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Tumor Vessel Associated-Pericytes

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Tumor-Associated Fibroblasts and their Matrix

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

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Abstract

In blood vessels, the crosstalk between vascular endothelial cells and mural cells (pericytes/vascular smooth muscle cells) play a central role in the regulation of vascular formation, maturation, remodeling, stabilization and function. During embryonic development as well as tumor growth and metastasis the process of angiogenesis is tightly regulated by vascular endothelial growth factor. Since vascular endothelial growth factor receptor is mainly expressed on endothelial cells, much effort has been made towards the context of endothelial cell biology in anti-angiogenic therapy. This endothelial cell-centred view has greatly ignored the fact that newly formed capillary networks stay in close contact to the surrounding tissue including peri-endothelial mural cells such as pericytes and smooth muscle cells. Pericytes play a pivotal role during vascular morphogenesis and stabilization. In this respect the interplay between endothelial cells and pericytes has drawn a lot of attention in the last decade. Today the mechanistic and molecular analysis of pericyte physiology is a rapidly growing field in biomedical research. It is highly appreciated that pericyte-mediated vessel maturation is a critical determinant of the therapeutic window in anti-angiogenic therapy. Due to the increasing evidence of the importance of pericytes in tumor biology this review summarizes the origin of pericytes, markers that determine, signaling pathways which are important in pericyte function and biology, as well as the role of pericytes during tumor progression.

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References

  • Abdollahi A, Lipson KE, Han X, Krempien R, Trinh T, Weber KJ, Hahnfeldt P, Hlatky L, Debus J, Howlett AR et al (2003) SU5416 and SU6668 attenuate the angiogenic effects of radiation-induced tumor cell growth factor production and amplify the direct anti-endothelial action of radiation in vitro. Cancer Res 63:3755–3763

    PubMed  CAS  Google Scholar 

  • Abramsson A, Berlin O, Papayan H, Paulin D, Shani M, Betsholtz C (2002) Analysis of mural cell recruitment to tumor vessels. Circulation 105:112–117

    Article  PubMed  CAS  Google Scholar 

  • Abramsson A, Lindblom P, Betsholtz C (2003) Endothelial and nonendothelial sources of PDGF-B regulate pericyte recruitment and influence vascular pattern formation in tumors. J Clin Invest 112:1142–1151

    PubMed  CAS  Google Scholar 

  • Adams RH (2003) Molecular control of arterial-venous blood vessel identity. J Anat 202:105–112

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Allende ML, Dreier JL, Mandala S, Proia RL (2004) Expression of the sphingosine 1-phosphate receptor, S1P1, on T-cells controls thymic emigration. J Biol Chem 279:15396–15401

    Article  PubMed  CAS  Google Scholar 

  • Armstrong EJ, Bischoff J (2004) Heart valve development: endothelial cell signaling and differentiation. Circ Res 95:459–470

    Article  PubMed  CAS  Google Scholar 

  • Bagley RG, Honma N, Weber W, Boutin P, Rouleau C, Shankara S, Kataoka S, Ishida I, Roberts BL, Teicher BA (2008) Endosialin/TEM 1/CD248 is a pericyte marker of embryonic and tumor neovascularization. Microvasc Res 76:180–188

    Article  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 

  • Benjamin LE, Hemo I, Keshet E (1998) A plasticity window for blood vessel remodelling is defined by pericyte coverage of the preformed endothelial network and is regulated by PDGF-B and VEGF. Development 125:1591–1598

    PubMed  CAS  Google Scholar 

  • Benjamin LE, Golijanin D, Itin A, Pode D, Keshet E (1999) Selective ablation of immature blood vessels in established human tumors follows vascular endothelial growth factor withdrawal. J Clin Invest 103:159–165

    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 

  • Brown EB, Campbell RB, Tsuzuki Y, Xu L, Carmeliet P, Fukumura D, Jain RK (2001) In vivo measurement of gene expression, angiogenesis and physiological function in tumors using multiphoton laser scanning microscopy. Nat Med 7:864–868

    Article  PubMed  CAS  Google Scholar 

  • Bruno S, Bussolati B, Grange C, Collino F, Graziano ME, Ferrando U, Camussi G (2006) CD133+ renal progenitor cells contribute to tumor angiogenesis. Am J Pathol 169:2223–2235

    Article  PubMed  CAS  Google Scholar 

  • Buchanan RA, Wagner RC (1990) Morphometric changes in pericyte-capillary endothelial cell associations correlated with vasoactive stimulus. Microcirc Endothelium Lymphatics 6:159–181

    PubMed  CAS  Google Scholar 

  • Carmeliet P (2003) Angiogenesis in health and disease. Nat Med 9:653–660

    Article  PubMed  CAS  Google Scholar 

  • Carmeliet P, Luttun A (2001) The emerging role of the bone marrow-derived stem cells in (therapeutic) angiogenesis. Thromb Haemost 86:289–297

