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Thrombospondin-1과 종양형성 억제작용

Thrombospondin-1 and Inhibition of Tumor Growth

정구보
대한체질인류학회|2015.12|해부·생물인류학 (Anatomy & Biological Anthropology)|제28권 제4호|pp. 175-184|DOI 10.11637/aba.2015.28.4.175

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참고문헌

키워드

VEGF혈관내피세포Endothelial cellsAngiogenesisVEGFR2CD36TSP-1신혈관형성CD47Thrombospondin-1
주제분류해부학

초록

Thrombospondin-1 (TSP-1)은 여러 가지 세포 수용체를 통해 혈관내피세포 및 암세포의 활성을 조절할 수 있는 다양한 기능을 갖는 단백질로 신혈관형성을 억제하며, 혈관내피세포와 암세포의 부착, 세포증식, 이동 및 세포의 생존 등을 조절한다. 또한 여러 연구자들에 의해 TSP-1의 발현을 증가시키면 종양의 성장과 전이가 억제되고 신혈관형성이 차단됨이 확인되었다. 신혈관형성 억제제는 지난 30년간 VEGF (vascular endothelial growth factor)의 신호전달기전을 차단하는 억제제를 중심으로 개발되어 왔으며 tyrosine kinase의 저분자 억제제들이 치료제로 승인되었다. TSP-1은여러 가지 기능성 도메인을 갖고 있어서 CD36과 CD47 수용체를 통해 종양의 신혈관형성을 억제한다. TSP-1은 CD47 과의 결합을 통해 VEGFR2의 인산화를 억제하고 하위신호전달 물질인 AKT 활성화를 차단하여 혈관내피세포에 대한VEGF의 작용을 억제한다. 최근 CD47 수용체에 결합하는 단클론항체를 이용하여 CD47 수용체의 작용을 차단하면큰포식세포와 세포독성 T 림프구의 작용을 활성화하여 암세포를 제거할 수 있다는 사실이 밝혀졌다. 이러한 사실들은TSP-1에 의해 암세포를 제거하고 종양의 혈관형성을 억제할 수 있는 새로운 시대가 도래하고 있음을 시사하는 것이다.

Abstract

Thrmobospondin-1 is the multifunctional protein that modulates endothelial cell and tumor cell behavior via several cell surface receptors and inhibits angiogenesis. In vitro, thrombospondin-1 alters adhesion, proliferation, motility, and survival of endothelial and cancer cells. Studies have confirmed that increased TSP-1 expression suppresses growth or metastasis of some tumors and inhibits angiogenesis. In the past three decades, inhibitors of angiogenesis have been developed as regulators target the vascular endothelial growth factor (VEGF) signaling pathway and small molecule tyrosine kinase inhibitors have been clinically approved. TSP-1 has several functional domain structures and inhibits tumor angiogenesis by engaging receptors CD36 and CD47. TSP-1 binding to CD47 dissociates it from VEGFR2, inhibiting downstream AKT activation and functional responses of endothelial cells to VEGF. Recently, macrophage phagocytosis and cytotoxic T-cell induction of tumor cells mediated by CD47-specific blocking antibodies have been proposed. These findings provide a new therapeutic paradigm for elinination of cancer cells and inhibition of angiogenesis of tumor by TSP-1.

참고문헌 (56)

