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PDGF and Vessel Maturation

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Angiogenesis Inhibition

Part of the book series: Recent Results in Cancer Research ((RECENTCANCER,volume 180))

Abstract

Pericytes are smooth muscle-like cells found in close contact with the endothelium in capillaries, where they regulate the morphology and function of the vessels. During vessel formation, platelet-derived growth factor-BB (PDGF-BB) is required for the recruitment and differentiation of pericytes. Tumor vessels display abnormal morphology and increased endothelial proliferation, resulting in leaky, tortuous vessels that are often poorly perfused. These vessels typically display decreased pericyte density, and the tumor-associated pericytes often express abnormal markers and show abnormal morphology. Anti-angiogenic therapy targeting pro-angiogenic growth factor pathways has been applied to a broad range of solid tumors with varying results. Studies utilizing mouse models indicate that the presence of pericytes protect endothelial cells against inhibition of vascular endothelial growth factor (VEGF) signaling. Simultaneous inhibition of PDGF receptors on pericytes therefore improves the effect of VEGF inhibitors on endothelial cells and enhances anti-angiogenic therapy.

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References

  • Abramsson A, Kurup S, Busse M, Yamada S, Lindblom P, Schallmeiner E, Stenzel D, Sauvaget D, Ledin J, Ringvall M, Landegren U, Kjellen L, Bondjers G, Li JP, Lindahl U, Spillmann D, Betsholtz C, Gerhardt H (2007) Defective N-sulfation of heparan sulfate proteoglycans limits PDGF-BB binding and pericyte recruitment in vascular development. Genes Dev 21:316–331

    Article  CAS  PubMed  Google Scholar 

  • Allende ML, Proia RL (2002) Sphingosine-1-phosphate receptors and the development of the vascular system. Biochim Biophys Acta 1582:222–227

    CAS  PubMed  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  CAS  PubMed  Google Scholar 

  • Baluk P, Morikawa S, Haskell A, Mancuso M, McDonald DM (2003) Abnormalities of basement membrane on blood vessels and endothelial sprouts in tumors. Am J Pathol 163: 1801–1815

    PubMed  Google Scholar 

  • Bergers G, Benjamin LE (2003) Tumorigenesis and the angiogenic switch. Nat Rev Cancer 3:401–410

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  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

    CAS  PubMed  Google Scholar 

  • Bertolino P, Deckers M, Lebrin F, ten Dijke P (2005) Transforming growth factor-beta signal transduction in angiogenesis and vascular disorders. Chest 128:585S–590S

    Article  CAS  PubMed  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  CAS  PubMed  Google Scholar 

  • Bjarnegard M, Enge M, Norlin J, Gustafsdottir S, Fredriksson S, Abramsson A, Takemoto M, Gustafsson E, Fässler R, Betsholtz C (2004) Endothelium-specific ablation of PDGFB leads to pericyte loss and glomerular, cardiac and placental abnormalities. Development 131:1847–1857

    Article  CAS  PubMed  Google Scholar 

  • Cao Y (2004) Antiangiogenic cancer therapy. Semin Cancer Biol 14:139–145

    Article  CAS  PubMed  Google Scholar 

  • Claes A, Wesseling P, Jeuken J, Maass C, Heerschap A, Leenders WP (2008) Antiangiogenic compounds interfere with chemotherapy of brain tumors due to vessel normalization. Mol Cancer Ther 7:71–78

    Article  CAS  PubMed  Google Scholar 

  • Cobleigh MA, Langmuir VK, Sledge GW, Miller KD, Haney L, Novotny WF, Reimann JD, Vassel A (2003) A phase I/II dose-escalation trial of bevacizumab in previously treated metastatic breast cancer. Semin Oncol 30:117–124

    Article  CAS  PubMed  Google Scholar 

  • Crosby JR, Seifert RA, Soriano P, Bowen-Pope DF (1998) Chimaeric analysis reveals role of Pdgf receptors in all muscle lineages. Nat Genet 18:385–388