    PubMed  CAS  Google Scholar 

  • Chambers RC, Leoni P, Kaminski N, Laurent GJ, Heller R (2003) Global expression profiling of fibroblast responses to transforming growth factor-beta1 reveals the induction of inhibitor of differentiation-1 and provides evidence of smooth muscle cell phenotypic switching. Am J Pathol 162:533–546

    Article  PubMed  CAS  Google Scholar 

  • Christian S, Winkler R, Helfrich I, Boos AM, Besemfelder E, Schadendorf D, Augustin HG (2008) Endosialin (Tem1) is a marker of tumor-associated myofibroblasts and tumor vessel-associated mural cells. Am J Pathol 172:486–494

    Article  PubMed  CAS  Google Scholar 

  • Ciardiello F, Caputo R, Bianco R, Damiano V, Fontanini G, Cuccato S, De Placido S, Bianco AR, Tortora G (2001) Inhibition of growth factor production and angiogenesis in human cancer cells by ZD1839 (Iressa), a selective epidermal growth factor receptor tyrosine kinase inhibitor. Clin Cancer Res 7:1459–1465

    PubMed  CAS  Google Scholar 

  • Creazzo TL, Godt RE, Leatherbury L, Conway SJ, Kirby ML (1998) Role of cardiac neural crest cells in cardiovascular development. Annu Rev Physiol 60:267–286

    Article  PubMed  CAS  Google Scholar 

  • Crisan M, Yap S, Casteilla L, Chen CW, Corselli M, Park TS, Andriolo G, Sun B, Zheng B, Zhang L et al (2008) A perivascular origin for mesenchymal stem cells in multiple human organs. Cell Stem Cell 3:301–313

    Article  PubMed  CAS  Google Scholar 

  • Cuevas P, Gutierrez-Diaz JA, Reimers D, Dujovny M, Diaz FG, Ausman JI (1984) Pericyte endothelial gap junctions in human cerebral capillaries. Anat Embryol (Berl) 170:155–159

    Article  CAS  Google Scholar 

  • da Silva Meirelles L, Caplan AI, Nardi NB (2008) In search of the in vivo identity of mesenchymal stem cells. Stem Cells 26:2287–2299

    Article  Google Scholar 

  • Davis GE, Senger DR (2005) Endothelial extracellular matrix: biosynthesis, remodeling, and functions during vascular morphogenesis and neovessel stabilization. Circ Res 97:1093–1107

    Article  PubMed  CAS  Google Scholar 

  • Davis S, Aldrich TH, Jones PF, Acheson A, Compton DL, Jain V, Ryan TE, Bruno J, Radziejewski C, Maisonpierre PC et al (1996) Isolation of angiopoietin-1, a ligand for the TIE2 receptor, by secretion-trap expression cloning. Cell 87:1161–1169

    Article  PubMed  CAS  Google Scholar 

  • De Palma M, Venneri MA, Galli R, Sergi Sergi L, Politi LS, Sampaolesi M, Naldini L (2005) Tie2 identifies a hematopoietic lineage of proangiogenic monocytes required for tumor vessel formation and a mesenchymal population of pericyte progenitors. Cancer Cell 8:211–226

    Article  PubMed  CAS  Google Scholar 

  • Diaz-Flores L, Gutierrez R, Varela H (1992) Behavior of postcapillary venule pericytes during postnatal angiogenesis. J Morphol 213:33–45

    Article  PubMed  CAS  Google Scholar 

  • Ding R, Darland DC, Parmacek MS, D’Amore PA (2004) Endothelial-mesenchymal interactions in vitro reveal molecular mechanisms of smooth muscle/pericyte differentiation. Stem Cells Dev 13:509–520

    PubMed  CAS  Google Scholar 

  • Domenga V, Fardoux P, Lacombe P, Monet M, Maciazek J, Krebs LT, Klonjkowski B, Berrou E, Mericskay M, Li Z et al (2004) Notch3 is required for arterial identity and maturation of vascular smooth muscle cells. Genes Dev 18:2730–2735

    Article  PubMed  CAS  Google Scholar 

  • Dumont DJ, Gradwohl G, Fong GH, Puri MC, Gertsenstein M, Auerbach A, Breitman ML (1994) Dominant-negative and targeted null mutations in the endothelial receptor tyrosine kinase, tek, reveal a critical role in vasculogenesis of the embryo. Genes Dev 8:1897–1909

    Article  PubMed  CAS  Google Scholar 

  • Eberhard A, Kahlert S, Goede V, Hemmerlein B, Plate KH, Augustin HG (2000) Heterogeneity of angiogenesis and blood vessel maturation in human tumors: implications for antiangiogenic tumor therapies. Cancer Res 60:1388–1393

