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Medical Oncology

, 32:202 | Cite as

Pericytes in sarcomas of bone

  • Le Chang
  • Vi Nguyen
  • Alan Nguyen
  • Michelle A. Scott
  • Aaron W. JamesEmail author
Review Paper
  • 288 Downloads

Abstract

Pericytes are mesenchymal cells that closely enwrap small blood vessels, lying in intimate association with the endothelium. Pericytes have recently gained attention as an important mediator of vascular biology and angiogenesis in cancer. Although better studied in carcinoma, pericytes have known interaction with sarcomas of bone, including Ewing’s sarcoma, osteosarcoma, and chondrosarcoma. Best studied is Ewing’s sarcoma (ES), which displays a prominent perivascular growth pattern. Signaling pathways of known importance in intratumoral pericytes in ES include Notch, PDGF/PDGFR-β, and VEGF signaling. In summary, pericytes serve important functions in the tumor microenvironment. Improved understanding of pericyte biology may hold significant implications for the development of new therapies in sarcoma.

Keywords

Pericyte Ewing’s sarcoma Osteosarcoma Chondrosarcoma Notch pathway Platelet-derived growth factor beta PDGF Vascular endothelial growth factor VEGF 

Notes

Acknowledgments

The present work was supported by the UCLA Department of Pathology and Laboratory Medicine, the UCLA Daljit S. and Elaine Sarkaria Fellowship award, and the Orthopaedic Research and Education Foundation with funding provided by the Musculoskeletal Transplant Foundation. The authors thank A. S. James for his excellent technical assistance.