    Article  CAS  PubMed  Google Scholar 

  • Dings RP, Loren M, Heun H, McNiel E, Griffioen AW, Mayo KH, Griffin RJ (2007) Scheduling of radiation with angiogenesis inhibitors anginex and Avastin improves therapeutic outcome via vessel normalization. Clin Cancer Res 13:3395–3402

    Article  CAS  PubMed  Google Scholar 

  • Dore-Duffy P, Katychev A, Wang X, Van Buren E (2006) CNS microvascular pericytes exhibit multipotential stem cell activity. J Cereb Blood Flow Metab 26:613–624

    Article  CAS  PubMed  Google Scholar 

  • Erber R, Thurnher A, Katsen AD, Groth G, Kerger H, Hammes HP, Menger MD, Ullrich A, Vajkoczy P (2004) Combined inhibition of VEGF and PDGF signaling enforces tumor vessel regression by interfering with pericyte-mediated endothelial cell survival mechanisms. FASEB J 18:338–340

    CAS  PubMed  Google Scholar 

  • Folkman J (1971) Tumor angiogenesis: therapeutic implications. N Engl J Med 285:1182–1186

    Article  CAS  PubMed  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  CAS  PubMed  Google Scholar 

  • Furuhashi M, Sjöblom T, Abramsson A, Ellingsen J, Micke P, Li H, Bergsten-Folestad E, Eriksson U, Heuchel R, Betsholtz C, Heldin CH, Östman 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  CAS  PubMed  Google Scholar 

  • Gerhardt H, Golding M, Fruttiger M, Ruhrberg C, Lundkvist A, Abramsson A, Jeltsch M, Mitchell C, Alitalo K, Shima D, Betsholtz C (2003) VEGF guides angiogenic sprouting utilizing endothelial tip cell filopodia. J Cell Biol 161:1163–1177

    Article  CAS  PubMed  Google Scholar 

  • Hashizume H, Baluk P, Morikawa S, McLean JW, Thurston G, Roberge S, Jain RK, McDonald DM (2000) Openings between defective endothelial cells explain tumor vessel leakiness. Am J Pathol 156:1363–1380

    CAS  PubMed  Google Scholar 

  • Hasumi Y, Klosowska-Wardega A, Furuhashi M, Östman 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  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Hellström M, Gerhardt H, Kalen M, Li X, Eriksson U, Wolburg H, Betsholtz C (2001) Lack of pericytes leads to endothelial hyperplasia and abnormal vascular morphogenesis. J Cell Biol 153:543–553

    Article  CAS  PubMed  Google Scholar 

  • Hellström M, Kalén M, Lindahl P, Abramsson A, Betsholtz C (1999) Role of PDGF-B and PDGFR-beta in recruitment of vascular smooth muscle cells and pericytes during embryonic blood vessel formation in the mouse. Development 126:3047–3055

    CAS  PubMed  Google Scholar 

  • Heuchel R, Berg A, Tallquist M, Åhlen K, Reed RK, Rubin K, Claesson-Welsh L, Heldin CH, Soriano P (1999) Platelet-derived growth factor beta receptor regulates interstitial fluid homeostasis through phosphatidylinositol-3’ kinase signaling. Proc Natl Acad Sci U S A 96:11410–11415

    Article  CAS  PubMed  Google Scholar 

  • Hlushchuk R, Baum O, Gruber G, Wood J, Djonov V (2007) The synergistic action of a VEGF-receptor tyrosine-kinase inhibitor and a sensitizing PDGF-receptor blocker depends upon the stage of vascular maturation. Microcirculation 14:813–825

    Article  CAS  PubMed  Google Scholar 

  • Hofmeister V, Schrama D, Becker JC (2008) Anti-cancer therapies targeting the tumor stroma. Cancer Immunol Immunother 57:1–17