    PubMed  CAS  Google Scholar 

  • Ema M, Rossant J (2003) Cell fate decisions in early blood vessel formation. Trends Cardiovasc Med 13:254–259

    Article  PubMed  CAS  Google Scholar 

  • Falcon BL, Hashizume H, Koumoutsakos P, Chou J, Bready JV, Coxon A, Oliner JD, McDonald DM (2009) Contrasting actions of selective inhibitors of angiopoietin-1 and angiopoietin-2 on the normalization of tumor blood vessels. Am J Pathol 175:2159–2170

    Article  PubMed  CAS  Google Scholar 

  • Folkman J (1985) Tumor angiogenesis. Adv Cancer Res 43:175–203

    Article  PubMed  CAS  Google Scholar 

  • Fournie-Zaluski MC, Fassot C, Valentin B, Djordjijevic D, Reaux-Le Goazigo A, Corvol P, Roques BP, Llorens-Cortes C (2004) Brain renin-angiotensin system blockade by systemically active aminopeptidase A inhibitors: a potential treatment of salt-dependent hypertension. Proc Natl Acad Sci U S A 101:7775–7780

    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 et al (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 

  • Furuya M, Yonemitsu Y (2008) Cancer neovascularization and proinflammatory microenvironments. Curr Cancer Drug Targets 8:253–265

    Article  PubMed  CAS  Google Scholar 

  • Gee MS, Procopio WN, Makonnen S, Feldman MD, Yeilding NM, Lee WM (2003) Tumor vessel development and maturation impose limits on the effectiveness of anti-vascular therapy. Am J Pathol 162:183–193

    Article  PubMed  Google Scholar 

  • Gerhardt H, Betsholtz C (2003) Endothelial-pericyte interactions in angiogenesis. Cell Tissue Res 314:15–23

    Article  PubMed  Google Scholar 

  • Gerhardt H, Wolburg H, Redies C (2000) N-cadherin mediates pericytic-endothelial interaction during brain angiogenesis in the chicken. Dev Dyn 218:472–479

    Article  PubMed  CAS  Google Scholar 

  • Goretzki L, Burg MA, Grako KA, Stallcup WB (1999) High-affinity binding of basic fibroblast growth factor and platelet-derived growth factor-AA to the core protein of the NG2 proteoglycan. J Biol Chem 274:16831–16837

    Article  PubMed  CAS  Google Scholar 

  • Goumans MJ, Valdimarsdottir G, Itoh S, Rosendahl A, Sideras P, ten Dijke P (2002) Balancing the activation state of the endothelium via two distinct TGF-beta type I receptors. EMBO J 21:1743–1753

    Article  PubMed  CAS  Google Scholar 

  • Greenberg JI, Shields DJ, Barillas SG, Acevedo LM, Murphy E, Huang J, Scheppke L, Stockmann C, Johnson RS, Angle N et al (2008) A role for VEGF as a negative regulator of pericyte function and vessel maturation. Nature 456:809–813

    Article  PubMed  CAS  Google Scholar 

  • Grunewald M, Avraham I, Dor Y, Bachar-Lustig E, Itin A, Jung S, Chimenti S, Landsman L, Abramovitch R, Keshet E (2006) VEGF-induced adult neovascularization: recruitment, retention, and role of accessory cells. Cell 124:175–189

    Article  PubMed  CAS  Google Scholar 

  • Hammes HP, Lin J, Wagner P, Feng Y, Vom Hagen F, Krzizok T, Renner O, Breier G, Brownlee M, Deutsch U (2004) Angiopoietin-2 causes pericyte dropout in the normal retina: evidence for involvement in diabetic retinopathy. Diabetes 53:1104–1110

    Article  PubMed  CAS  Google Scholar 

  • Hamzah J, Jugold M, Kiessling F, Rigby P, Manzur M, Marti HH, Rabie T, Kaden S, Grone HJ, Hammerling GJ et al (2008) Vascular normalization in Rgs5-deficient tumours promotes immune destruction. Nature 453:410–414

    Article  PubMed  CAS  Google Scholar 

  • Hanahan D, Folkman J (1996) Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 86:353–364

    Article  PubMed  CAS  Google Scholar 

  • Hattori K, Heissig B, Wu Y, Dias S, Tejada R, Ferris B, Hicklin DJ, Zhu Z, Bohlen P, Witte L et al (2002) Placental growth factor reconstitutes hematopoiesis by recruiting VEGFR1(+) stem cells from bone-marrow microenvironment. Nat Med 8:841–849