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Risau W. Mechanisms of angiogenesis. Nature. 1997;386(6626):671–4.PubMedCrossRefGoogle Scholar
  2. 2.
    Betsholtz C, Lindblom P, Gerhardt H. Role of pericytes in vascular morphogenesis. EXS. 2005;94:115–25.PubMedGoogle Scholar
  3. 3.
    Bergers G, Benjamin LE. Tumorigenesis and the angiogenic switch. Nat Rev Cancer. 2003;3(6):401–10.PubMedCrossRefGoogle Scholar
  4. 4.
    Armulik A, Abramsson A, Betsholtz C. Endothelial/pericyte interactions. Circ Res. 2005;97(6):512–23.PubMedCrossRefGoogle Scholar
  5. 5.
    Hirschi KK, D’Amore PA. Pericytes in the microvasculature. Cardiovasc Res. 1996;32(4):687–98.PubMedCrossRefGoogle Scholar
  6. 6.
    Stark K, et al. Capillary and arteriolar pericytes attract innate leukocytes exiting through venules and ‘instruct’ them with pattern-recognition and motility programs. Nat Immunol. 2013;14(1):41–51.PubMedCrossRefGoogle Scholar
  7. 7.
    Schönfelder U, et al. In situ observation of living pericytes in rat retinal capillaries. Microvasc Res. 1998;56(1):22–9.PubMedCrossRefGoogle Scholar
  8. 8.
    Lindahl P, et al. Pericyte loss and microaneurysm formation in PDGF-B-deficient mice. Science. 1997;277(5323):242–5.PubMedCrossRefGoogle Scholar
  9. 9.
    Hellström M, et al. Lack of pericytes leads to endothelial hyperplasia and abnormal vascular morphogenesis. J Cell Biol. 2001;153(3):543–53.PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    Abramsson A, et al. Analysis of mural cell recruitment to tumor vessels. Circulation. 2002;105(1):112–7.PubMedCrossRefGoogle Scholar
  11. 11.
    Cooke VG, 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.PubMedCentralPubMedCrossRefGoogle Scholar
  12. 12.
    Xian X, et al. Pericytes limit tumor cell metastasis. J Clin Invest. 2006;116(3):642–51.PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    Lindblom P, et al. Endothelial PDGF-B retention is required for proper investment of pericytes in the microvessel wall. Genes Dev. 2003;17(15):1835–40.PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Potente M, Gerhardt H, Carmeliet P. Basic and therapeutic aspects of angiogenesis. Cell. 2011;146(6):873–87.PubMedCrossRefGoogle Scholar
  15. 15.
    Armulik A, Genove G, Betsholtz C. Pericytes: developmental, physiological, and pathological perspectives, problems, and promises. Dev Cell. 2011;21(2):193–215.PubMedCrossRefGoogle Scholar
  16. 16.
    Shih SC, et al. Transforming growth factor beta1 induction of vascular endothelial growth factor receptor 1: mechanism of pericyte-induced vascular survival in vivo. Proc Natl Acad Sci USA. 2003;100(26):15859–64.PubMedCentralPubMedCrossRefGoogle Scholar
  17. 17.
    Ozerdem U, et al. NG2 proteoglycan is expressed exclusively by mural cells during vascular morphogenesis. Dev Dyn. 2001;222(2):218–27.PubMedCrossRefGoogle Scholar
  18. 18.
    Greenhalgh SN, Iredale JP, Henderson NC, Origins of fibrosis: pericytes take centre stage. F1000Prime Rep. 2013;5:37.Google Scholar
  19. 19.
    Schrimpf C, Duffield JS. Mechanisms of fibrosis: the role of the pericyte. Curr Opin Nephrol Hypertens. 2011;20(3):297–305.PubMedCrossRefGoogle Scholar
  20. 20.
    Dulmovits BM, Herman IM. Microvascular remodeling and wound healing: a role for pericytes. Int J Biochem Cell Biol. 2012;44(11):1800–12.PubMedCentralPubMedCrossRefGoogle Scholar
  21. 21.
    Quaegebeur A, Segura I, Carmeliet P. Pericytes: blood-brain barrier safeguards against neurodegeneration? Neuron. 2010;68(3):321–3.PubMedCrossRefGoogle Scholar
  22. 22.
    Farrington-Rock C, et al. Chondrogenic and adipogenic potential of microvascular pericytes. Circulation. 2004;110(15):2226–32.PubMedCrossRefGoogle Scholar
  23. 23.
    Paquet-Fifield S, et al. A role for pericytes as microenvironmental regulators of human skin tissue regeneration. J Clin Invest. 2009;119(9):2795–806.PubMedCentralPubMedGoogle Scholar
  24. 24.
    Murray IR, et al. Natural history of mesenchymal stem cells, from vessel walls to culture vessels. Cell Mol Life Sci. 2014;71(8):1353–74.PubMedCrossRefGoogle Scholar
  25. 25.
    Gerhardt H, Semb H. Pericytes: gatekeepers in tumour cell metastasis? J Mol Med (Berl). 2008;86(2):135–44.CrossRefGoogle Scholar
  26. 26.
