Scholar 

  • Irusta PM, Luo Y, Bakht O, Lai CC, Smith SO, DiMaio D (2002) Definition of an inhibitory juxtamembrane WW-like domain in the platelet-derived growth factor beta receptor. J Biol Chem 277:38627–38634

    Article  PubMed  CAS  Google Scholar 

  • Jain RK (1987a) Transport of molecules across tumor vasculature. Cancer Metastasis Rev 6:559–593

    Article  CAS  Google Scholar 

  • Jain RK (1987b) Transport of molecules in the tumor interstitium: a review. Cancer Res 47:3039–3051

    CAS  Google Scholar 

  • Jain RK (2003) Molecular regulation of vessel maturation. Nat Med 9:685–693

    Article  PubMed  CAS  Google Scholar 

  • Jain RK (2005) Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307:58–62

    Article  PubMed  CAS  Google Scholar 

  • Jones AV, Cross NC (2004) Oncogenic derivatives of platelet-derived growth factor receptors. Cell Mol Life Sci 61:2912–2923

    Article  PubMed  CAS  Google Scholar 

  • Karpanen T, Alitalo K (2008) Molecular biology and pathology of lymphangiogenesis. Annu Rev Pathol 3:367–397

    Article  PubMed  CAS  Google Scholar 

  • Katz M, Amit I, Yarden Y (2007) Regulation of MAPKs by growth factors and receptor tyrosine kinases. Biochim Biophys Acta 1773:1161–1176

    Article  PubMed  CAS  Google Scholar 

  • Kazlauskas A, Feng GS, Pawson T, Valius M (1993) The 64-kDa protein that associates with the platelet-derived growth factor receptor beta subunit via Tyr-1009 is the SH2-containing phosphotyrosine phosphatase Syp. Proc Natl Acad Sci U S A 90:6939–6943

    Article  PubMed  CAS  Google Scholar 

  • Klinghoffer RA, Kazlauskas A (1995) Identification of a putative Syp substrate, the PDGF beta receptor. J Biol Chem 270:22208–22217

    Article  PubMed  CAS  Google Scholar 

  • Kumabe T, Sohma Y, Kayama T, Yoshimoto T, Yamamoto T (1992) Amplification of alpha-platelet-derived growth factor receptor gene lacking an exon coding for a portion of the extracellular region in a primary brain tumor of glial origin. Oncogene 7:627–633

    PubMed  CAS  Google Scholar 

  • Lechleider RJ, Sugimoto S, Bennett AM, Kashishian AS, Cooper JA, Shoelson SE, Walsh CT, Neel BG (1993) Activation of the SH2-containing phosphotyrosine phosphatase SH-PTP2 by its binding site, phosphotyrosine 1009, on the human platelet-derived growth factor receptor β. J Biol Chem 268:21478–21481

    PubMed  CAS  Google Scholar 

  • Liden A, Berg A, Nedrebo T, Reed RK, Rubin K (2006) Platelet-derived growth factor BB-mediated normalization of dermal interstitial fluid pressure after mast cell degranulation depends on beta3 but not beta1 integrins. Circ Res 98:635–641

    Article  PubMed  CAS  Google Scholar 

  • Markova B, Herrlich P, Ronnstrand L, Bohmer FD (2003) Identification of protein tyrosine phosphatases associating with the PDGF receptor. Biochemistry 42:2691–2699

    Article  PubMed  CAS  Google Scholar 

  • Micke P, Ostman A (2004) Tumour-stroma interaction: cancer-associated fibroblasts as novel targets in anti-cancer therapy? Lung Cancer 45 (Suppl 2):S163–S175

    Article  PubMed  Google Scholar 

  • Mooney RA, Freund GG, Way BA, Bordwell KL (1992) Expression of a transmembrane phosphotyrosine phosphatase inhibits cellular response to platelet-derived growth factor and insulin-like growth factor-1. J Biol Chem 267:23443–23446

    PubMed  CAS  Google Scholar 

  • Mosesson Y, Mills GB, Yarden Y (2008) Derailed endocytosis: an emerging feature of cancer. Nat Rev Cancer 8:835–850

    Article  PubMed  CAS  Google Scholar 

  • Ostman A (2004) PDGF receptors-mediators of autocrine tumor growth and regulators of tumor vasculature and stroma. Cytokine Growth Factor Rev 15:275–286