    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 

  • Hellstrom M, Kalen 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

    PubMed  CAS  Google Scholar 

  • Hollinger S, Hepler JR (2002) Cellular regulation of RGS proteins: modulators and integrators of G protein signaling. Pharmacol Rev 54:527–559

    Article  PubMed  CAS  Google Scholar 

  • Hu JC, Zhang C, Slavkin HC (1995) The role of platelet-derived growth factor in the development of mouse molars. Int J Dev Biol 39:939–945

    PubMed  CAS  Google Scholar 

  • Iivanainen E, Nelimarkka L, Elenius V, Heikkinen SM, Junttila TT, Sihombing L, Sundvall M, Maatta JA, Laine VJ, Yla-Herttuala S et al (2003) Angiopoietin-regulated recruitment of vascular smooth muscle cells by endothelial-derived heparin binding EGF-like growth factor. FASEB J 17:1609–1621

    Article  PubMed  CAS  Google Scholar 

  • Iivanainen E, Lauttia S, Zhang N, Tvorogov D, Kulmala J, Grenman R, Salven P, Elenius K (2009) The EGFR inhibitor gefitinib suppresses recruitment of pericytes and bone marrow-derived perivascular cells into tumor vessels. Microvasc Res 78:278–285

    Article  PubMed  CAS  Google Scholar 

  • Inai T, Mancuso M, Hashizume H, Baffert F, Haskell A, Baluk P, Hu-Lowe DD, Shalinsky DR, Thurston G, Yancopoulos GD et al (2004) Inhibition of vascular endothelial growth factor (VEGF) signaling in cancer causes loss of endothelial fenestrations, regression of tumor vessels, and appearance of basement membrane ghosts. Am J Pathol 165:35–52

    Article  PubMed  CAS  Google Scholar 

  • Iwamoto R, Yamazaki S, Asakura M, Takashima S, Hasuwa H, Miyado K, Adachi S, Kitakaze M, Hashimoto K, Raab G et al (2003) Heparin-binding EGF-like growth factor and ErbB signaling is essential for heart function. Proc Natl Acad Sci U S A 100:3221–3226

    Article  PubMed  CAS  Google Scholar 

  • Jackson LF, Qiu TH, Sunnarborg SW, Chang A, Zhang C, Patterson C, Lee DC (2003) Defective valvulogenesis in HB-EGF and TACE-null mice is associated with aberrant BMP signaling. EMBO J 22:2704–2716

    Article  PubMed  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 

  • Jin S, Hansson EM, Tikka S, Lanner F, Sahlgren C, Farnebo F, Baumann M, Kalimo H, Lendahl U (2008) Notch signaling regulates platelet-derived growth factor receptor-beta expression in vascular smooth muscle cells. Circ Res 102:1483–1491

    Article  PubMed  CAS  Google Scholar 

  • Johnson JP, Bruce JN (1997) Angiogenesis in human gliomas: prognostic and therapeutic implications. EXS 79:29–46

    PubMed  CAS  Google Scholar 

  • Kalimo H, Ruchoux MM, Viitanen M, Kalaria RN (2002) CADASIL: a common form of hereditary arteriopathy causing brain infarcts and dementia. Brain Pathol 12:371–384

    Article  PubMed  CAS  Google Scholar 

  • Kashiwagi S, Tsukada K, Xu L, Miyazaki J, Kozin SV, Tyrrell JA, Sessa WC, Gerweck LE, Jain RK, Fukumura D (2008) Perivascular nitric oxide gradients normalize tumor vasculature. Nat Med 14:255–257

    Article  PubMed  CAS  Google Scholar 

  • Kim Y, Imdad RY, Stephenson AH, Sprague RS, Lonigro AJ (1998) Vascular endothelial growth factor mRNA in pericytes is upregulated by phorbol myristate acetate. Hypertension 31:511–515

    Article  PubMed  CAS  Google Scholar 

  • Kobayashi H, DeBusk LM, Babichev YO, Dumont DJ, Lin PC (2006) Hepatocyte growth factor mediates angiopoietin-induced smooth muscle cell recruitment. Blood 108:1260–1266

    Article  PubMed  CAS  Google Scholar 

  • Kundra V, Escobedo JA, Kazlauskas A, Kim HK, Rhee SG, Williams LT, Zetter BR (1994) Regulation of chemotaxis by the platelet-derived growth factor receptor-beta. Nature 367:474–476

    Article  PubMed  CAS  Google Scholar 

  • Kunz J, Krause D, Gehrmann J, Dermietzel R (1995) Changes in the expression pattern of blood-brain barrier-associated pericytic aminopeptidase N (pAP N) in the course of acute experimental autoimmune encephalomyelitis. J Neuroimmunol 59:41–55

    Article  PubMed  CAS  Google Scholar 

  • Kunz J, Krause D, Kremer M, Dermietzel R (1994) The 140 kDa protein of blood-brain barrier-associated pericytes is identical to aminopeptidase N. J Neurochem 62:2375–2386