    Morikawa S, et al. Abnormalities in pericytes on blood vessels and endothelial sprouts in tumors. Am J Pathol. 2002;160(3):985–1000.PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    Cao Y, et al. Pericyte coverage of differentiated vessels inside tumor vasculature is an independent unfavorable prognostic factor for patients with clear cell renal cell carcinoma. Cancer. 2013;119(2):313–24.PubMedCrossRefGoogle Scholar
  28. 28.
    Xu L, et al. Blocking platelet-derived growth factor-D/platelet-derived growth factor receptor beta signaling inhibits human renal cell carcinoma progression in an orthotopic mouse model. Cancer Res. 2005;65(13):5711–9.PubMedCrossRefGoogle Scholar
  29. 29.
    Paulsson J, 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.PubMedCentralPubMedCrossRefGoogle Scholar
  30. 30.
    Kitadai Y, 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.PubMedCrossRefGoogle Scholar
  31. 31.
    Wang W, et al. Effect of platelet-derived growth factor-B on renal cell carcinoma growth and progression. Urol Oncol. 2015;33(4):168.e17–27.Google Scholar
  32. 32.
    Minami Y, et al. Prostaglandin I2 analog suppresses lung metastasis by recruiting pericytes in tumor angiogenesis. Int J Oncol. 2015;46(2):548–54.PubMedGoogle Scholar
  33. 33.
    Delattre O, et al. The Ewing family of tumors–a subgroup of small-round-cell tumors defined by specific chimeric transcripts. N Engl J Med. 1994;331(5):294–9.PubMedCrossRefGoogle Scholar
  34. 34.
    Downing JR, et al. Detection of the (11;22)(q24;q12) translocation of Ewing’s sarcoma and peripheral neuroectodermal tumor by reverse transcription polymerase chain reaction. Am J Pathol. 1993;143(5):1294–300.PubMedCentralPubMedGoogle Scholar
  35. 35.
    Maheshwari AV, Cheng EY. Ewing sarcoma family of tumors. J Am Acad Orthop Surg. 2010;18(2):94–107.PubMedGoogle Scholar
  36. 36.
    Subbiah V, et al. Ewing’s sarcoma: standard and experimental treatment options. Curr Treat Options Oncol. 2009;10(1–2):126–40.PubMedCrossRefGoogle Scholar
  37. 37.
    Yu L, et al. Vasculogenesis driven by bone marrow-derived cells is essential for growth of Ewing’s sarcomas. Cancer Res. 2010;70(4):1334–43.PubMedCentralPubMedCrossRefGoogle Scholar
  38. 38.
    Reddy K, et al. Bone marrow subsets differentiate into endothelial cells and pericytes contributing to Ewing’s tumor vessels. Mol Cancer Res. 2008;6(6):929–36.PubMedCentralPubMedCrossRefGoogle Scholar
  39. 39.
    Zhou Z, et al. Bone marrow cells participate in tumor vessel formation that supports the growth of Ewing’s sarcoma in the lung. Angiogenesis. 2011;14(2):125–33.PubMedCentralPubMedCrossRefGoogle Scholar
  40. 40.
    Gridley T. Notch signaling in the vasculature. Curr Top Dev Biol. 2010;92:277–309.PubMedCentralPubMedCrossRefGoogle Scholar
  41. 41.
    Roca C, Adams RH. Regulation of vascular morphogenesis by Notch signaling. Genes Dev. 2007;21(20):2511–24.PubMedCrossRefGoogle Scholar
  42. 42.
    Shawber CJ, Kitajewski J. Notch function in the vasculature: insights from zebrafish, mouse and man. BioEssays. 2004;26(3):225–34.PubMedCrossRefGoogle Scholar
  43. 43.
    Thomas JL, et al. Interactions between VEGFR and Notch signaling pathways in endothelial and neural cells. Cell Mol Life Sci. 2013;70(10):1779–92.PubMedCentralPubMedCrossRefGoogle Scholar
  44. 44.
    Villa N, et al. Vascular expression of Notch pathway receptors and ligands is restricted to arterial vessels. Mech Dev. 2001;108(1–2):161–4.PubMedCrossRefGoogle Scholar
  45. 45.
    Liu H, Kennard S, Lilly B. NOTCH3 expression is induced in mural cells through an autoregulatory loop that requires endothelial-expressed JAGGED1. Circ Res. 2009;104(4):466–75.PubMedCentralPubMedCrossRefGoogle Scholar
  46. 46.
    Kofler NM, et al. Notch signaling in developmental and tumor angiogenesis. Genes Cancer. 2011;2(12):1106–16.PubMedCentralPubMedCrossRefGoogle Scholar
  47. 47.
    Zhou Z, Yu L, Kleinerman ES. EWS-FLI-1 regulates the neuronal repressor gene REST, which controls Ewing sarcoma growth and vascular morphology. Cancer. 2014;120(4):579–88.PubMedCentralPubMedCrossRefGoogle Scholar
  48. 48.
    Stewart KS, et al. Delta-like ligand 4-Notch signaling regulates bone marrow-derived pericyte/vascular smooth muscle cell formation. Blood. 2011;117(2):719–26.PubMedCentralPubMedCrossRefGoogle Scholar
  49. 49.