  1. Folkman J, "Tumor angiogenesis : therapeutic implications", New Eng J Med, 285, pp.1182~1186 (1971)
  2. Cook KM., "Angiogenesis inhibitors : current strategies and future prospects", CA Cancer J Clin, 60, pp.222~243 (2010)
  3. Bergers G., "Tumorigenesis and the angiogenic switch", Nat Rev Cancer, 3, pp.401~410 (2003)
  4. Folkman J, "What is the evidence that tumors are angiogenesis dependent?", J Natl Cancer Inst, 82, pp.4~6 (1990)
  5. Verheul HM., "Are tumors angiogenesis-dependent?", J Pathol, 202, pp.5~13 (2004)
  6. Folkman J, "Angiogenesis: an organizing principle for drug discovery?", Nat Rev Drug Discov, 6, pp.273~286 (2007)
  7. Faivre S., "Molecular basis for sunitinib efficacy and future clinical development", Nat Rev Drug Discov, 6, pp.734~745 (2007)
  8. Wilhelm S., "Discovery and development of sorafenib : a multikinase inhibitor for treating cancer", Nat Rev Drug Discov, 5, pp.835~844 (2006)
  9. Motzer RJ., "Targeted therapy for metastatic renal cell carcinoma", J Clin Oncol, 24, pp.5601~5608 (2006)
  10. Bergers G., "Modes of resistance to anti-angiogenic therapy", Nat Rev Cancer, 8, pp.592~603 (2008)
  11. Verheul HM., "Possible molecular mechanisms involved in the toxicity of angiogenesis inhibition", Nat Rev Cancer, 7, pp.475~485 (2007)
  12. Urbich C., "Role of microRNAs in vascular diseases, inflammation, and angiogenesis", Cardiovasc Res, 79, pp.581~588 (2008)
  13. Wang S., "The endothelial-specific microRNA miR-126 governs vascular integrity and angiogenesis", Dev Cell, 15, pp.261~271 (2008)
  14. Wang S., "AngiomiRs-key regulators of angiogenesis", Curr Opin Genet Dev, 19, pp.205~211 (2009)
  15. Albelda SM, "Role of integrins and other cell adhesion molecules in tumor progression and metastasis", Lab Invest, 68, pp.4~17 (1993)
  16. Roberts DD, "Regulaton of tumor growth and metastasis by thrombospondin-1", FASEB J, 10, pp.1183~1191 (1996)
  17. Morandi V., "Role of thrombospondin in the adhesion of human endothelial cells in primary culture", In Vitro Cell Dev Biol Anim, 29, pp.585~591 (1993)
  18. Dreyfus M., "An apparent dependence on synthesis and on preformed fibrillar matrix", Eur J Cell Biol, 47, pp.275~282 (1988)
  19. Lawler J, "The functions of thrombospondin-1 and -2", Curr Opin Cell Biol, 2, pp.634~640 (2000)
  20. Wang TN., "The effect of thrombospondin on oral squamous carcinoma cell invasion of collagen", Am J Surg, 170, pp.502~505 (1995)
  21. Lawler J., "Thrombin and chymotrypsin interactions with thrombospondin", Ann NY Acd Sci, 485, pp.273~287 (1986)
  22. Bein K., "Regulation of metalloproteinase activity", J Biol Chem, 275, pp.32167~32173 (2000)
  23. Iruela-Arispe ML., "Inhibition of angiogenesis by thrombospondin-1 is mediated by 2 independent regions within the type 1repeats", Circulation, 100, pp.1423~1431 (1999)
  24. Chen H., "Metabolism of thrombospondin 2. Binding and degradation by 3t3 cells and glycosaminoglycan-variant Chinese hamster ovary cells", J Biol Chem, 271, pp.15993~15999 (1996)
  25. Murphy-Ullrich JE., "Transforming growth factor-beta complexes with thrombospondin", Mol Biol Cell, 3, pp.181~188 (1992)
  26. Ribeiro SM., "The activation sequence of thrombospondin-1 interacts with the latency-associated peptide to regulate activation of latent transforming growth factorbeta", J Biol Chem, 274, pp.13586~13593 (1999)
  27. Good DJ., "A tumor suppressor-dependent inhibitor of angiogenesis is immunologically and functionally indistinguishable from a fragment of thrombospondin", Proc Natl Acad Sci USA, 87, pp.6624~6628 (1990)
  28. Tolsma SS., "Peptides derived from two separate domains of the matrix protein thrombospondin-1 have anti-angiogenic activity", J Cell Biol, 122, pp.497~511 (1993)
  29. Dawson DW., "Thrombospondin as an inhibitor of angiogenesis. In Antiangiogenic agents in cancer therapy", pp.185~203 (1999), Human Press Inc
  30. Kyriakides TR., "Mice that lack the angiogenesis inhibitor, thrombospondin-2, mount an altered foreign body reaction characterized by increased vascularity", Proc Natl Acd Sci USA, 96, pp.4449~4454 (1999)
  31. Weinstat-Saslow DL., "Transfection of thrombospondin 1 complementary DNA into a human breast carcinoma cell line reduces primary tumor growth, metastatic potential and angiogenesis", Cancer Res, 54, pp.6504~6511 (1994)
  32. Bleuel K., "Tumor suppression in human skin carcinoma cells by chromosome 15 transfer or thrombospondin-1 overexpression through halted tumor vascularization", Proc Natl Acad Sci USA, 96, pp.2065~2070 (1999)
  33. Streit M., "Thrombospondin-2 : a potent endogenous inhibitor of tumor growth and angiogenesis", Proc Natl Acad Sci USA, 96, pp.14888~14893 (1999)
  34. Greenwalt DE., "Membrane glycoprotein CD36 : A review of its roles in adherence, signal transduction, and transfusion medicine", Blood, 80, pp.1105~1115 (1992)
  35. Jimenez B., "Signals leading to apoptosis-dependent inhibition of neovascularization by thrombospondin-1", Nat Med, 6, pp.41~48 (2000)
  36. Vogel T., "Modulation of endothelial cell proliferation, adhesion, and motility by recombinant heparin-binding domain and synthetic peptides from the type 1 repeats of thrombospondin", J Cell Biochem, 53, pp.74~84 (1993)
  37. Kanda S., "Role of thrombospondin-1-derived peptide, 4N1K, in FGF-2-induced angiogenesis", Exp Cell Res, 252, pp.262~272 (1999)
  38. Roberts., "The matricellular protein thrombospondin-1 globally regulates cardiovascular function and responses to stress via CD47", Matrix Biol, 31, pp.162~169 (2012)
  39. Isenberg JS., "Regulation of nitric oxide signalling by thrombospondin 1 : implications for anti-angiogenic therapies", Nat Rev Cancer, 9, pp.182~194 (2009)
  40. Kaur S., "Thrombospondin-1 inhibits VEGF receptor-2 signaling by disrupting its association with CD47", J Biol Chem, 285, pp.38923~38932 (2010)
  41. Gardai SJ., "Cell-surface calreticulin initiates clearance of viable or apoptotic cells through transactivation of LRP on the phagocyte", Cell, 123, pp.321~334 (2005)
  42. Chao MP., "Calreticulin is the dominant pro-phagocytic signal on multiple human cancers andis counterbalanced by CD47", Sci Transl Med, 2, pp.63ra94~ (2010)
  43. Chao MP., "Programmed cell removal : a new obstacle in the road to developing cancer", Nat Rev Cancer, 12, pp.58~67 (2011)
  44. Oldenborg PA., "Role of CD47 as a marker of self on red blood cells", Science, 288, pp.2051~2054 (2000)
  45. Blazar BR., "CD47(integrin-associated protein)engagement of dendritic cell and macrophage counterreceptors is required to prevent the clearance of donor lymphohematopoietic cells", J Exp Med, 194, pp.541~549 (2001)
  46. Barclay AN., "The interaction between signal regulatory protein alpha(SIRPα)and CD47 : structure, function, and therapeutic target", Annu Rev Immunol, 32, pp.25~50 (2014)
  47. Yamao T., "Negative regulation of platelet clearance and of the macrophage phagocytic response by the transmembrane glycoprotein SHPS-1", J Biol Chem, 277, pp.39833~39839 (2002)
  48. Olsson M., "Platelet homeostasis is regulated by platelet expression of CD47 under normal conditions and in passive immune thrombocytopenia", Blood, 105, pp.3577~3582 (2005)
  49. Jaiswal S., "CD47 is upregulated on circulating hematopoietic stem cells and leukemia cells to avoid phagocytosis", Cell, 138, pp.271~285 (2009)
  50. Majeti R., "CD47 is an adverse prognostic factor and therapeutic antibody target on human acute myeloid leukemia stem cells", Cell, 138, pp.286~299 (2009)
  51. Rendtlew Danielsen JM., "Dysregulation of CD47 and the ligands thrombospondin 1 and 2 in multiple myeloma", Br J Haematol, 138, pp.756~760 (2007)
  52. Chan KS., "Identification, molecular characterization, clinical prognosis, and therapeutic targeting of human bladder tumorinitiating cells", Proc Natl Acad Sci USA, 106, pp.14016~14021 (2009)
  53. Chan KS., "Cancer stem cells in bladder cancer : a revisited and evolving concept", Curr Opin Urol, 20, pp.393~397 (2010)
  54. Liu X., "CD47 blockade triggers T cell-mediated destruction of immunogenic tumors", Nat Med, 21, pp.1209~1215 (2015)
  55. Kaur S, "Thrombospondin-1 signaling through CD47 inhibits self renewal by regulating c-myc and other stem cell transcription factors", Sci Rep, 3, pp.1673~ (2013)[DOI]
  56. Wang W., "MicroRNAs in tumor angiogenesis", Life Sci, 136, pp.28~35 (2015)