    Article  PubMed  CAS  Google Scholar 

  • Lach B, Gregor A, Rippstein P, Omulecka A (1999) Angiogenic histogenesis of stromal cells in hemangioblastoma: ultrastructural and immunohistochemical study. Ultrastruct Pathol 23:299–310

    Article  PubMed  CAS  Google Scholar 

  • Lawson ND, Scheer N, Pham VN, Kim CH, Chitnis AB, Campos-Ortega JA, Weinstein BM (2001) Notch signaling is required for arterial-venous differentiation during embryonic vascular development. Development 128:3675–3683

    PubMed  CAS  Google Scholar 

  • Lebrin F, Goumans MJ, Jonker L, Carvalho RL, Valdimarsdottir G, Thorikay M, Mummery C, Arthur HM, ten Dijke P (2004) Endoglin promotes endothelial cell proliferation and TGF-beta/ALK1 signal transduction. EMBO J 23:4018–4028

    Article  PubMed  CAS  Google Scholar 

  • Leveen P, Pekny M, Gebre-Medhin S, Swolin B, Larsson E, Betsholtz C (1994) Mice deficient for PDGF B show renal, cardiovascular, and hematological abnormalities. Genes Dev 8:1875–1887

    Article  PubMed  CAS  Google Scholar 

  • Li DY, Sorensen LK, Brooke BS, Urness LD, Davis EC, Taylor DG, Boak BB, Wendel DP (1999) Defective angiogenesis in mice lacking endoglin. Science 284:1534–1537

    Article  PubMed  CAS  Google Scholar 

  • Li M, Ping G, Plathow C, Trinh T, Lipson KE, Hauser K, Krempien R, Debus J, Abdollahi A, Huber PE (2006) Small molecule receptor tyrosine kinase inhibitor of platelet-derived growth factor signaling (SU9518) modifies radiation response in fibroblasts and endothelial cells. BMC Cancer 6:79

    Article  PubMed  CAS  Google Scholar 

  • Liu Y, Wada R, Yamashita T, Mi Y, Deng CX, Hobson JP, Rosenfeldt HM, Nava VE, Chae SS, Lee MJ et al (2000) Edg-1, the G protein-coupled receptor for sphingosine-1-phosphate, is essential for vascular maturation. J Clin Invest 106:951–961

    Article  PubMed  CAS  Google Scholar 

  • Lonigro AJ, McMurdo L, Stephenson AH, Sprague RS, Weintraub NL (1996) Hypotheses regarding the role of pericytes in regulating movement of fluid, nutrients, and hormones across the microcirculatory endothelial barrier. Diabetes 45(Suppl 1):S38–S43

    PubMed  Google Scholar 

  • Lyden D, Hattori K, Dias S, Costa C, Blaikie P, Butros L, Chadburn A, Heissig B, Marks W, Witte L et al (2001) Impaired recruitment of bone-marrow-derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth. Nat Med 7:1194–1201

    Article  PubMed  CAS  Google Scholar 

  • Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, Harris PL, Haserlat SM, Supko JG, Haluska FG et al (2004) Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 350:2129–2139

    Article  PubMed  CAS  Google Scholar 

  • Morelli MP, Cascone T, Troiani T, Tuccillo C, Bianco R, Normanno N, Romano M, Veneziani BM, Fontanini G, Eckhardt SG et al (2006) Anti-tumor activity of the combination of cetuximab, an anti-EGFR blocking monoclonal antibody and ZD6474, an inhibitor of VEGFR and EGFR tyrosine kinases. J Cell Physiol 208:344–353

    Article  PubMed  CAS  Google Scholar 

  • Morikawa S, Baluk P, Kaidoh T, Haskell A, Jain RK, McDonald DM (2002) Abnormalities in pericytes on blood vessels and endothelial sprouts in tumors. Am J Pathol 160:985–1000

    Article  PubMed  Google Scholar 

  • Murphy DD, Wagner RC (1994) Differential contractile response of cultured microvascular pericytes to vasoactive agents. Microcirculation 1:121–128

    Article  PubMed  CAS  Google Scholar 

  • Nasarre P, Thomas M, Kruse K, Helfrich I, Wolter V, Deppermann C, Schadendorf D, Thurston G, Fiedler U, Augustin HG (2009) Host-derived angiopoietin-2 affects early stages of tumor development and vessel maturation but is dispensable for later stages of tumor growth. Cancer Res 69:1324–1333

    Article  PubMed  CAS  Google Scholar 

  • Nehls V, Drenckhahn D (1993) The versatility of microvascular pericytes: from mesenchyme to smooth muscle? Histochemistry 99:1–12