    Article  PubMed  Google Scholar 

  • Östman A, Böhmer FD (2001) Regulation of receptor tyrosine kinase signaling by protein tyrosine phosphatases. Trends Cell Biol 11:258–266

    Article  PubMed  Google Scholar 

  • Östman A, Heldin CH (2001) Involvement of platelet-derived growth factor in disease: development of specific antagonists. Adv Cancer Res 80:1–38

    Article  PubMed  Google Scholar 

  • Ostman A, Heldin CH (2007) PDGF receptors as targets in tumor treatment. Adv Cancer Res 97:247–274

    Article  PubMed  Google Scholar 

  • Persson C, Engström U, Mowbray SL, Östman A (2002) Primary sequence determinants responsible for site-selective dephosphorylation of the PDGF beta-receptor by the receptor-like protein tyrosine phosphatase DEP-1. FEBS Lett 517:27–31

    Article  PubMed  CAS  Google Scholar 

  • Persson C, Savenhed C, Bourdeau A, Tremblay ML, Markova B, Bohmer FD, Haj FG, Neel BG, Elson A, Heldin CH, Ronnstrand L, Ostman A, Hellberg C (2004) Site-selective regulation of platelet-derived growth factor beta receptor tyrosine phosphorylation by T-cell protein tyrosine phosphatase. Mol Cell Biol 24:2190–2201

    Article  PubMed  CAS  Google Scholar 

  • Pietras K, Sjoblom T, Rubin K, Heldin CH, Ostman A (2003) PDGF receptors as cancer drug targets. Cancer Cell 3:439–443

    Article  PubMed  CAS  Google Scholar 

  • Rodt SA, Ahlen K, Berg A, Rubin K, Reed RK (1996) A novel physiological function for platelet-derived growth factor-BB in rat dermis. J Physiol 495:193–200

    PubMed  CAS  Google Scholar 

  • Sorkin A, Goh LK (2009) Endocytosis and intracellular trafficking of ErbBs. Exp Cell Res 315:683–696

    Article  PubMed  CAS  Google Scholar 

  • Sörby M, Östman A (1996) Protein-tyrosine phosphatase-mediated decrease of epidermal growth factor and platelet-derived growth factor receptor tyrosine phosphorylation in high cell density cultures. J Biol Chem 271:10963–10966

    Article  PubMed  Google Scholar 

  • Tallquist M, Kazlauskas A (2004) PDGF signaling in cells and mice. Cytokine Growth Factor Rev 15:205–213

    Article  PubMed  CAS  Google Scholar 

  • Uutela M, Wizrenius M, Paavonen K, Rajantie I, He Y, Karpanen T, Lohela M, Wiig H, Salven P, Pajusola K, Eriksson U, Alitalo K (2009) PDGF-D induces macrophage recruitment, increased interstitial pressure, and blood vessel maturation during angiogenesis. Blood 104:3198–3204

    Article  Google Scholar 

  • Wang Y, Pennock SD, Chen X, Kazlauskas A, Wang Z (2004) Platelet-derived growth factor receptor-mediated signal transduction from endosomes. J Biol Chem 279:8038–8046

    Article  PubMed  CAS  Google Scholar 

  • Werner S, Grose R (2003) Regulation of wound healing by growth factors and cytokines. Physiol Rev 83:835–870

    PubMed  CAS  Google Scholar 

  • Zwang Y, Yarden Y (2009) Systems biology of growth factor-induced receptor endocytosis. Traffic 10:349–363

    Article  PubMed  CAS  Google Scholar 

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Author information

Authors and Affiliations

  1. Ludwig Institute for Cancer Research, Uppsala University, Box 595, SE 751 24, Uppsala, Sweden

    Carina Hellberg & Carl-Henrik Heldin

Authors
  1. Carina Hellberg
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  2. Carl-Henrik Heldin
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Correspondence to Carina Hellberg .

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Editors and Affiliations

  1. Siederstrasse 13, Villingen-Schwenningen, 78054, Germany

    Margareta M. Mueller

  2. Am Pferchelhang 32, Heidelberg, 69118, Germany

    Norbert E. Fusenig

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Hellberg, C., Heldin, CH. (2011). Role of PDGF in Tumor-Stroma Interactions. In: Mueller, M., Fusenig, N. (eds) Tumor-Associated Fibroblasts and their Matrix. The Tumor Microenvironment, vol 4. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-0659-0_14

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