    Schadler KL, et al. Delta-like ligand 4 plays a critical role in pericyte/vascular smooth muscle cell formation during vasculogenesis and tumor vessel expansion in Ewing’s sarcoma. Clin Cancer Res. 2010;16(3):848–56.PubMedCentralPubMedCrossRefGoogle Scholar
  50. 50.
    Dufraine J, Funahashi Y, Kitajewski J. Notch signaling regulates tumor angiogenesis by diverse mechanisms. Oncogene. 2008;27(38):5132–7.PubMedCentralPubMedCrossRefGoogle Scholar
  51. 51.
    Rehman AO, Wang CY. Notch signaling in the regulation of tumor angiogenesis. Trends Cell Biol. 2006;16(6):293–300.PubMedCrossRefGoogle Scholar
  52. 52.
    Lindahl P, et al. Pericyte loss and microaneurysm formation in PDGF-B-deficient mice. Science. 1997;277(5323):242–5.PubMedCrossRefGoogle Scholar
  53. 53.
    Bergers G, Song S. The role of pericytes in blood-vessel formation and maintenance. Neuro Oncol. 2005;7(4):452–64.PubMedCentralPubMedCrossRefGoogle Scholar
  54. 54.
    Uren A, et al. Beta-platelet-derived growth factor receptor mediates motility and growth of Ewing’s sarcoma cells. Oncogene. 2003;22(15):2334–42.PubMedCrossRefGoogle Scholar
  55. 55.
    Wang YX, et al. Inhibiting platelet-derived growth factor beta reduces Ewing’s sarcoma growth and metastasis in a novel orthotopic human xenograft model. In Vivo. 2009;23(6):903–9.PubMedGoogle Scholar
  56. 56.
    González I, et al. Imatinib inhibits proliferation of Ewing tumor cells mediated by the stem cell factor/KIT receptor pathway, and sensitizes cells to vincristine and doxorubicin-induced apoptosis. Clin Cancer Res. 2004;10(2):751–61.PubMedCrossRefGoogle Scholar
  57. 57.
    Merchant MS, et al. Potential use of imatinib in Ewing’s Sarcoma: evidence for in vitro and in vivo activity. J Natl Cancer Inst. 2002;94(22):1673–9.PubMedCrossRefGoogle Scholar
  58. 58.
    Bond M, et al. A phase II study of imatinib mesylate in children with refractory or relapsed solid tumors: a Children’s Oncology Group study. Pediatr Blood Cancer. 2008;50(2):254–8.PubMedCrossRefGoogle Scholar
  59. 59.
    Chao J, et al. Phase II clinical trial of imatinib mesylate in therapy of KIT and/or PDGFRalpha-expressing Ewing sarcoma family of tumors and desmoplastic small round cell tumors. Anticancer Res. 2010;30(2):547–52.PubMedGoogle Scholar
  60. 60.
    Chugh R, et al. Phase II multicenter trial of imatinib in 10 histologic subtypes of sarcoma using a bayesian hierarchical statistical model. J Clin Oncol. 2009;27(19):3148–53.PubMedCrossRefGoogle Scholar
  61. 61.
    Dubois SG, et al. Phase I and pharmacokinetic study of sunitinib in pediatric patients with refractory solid tumors: a children’s oncology group study. Clin Cancer Res. 2011;17(15):5113–22.PubMedCentralPubMedCrossRefGoogle Scholar
  62. 62.
    Wang Y, et al. Platelet-derived growth factor receptor beta inhibition increases tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) sensitivity: imatinib and TRAIL dual therapy. Cancer. 2010;116(16):3892–902.PubMedCrossRefGoogle Scholar
  63. 63.
    Reddy K, et al. Stromal cell-derived factor-1 stimulates vasculogenesis and enhances Ewing’s sarcoma tumor growth in the absence of vascular endothelial growth factor. Int J Cancer. 2008;123(4):831–7.PubMedCentralPubMedCrossRefGoogle Scholar
  64. 64.
    Hamdan R, Zhou Z, Kleinerman ES. Blocking SDF-1alpha/CXCR4 downregulates PDGF-B and inhibits bone marrow-derived pericyte differentiation and tumor vascular expansion in Ewing tumors. Mol Cancer Ther. 2014;13(2):483–91.PubMedCentralPubMedCrossRefGoogle Scholar
  65. 65.
    Hagedorn M, et al. VEGF coordinates interaction of pericytes and endothelial cells during vasculogenesis and experimental angiogenesis. Dev Dyn. 2004;230(1):23–33.PubMedCrossRefGoogle Scholar
  66. 66.
    Reddy K, et al. VEGF165 expression in the tumor microenvironment influences the differentiation of bone marrow-derived pericytes that contribute to the Ewing’s sarcoma vasculature. Angiogenesis. 2008;11(3):257–67.PubMedCentralPubMedCrossRefGoogle Scholar
  67. 67.
    Lee TH, et al. Production of VEGF165 by Ewing’s sarcoma cells induces vasculogenesis and the incorporation of CD34 + stem cells into the expanding tumor vasculature. Int J Cancer. 2006;119(4):839–46.PubMedCrossRefGoogle Scholar
  68. 68.
    Zhou Z, et al. Suppression of Ewing’s sarcoma tumor growth, tumor vessel formation, and vasculogenesis following anti vascular endothelial growth factor receptor-2 therapy. Clin Cancer Res. 2007;13(16):4867–73.PubMedCrossRefGoogle Scholar