    Article  PubMed  CAS  Google Scholar 

  • Oliner J, Min H, Leal J, Yu D, Rao S, You E, Tang X, Kim H, Meyer S, Han SJ et al (2004) Suppression of angiogenesis and tumor growth by selective inhibition of angiopoietin-2. Cancer Cell 6:507–516

    Article  PubMed  CAS  Google Scholar 

  • Onimaru M, Yonemitsu Y, Fujii T, Tanii M, Nakano T, Nakagawa K, Kohno R, Hasegawa M, Nishikawa S, Sueishi K (2009) VEGF-C regulates lymphangiogenesis and capillary stability by regulation of PDGF-B. Am J Physiol Heart Circ Physiol 297:H1685–H1696

    Article  PubMed  CAS  Google Scholar 

  • Orlidge A, D’Amore PA (1987) Inhibition of capillary endothelial cell growth by pericytes and smooth muscle cells. J Cell Biol 105:1455–1462

    Article  PubMed  CAS  Google Scholar 

  • Oshima M, Oshima H, Taketo MM (1996) TGF-beta receptor type II deficiency results in defects of yolk sac hematopoiesis and vasculogenesis. Dev Biol 179:297–302

    Article  PubMed  CAS  Google Scholar 

  • Ostman A, Andersson M, Betsholtz C, Westermark B, Heldin CH (1991) 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 2:503–512

    PubMed  CAS  Google Scholar 

  • Ozerdem U, Stallcup WB (2003) Early contribution of pericytes to angiogenic sprouting and tube formation. Angiogenesis 6:241–249

    Article  PubMed  CAS  Google Scholar 

  • Paez JG, Janne PA, Lee JC, Tracy S, Greulich H, Gabriel S, Herman P, Kaye FJ, Lindeman N, Boggon TJ et al (2004) EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304:1497–1500

    Article  PubMed  CAS  Google Scholar 

  • Paik JH, Skoura A, Chae SS, Cowan AE, Han DK, Proia RL, Hla T (2004) Sphingosine 1-phosphate receptor regulation of N-cadherin mediates vascular stabilization. Genes Dev 18:2392–2403

    Article  PubMed  CAS  Google Scholar 

  • Paquet-Fifield S, Schluter H, Li A, Aitken T, Gangatirkar P, Blashki D, Koelmeyer R, Pouliot N, Palatsides M, Ellis S et al (2009) A role for pericytes as microenvironmental regulators of human skin tissue regeneration. J Clin Invest 119:2795–2806

    PubMed  CAS  Google Scholar 

  • Perrotte P, Matsumoto T, Inoue K, Kuniyasu H, Eve BY, Hicklin DJ, Radinsky R, Dinney CP (1999) Anti-epidermal growth factor receptor antibody C225 inhibits angiogenesis in human transitional cell carcinoma growing orthotopically in nude mice. Clin Cancer Res 5:257–265

    PubMed  CAS  Google Scholar 

  • Petit AM, Rak J, Hung MC, Rockwell P, Goldstein N, Fendly B, Kerbel RS (1997) Neutralizing antibodies against epidermal growth factor and ErbB-2/neu receptor tyrosine kinases down-regulate vascular endothelial growth factor production by tumor cells in vitro and in vivo: angiogenic implications for signal transduction therapy of solid tumors. Am J Pathol 151:1523–1530

    PubMed  CAS  Google Scholar 

  • Petrova TV, Karpanen T, Norrmen C, Mellor R, Tamakoshi T, Finegold D, Ferrell R, Kerjaschki D, Mortimer P, Yla-Herttuala S et al (2004) Defective valves and abnormal mural cell recruitment underlie lymphatic vascular failure in lymphedema distichiasis. Nat Med 10:974–981

    Article  PubMed  CAS  Google Scholar 

  • Powell DW, Mifflin RC, Valentich JD, Crowe SE, Saada JI, West AB (1999) Myofibroblasts. I. Paracrine cells important in health and disease. Am J Physiol 277:C1–C9

    PubMed  CAS  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  PubMed  CAS  Google Scholar 

  • Rangdaeng S, Truong LD (1991) Comparative immunohistochemical staining for desmin and muscle-specific actin. A study of 576 cases. Am J Clin Pathol 96:32–45

    PubMed  CAS  Google Scholar 

  • Reinmuth N, Liu W, Jung YD, Ahmad SA, Shaheen RM, Fan F, Bucana CD, McMahon G, Gallick GE, Ellis LM (2001) Induction of VEGF in perivascular cells defines a potential paracrine mechanism for endothelial cell survival. FASEB J 15:1239–1241

    PubMed  CAS  Google Scholar 

  • Rouget C (1873) Memoire sur les developpement, la structure et les proprietes physiologiques des capillaires sanguins et lymphatiques. Arch Physiol Norm Pathol 5:603–633