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Thrombospondin-1 첫 번째 type I repeat 펩티드의 신혈관형성 억제작용유보임, 정구보대한체질인류학회 · 해부·생물인류학2015 · 제28권 제4호간세포암종에서 Thrombospondin-1 및 -2의 발현: 종양 혈관신생 및 p53 과발현과의 연관성강명재, 문우성, 박호성, 손현진, 정재신대한병리학회 · Journal of Pathology and Translational Medicine2005 · 제39권 제4호윤성 자궁경부암에서 내피성장인자 (Vascular endothelial growth factor: VEGF), Trombospodin-1 mRNA 발현과 미세혈관밀도의 상관관계에 대한 연구이선경, 이지은, 지성길대한산부인과학회 · Obstetrics & Gynecology Science2006 · 제49권 제12호Thrombospondin-1 이 골조직 세포의성장과 활성에 미치는 영향고선일, Boo-Nyun Kim, Se-WonKim대한구강해부학회 · 대한구강해부학회지2005 · 제29권 제1호침윤성 자궁경부암에서 Thrombospondin-1 mRNA 발현의 신생혈관형성과 임상병리학적 인자와의 상관관계김승보, 김여홍, 이선경, 이주희, 지성길대한산부인과학회 · Obstetrics & Gynecology Science2003 · 제46권 제11호자궁경부암에서 p73 과발현과 Vascular Endothelial Growth Factor (VEGF) 및 Thrombospondin-1 (TSP-1) 생성과의 상관관계김승보, 서상기, 이선경, 지성길대한산부인과학회 · Obstetrics & Gynecology Science2006 · 제49권 제3호

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