    Article  CAS  PubMed  Google Scholar 

  • Howson KM, Aplin AC, Gelati M, Alessandri G, Parati EA, Nicosia RF (2005) The postnatal rat aorta contains pericyte progenitor cells that form spheroidal colonies in suspension culture. Am J Physiol Cell Physiol 289:C1396–C1407

    Article  CAS  PubMed  Google Scholar 

  • Huang J, Soffer SZ, Kim ES, McCrudden KW, New T, Manley CA, Middlesworth W, O’Toole K, Yamashiro DJ, Kandel JJ (2004) Vascular remodeling marks tumors that recur during chronic suppression of angiogenesis. Mol Cancer Res 2:36–42

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Lamagna C, Bergers G (2006) The bone marrow constitutes a reservoir of pericyte progenitors. J Leukoc Biol 80:677–681

    Article  CAS  PubMed  Google Scholar 

  • Lee CG, Heijn M, di Tomaso E, Griffon-Etienne G, Ancukiewicz M, Koike C, Park KR, Ferrara N, Jain RK, Suit HD, Boucher Y (2000) Anti-vascular endothelial growth factor treatment augments tumor radiation response under normoxic or hypoxic conditions. Cancer Res 60:5565–5570

    CAS  PubMed  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  CAS  PubMed  Google Scholar 

  • Lindahl P, Johansson BR, Leveen P, Betsholtz C (1997) Pericyte loss and microaneurysm formation in PDGF-B-deficient mice. Science 277:242–245

    Article  CAS  PubMed  Google Scholar 

  • Lindblom P, Gerhardt H, Liebner S, Abramsson A, Enge M, Hellström M, Bäckstrom G, Fredriksson S, Landegren U, Nystrom HC, Bergström G, Dejana E, Ostman A, Lindahl P, Betsholtz C (2003) Endothelial PDGF-B retention is required for proper investment of pericytes in the microvessel wall. Genes Dev 17:1835–1840

    Article  CAS  PubMed  Google Scholar 

  • Lyden D, Hattori K, Dias S, Costa C, Blaikie P, Butros L, Chadburn A, Heissig B, Marks W, Witte L, Wu Y, Hicklin D, Zhu Z, Hackett NR, Crystal RG, Moore MA, Hajjar KA, Manova K, Benezra R, Rafii S (2001) Impaired recruitment of bone-marrow-derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth. Nat Med 7:1194–1201

    Article  CAS  PubMed  Google Scholar 

  • Miller DW, Vosseler S, Mirancea N, Hicklin DJ, Bohlen P, Volcker HE, Holz FG, Fusenig NE (2005) Rapid vessel regression, protease inhibition, and stromal normalization upon short-term vascular endothelial growth factor receptor 2 inhibition in skin carcinoma heterotransplants. Am J Pathol 167:1389–1403

    CAS  PubMed  Google Scholar 

  • Moeller BJ, Richardson RA, Dewhirst MW (2007) Hypoxia and radiotherapy: opportunities for improved outcomes in cancer treatment. Cancer Metastasis Rev 26:241–248

    Article  CAS  PubMed  Google Scholar 

  • Morisada T, Kubota Y, Urano T, Suda T, Oike Y (2006) Angiopoietins and angiopoietin-like proteins in angiogenesis. Endothelium 13:71–79

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  • Petit I, Jin D, Rafii S (2007) The SDF-1-CXCR4 signaling pathway: a molecular hub modulating neo-angiogenesis. Trends Immunol 28:299–307

    Article  CAS  PubMed  Google Scholar 

  • Pietras K, Östman A, Sjöquist M, Buchdunger E, Reed RK, Heldin CH, Rubin K (2001) Inhibition of platelet-derived growth factor receptors reduces interstitial hypertension and increases transcapillary transport in tumors. Cancer Res 61:2929–2934

    CAS  PubMed  Google Scholar 

  • Pietras K, Rubin K, Sjöblom T, Buchdunger E, Sjöquist M, Heldin CH, Östman A (2002) Inhibition of PDGF receptor signaling in tumor stroma enhances antitumor effect of chemotherapy. Cancer Res 62:5476–5484