    Google Scholar 

  • Saharinen P, Alitalo K (2003) Double target for tumor mass destruction. J Clin Invest 111:1277–1280

    PubMed  CAS  Google Scholar 

  • Sainson RC, Aoto J, Nakatsu MN, Holderfield M, Conn E, Koller E, Hughes CC (2005) Cell-autonomous notch signaling regulates endothelial cell branching and proliferation during vascular tubulogenesis. FASEB J 19:1027–1029

    PubMed  CAS  Google Scholar 

  • Salvucci O, Maric D, Economopoulou M, Sakakibara S, Merlin S, Follenzi A, Tosato G (2009) EphrinB reverse signaling contributes to endothelial and mural cell assembly into vascular structures. Blood 114:1707–1716

    Article  PubMed  CAS  Google Scholar 

  • Sarraf-Yazdi S, Mi J, Moeller BJ, Niu X, White RR, Kontos CD, Sullenger BA, Dewhirst MW, Clary BM (2008) Inhibition of in vivo tumor angiogenesis and growth via systemic delivery of an angiopoietin 2-specific RNA aptamer. J Surg Res 146:16–23

    Article  PubMed  CAS  Google Scholar 

  • Sato Y, Rifkin DB (1989) Inhibition of endothelial cell movement by pericytes and smooth muscle cells: activation of a latent transforming growth factor-beta 1-like molecule by plasmin during co-culture. J Cell Biol 109:309–315

    Article  PubMed  CAS  Google Scholar 

  • Sato TN, Tozawa Y, Deutsch U, Wolburg-Buchholz K, Fujiwara Y, Gendron-Maguire M, Gridley T, Wolburg H, Risau W, Qin Y (1995) Distinct roles of the receptor tyrosine kinases Tie-1 and Tie-2 in blood vessel formation. Nature 376:70–74

    Article  PubMed  CAS  Google Scholar 

  • Schlingemann RO, Rietveld FJ, de Waal RM, Ferrone S, Ruiter DJ (1990) Expression of the high molecular weight melanoma-associated antigen by pericytes during angiogenesis in tumors and in healing wounds. Am J Pathol 136:1393–1405

    PubMed  CAS  Google Scholar 

  • Schlingemann RO, Rietveld FJ, Kwaspen F, van de Kerkhof PC, de Waal RM, Ruiter DJ (1991) Differential expression of markers for endothelial cells, pericytes, and basal lamina in the microvasculature of tumors and granulation tissue. Am J Pathol 138:1335–1347

    PubMed  CAS  Google Scholar 

  • Seger R, Krebs EG (1995) The MAPK signaling cascade. FASEB J 9:726–735

    PubMed  CAS  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  PubMed  CAS  Google Scholar 

  • Shepro D, Morel NM (1993) Pericyte physiology. FASEB J 7:1031–1038

    PubMed  CAS  Google Scholar 

  • Shim WS, Teh M, Mack PO, Ge R (2001) Inhibition of angiopoietin-1 expression in tumor cells by an antisense RNA approach inhibited xenograft tumor growth in immunodeficient mice. Int J Cancer 94:6–15

    Article  PubMed  CAS  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  PubMed  CAS  Google Scholar 

  • Soriano P (1994) Abnormal kidney development and hematological disorders in PDGF beta-receptor mutant mice. Genes Dev 8:1888–1896

    Article  PubMed  CAS  Google Scholar 

  • Stallcup WB, Huang FJ (2008) A role for the NG2 proteoglycan in glioma progression. Cell Adh Migr 2:192–201

    Article  PubMed  Google Scholar 

  • Stratmann A, Risau W, Plate KH (1998) Cell type-specific expression of angiopoietin-1 and angiopoietin-2 suggests a role in glioblastoma angiogenesis. Am J Pathol 153:1459–1466

    Article  PubMed  CAS  Google Scholar 

  • Sullivan CC, Du L, Chu D, Cho AJ, Kido M, Wolf PL, Jamieson SW, Thistlethwaite PA (2003) Induction of pulmonary hypertension by an angiopoietin 1/TIE2/serotonin pathway. Proc Natl Acad Sci U S A 100:12331–12336

    Article  PubMed  CAS  Google Scholar 

  • Sundberg C, Kowanetz M, Brown LF, Detmar M, Dvorak HF (2002) Stable expression of angiopoietin-1 and other markers by cultured pericytes: phenotypic similarities to a subpopulation of cells in maturing vessels during later stages of angiogenesis in vivo. Lab Invest 82:387–401

    Article  PubMed  CAS  Google Scholar 

  • Suri C, Jones PF, Patan S, Bartunkova S, Maisonpierre PC, Davis S, Sato TN, Yancopoulos GD (1996) Requisite role of angiopoietin-1, a ligand for the TIE2 receptor, during embryonic angiogenesis. Cell 87:1171–1180