  69. 69.
    Greenberg JI, et al. A role for VEGF as a negative regulator of pericyte function and vessel maturation. Nature. 2008;456(7223):809–13.PubMedCentralPubMedCrossRefGoogle Scholar
  70. 70.
    Glade Bender JL, et al. Phase I trial and pharmacokinetic study of bevacizumab in pediatric patients with refractory solid tumors: a Children’s Oncology Group Study. J Clin Oncol. 2008;26(3):399–405.PubMedCrossRefGoogle Scholar
  71. 71.
    Widemann BC, et al. A phase I trial and pharmacokinetic study of sorafenib in children with refractory solid tumors or leukemias: a Children’s Oncology Group Phase I Consortium report. Clin Cancer Res. 2012;18(21):6011–22.PubMedCentralPubMedCrossRefGoogle Scholar
  72. 72.
    Ottaviani G, Jaffe N. The epidemiology of osteosarcoma. Cancer Treat Res. 2009;152:3–13.PubMedCrossRefGoogle Scholar
  73. 73.
    Rytting M, et al. Osteosarcoma in preadolescent patients. Clin Orthop Relat Res. 2000;373:39–50.PubMedCrossRefGoogle Scholar
  74. 74.
    Ferguson WS, Goorin AM. Current treatment of osteosarcoma. Cancer Invest. 2001;19(3):292–315.PubMedCrossRefGoogle Scholar
  75. 75.
    Fletcher CDM, et al. World health organization classifications of tumours of soft tissue and bone. Lyon: International Agency for Research on Cancer; 2013.Google Scholar
  76. 76.
    Leddy LR, Holmes RE. Chondrosarcoma of bone. Cancer Treat Res. 2014;162:117–30.PubMedCrossRefGoogle Scholar
  77. 77.
    Hemingway F, et al. Smooth muscle actin expression in primary bone tumours. Virchows Arch. 2012;460(5):525–34.PubMedCrossRefGoogle Scholar
  78. 78.
    McGary EC, et al. Inhibition of platelet-derived growth factor-mediated proliferation of osteosarcoma cells by the novel tyrosine kinase inhibitor STI571. Clin Cancer Res. 2002;8(11):3584–91.PubMedGoogle Scholar
  79. 79.
    Kalinski T, et al. Heterogeneity of angiogenesis and blood vessel maturation in cartilage tumors. Pathol Res Pract. 2009;205(5):339–45.PubMedCrossRefGoogle Scholar
  80. 80.
    Engin F, et al. Notch signaling contributes to the pathogenesis of human osteosarcomas. Hum Mol Genet. 2009;18(8):1464–70.PubMedCentralPubMedCrossRefGoogle Scholar
  81. 81.
    Zhang P, et al. Regulation of NOTCH signaling by reciprocal inhibition of HES1 and Deltex 1 and its role in osteosarcoma invasiveness. Oncogene. 2010;29(20):2916–26.PubMedCentralPubMedCrossRefGoogle Scholar
  82. 82.
    Hughes DP. How the NOTCH pathway contributes to the ability of osteosarcoma cells to metastasize. Cancer Treat Res. 2009;152:479–96.PubMedCrossRefGoogle Scholar
  83. 83.
    Tanaka M, et al. Inhibition of Notch pathway prevents osteosarcoma growth by cell cycle regulation. Br J Cancer. 2009;100(12):1957–65.PubMedCentralPubMedCrossRefGoogle Scholar
  84. 84.
    Kuzmanov A, et al. Overexpression of factor inhibiting HIF-1 enhances vessel maturation and tumor growth via platelet-derived growth factor-C. Int J Cancer. 2012;131(5):E603–13.PubMedCrossRefGoogle Scholar
  85. 85.
    Niu F, et al. Identification and functional analysis of differentially expressed genes related to metastatic osteosarcoma. Asian Pac J Cancer Prev. 2014;15(24):10797–801.PubMedCrossRefGoogle Scholar
  86. 86.
    Maniscalco L, et al. PDGFs and PDGFRs in canine osteosarcoma: new targets for innovative therapeutic strategies in comparative oncology. Vet J. 2013;195(1):41–7.PubMedCrossRefGoogle Scholar
  87. 87.
    Franchi A, et al. Dedifferentiated peripheral chondrosarcoma: a clinicopathologic, immunohistochemical, and molecular analysis of four cases. Virchows Arch. 2012;460(3):335–42.PubMedCrossRefGoogle Scholar
  88. 88.
    Sulzbacher I, et al. Platelet-derived growth factor-alpha receptor expression supports the growth of conventional chondrosarcoma and is associated with adverse outcome. Am J Surg Pathol. 2001;25(12):1520–7.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Le Chang
    • 1
  • Vi Nguyen
    • 1
  • Alan Nguyen
    • 1
  • Michelle A. Scott
    • 2
  • Aaron W. James
    • 1
    Email author
  1. 1.Department of Pathology and Laboratory Medicine, David Geffen School of MedicineUniversity of California, Los AngelesLos AngelesUSA
  2. 2.Nationwide Children’s HospitalColumbusUSA

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