    CAS  PubMed  Google Scholar 

  • Rajantie I, Ilmonen M, Alminaite A, Ozerdem U, Alitalo K, Salven P (2004) Adult bone marrow-derived cells recruited during angiogenesis comprise precursors for periendothelial vascular mural cells. Blood 104:2084–2086

    Article  CAS  PubMed  Google Scholar 

  • Robinson SP, Ludwig C, Paulsson J, Östman A (2008) The effects of tumor-derived platelet-derived growth factor on vascular morphology and function in vivo revealed by susceptibility MRI. Int J Cancer 122:1548–1556

    Article  CAS  PubMed  Google Scholar 

  • Sennino B, Falcon BL, McCauley D, Le T, McCauley T, Kurz JC, Haskell A, Epstein DM, McDonald DM (2007) Sequential loss of tumor vessel pericytes and endothelial cells after inhibition of platelet-derived growth factor B by selective aptamer AX102. Cancer Res 67: 7358–7367

    Article  CAS  PubMed  Google Scholar 

  • Shirakawa K, Shibuya M, Heike Y, Takashima S, Watanabe I, Konishi F, Kasumi F, Goldman CK, Thomas KA, Bett A, Terada M, Wakasugi H (2002) Tumor-infiltrating endothelial cells and endothelial precursor cells in inflammatory breast cancer. Int J Cancer 99:344–351

    Article  CAS  PubMed  Google Scholar 

  • Song S, Ewald AJ, Stallcup W, Werb Z, Bergers G (2005) PDGFRbeta+ perivascular progenitor cells in tumours regulate pericyte differentiation and vascular survival. Nat Cell Biol 7:870–879

    Article  CAS  PubMed  Google Scholar 

  • Taguchi E, Nakamura K, Miura T, Shibuya M, Isoe T (2008) Anti-tumor activity and tumor vessel normalization by the vascular endothelial growth factor receptor tyrosine kinase inhibitor KRN951 in a rat peritoneal disseminated tumor model. Cancer Sci 99(3):623–630

    Article  CAS  PubMed  Google Scholar 

  • Tamaki T, Okada Y, Uchiyama Y, Tono K, Masuda M, Wada M, Hoshi A, Akatsuka A (2007) Synchronized reconstitution of muscle fibers, peripheral nerves and blood vessels by murine skeletal muscle-derived CD34(-)/45 (-) cells. Histochem Cell Biol 128:349–360

    Article  CAS  PubMed  Google Scholar 

  • Tong RT, Boucher Y, Kozin SV, Winkler F, Hicklin DJ, Jain RK (2004) Vascular normalization by vascular endothelial growth factor receptor 2 blockade induces a pressure gradient across the vasculature and improves drug penetration in tumors. Cancer Res 64:3731–3736

    Article  CAS  PubMed  Google Scholar 

  • Willett CG, Boucher Y, di Tomaso E, Duda DG, Munn LL, Tong RT, Chung DC, Sahani DV, Kalva SP, Kozin SV, Mino M, Cohen KS, Scadden DT, Hartford AC, Fischman AJ, Clark JW, Ryan DP, Zhu AX, Blaszkowsky LS, Chen HX, Shellito PC, Lauwers GY, Jain RK (2004) Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Nat Med 10:145–147

    Article  CAS  PubMed  Google Scholar 

  • Yang JC, Haworth L, Sherry RM, Hwu P, Schwartzentruber DJ, Topalian SL, Steinberg SM, Chen HX, Rosenberg SA (2003) A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med 349:427–434

    Article  CAS  PubMed  Google Scholar 

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Hellberg, C., Östman, A., Heldin, CH. (2010). PDGF and Vessel Maturation. In: Liersch, R., Berdel, W., Kessler, T. (eds) Angiogenesis Inhibition. Recent Results in Cancer Research, vol 180. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-540-78281-0_7

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