    Article  PubMed  CAS  Google Scholar 

  • Thomas WE (1999) Brain macrophages: on the role of pericytes and perivascular cells. Brain Res Rev 31:42–57

    Article  PubMed  CAS  Google Scholar 

  • Timke C, Zieher H, Roth A, Hauser K, Lipson KE, Weber KJ, Debus J, Abdollahi A, Huber PE (2008) Combination of vascular endothelial growth factor receptor/platelet-derived growth factor receptor inhibition markedly improves radiation tumor therapy. Clin Cancer Res 14:2210–2219

    Article  PubMed  CAS  Google Scholar 

  • Uemura A, Ogawa M, Hirashima M, Fujiwara T, Koyama S, Takagi H, Honda Y, Wiegand SJ, Yancopoulos GD, Nishikawa S (2002) Recombinant angiopoietin-1 restores higher-order architecture of growing blood vessels in mice in the absence of mural cells. J Clin Invest 110:1619–1628

    PubMed  CAS  Google Scholar 

  • Wakui S, Furusato M, Muto T, Ohshige H, Takahashi H, Ushigome S (1997) Transforming growth factor-beta and urokinase plasminogen activator presents at endothelial cell-pericyte interdigitation in human granulation tissue. Microvasc Res 54:262–269

    Article  PubMed  CAS  Google Scholar 

  • Wesseling P, Schlingemann RO, Rietveld FJ, Link M, Burger PC, Ruiter DJ (1995) Early and extensive contribution of pericytes/vascular smooth muscle cells to microvascular proliferation in glioblastoma multiforme: an immuno-light and immuno-electron microscopic study. J Neuropathol Exp Neurol 54:304–310

    Article  PubMed  CAS  Google Scholar 

  • Yamashita J, Itoh H, Hirashima M, Ogawa M, Nishikawa S, Yurugi T, Naito M, Nakao K (2000) Flk1-positive cells derived from embryonic stem cells serve as vascular progenitors. Nature 408:92–96

    Article  PubMed  CAS  Google Scholar 

  • Zeisberg EM, Tarnavski O, Zeisberg M, Dorfman AL, McMullen JR, Gustafsson E, Chandraker A, Yuan X, Pu WT, Roberts AB et al (2007) Endothelial-to-mesenchymal transition contributes to cardiac fibrosis. Nat Med 13:952–961

    Article  PubMed  CAS  Google Scholar 

  • Zeisberg EM, Potenta SE, Sugimoto H, Zeisberg M, Kalluri R (2008) Fibroblasts in kidney fibrosis emerge via endothelial-to-mesenchymal transition. J Am Soc Nephrol 19:2282–2287

    Article  PubMed  Google Scholar 

  • Zengin E, Chalajour F, Gehling UM, Ito WD, Treede H, Lauke H, Weil J, Reichenspurner H, Kilic N, Ergun S (2006) Vascular wall resident progenitor cells: a source for postnatal vasculogenesis. Development 133:1543–1551

    Article  PubMed  CAS  Google Scholar 

  • Zhang L, Yang N, Park JW, Katsaros D, Fracchioli S, Cao G, O’Brien-Jenkins A, Randall TC, Rubin SC, Coukos G (2003) Tumor-derived vascular endothelial growth factor up-regulates angiopoietin-2 in host endothelium and destabilizes host vasculature, supporting angiogenesis in ovarian cancer. Cancer Res 63:3403–3412

    PubMed  CAS  Google Scholar 

  • Zimmermann KW (1923) Der feinere Bau der Blutkapillaren. Z Anat Entwicklungsgesch 68:3–109

    Article  Google Scholar 

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Authors and Affiliations

  1. Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ-ZMBH Alliance), 69120, Heidelberg, Germany

    Arne Bartol & Anna M. Laib

  2. Heidelberg University, Medical Faculty Mannheim, Vascular Biology and Tumor Angiogenesis, 68167, Mannheim, Germany

    Arne Bartol

  3. Joint Research Division Vascular Biology of the Medical Faculty Mannheim (CBTM), University of Heidelberg, and the German Cancer Research Center (DKFZ-ZMBH Alliance), University of Heidelberg and German Cancer Research Institute, 69120, Heidelberg, Germany

    Hellmut G. Augustin

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  1. Arne Bartol
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  2. Anna M. Laib
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Correspondence to Arne Bartol .

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    Margareta M. Mueller

  2. Am Pferchelhang 32, Heidelberg, 69118, Germany

    Norbert E. Fusenig

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Bartol, A., Laib, A.M., Augustin, H.G. (2011). Tumor Vessel Associated-Pericytes. 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_5

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