Endostatin

Endostatin monomer, basic amino acid residues shown in red (source: pdb.org, 1KOE).

Endostatin is a naturally-occurring, 20-kDa C-terminal fragment derived from type XVIII collagen. It is reported to serve as an anti-angiogenic agent, similar to angiostatin and thrombospondin.

Endostatin is a broad-spectrum angiogenesis inhibitor and may interfere with the pro-angiogenic action of growth factors such as basic fibroblast growth factor (bFGF/FGF-2) and vascular endothelial growth factor (VEGF).[1]

Background

Endostatin is an endogenous inhibitor of angiogenesis. It was first found secreted in the media of non-metastasizing mouse cells from a hemangioendothelioma cell line in 1997 and was subsequently found in humans.[2][3] It is produced by proteolytic cleavage of collagen XVIII, a member of the multiplexin family that is characterized by interruptions in the triple helix creating multiple domains, by proteases such as cathepsins.[4] Collagen is a component of epithelial and endothelial basement membranes. Endostatin, as a fragment of collagen 18, demonstrates a role of the ECM in suppression of neoangiogenesis.[2] Pro-angiogenic and anti-angiogenic factors can also be created by proteolysis during coagulation cascades.[5][6][7] Endogenous inhibitors of angiogenesis are present in both normal tissue and cancerous tissue.[8] Overall, endostatin down regulates many signaling cascades like ephrin, TNF-α, and NFκB signaling as well as coagulation and adhesion cascades.[9] Other collagen derived antiangiogenic factors include arresten, canstatin, tumstatin, α 6 collagen type IV antiangiogenic fragment, and restin.[10]

Structure

Human monomeric endostatin is a globular protein containing two disulfide bonds: Cys162−302 and Cys264−294.[11] It folds tightly, has a zinc binding domain at the N-terminus of the protein, and has a high affinity for heparin through an 11 arginine basic patch.[12][13][14] Endostatin also binds all heparan sulfate proteoglycans with low affinity.[15][16] Oligomeric endostatin (trimer or dimer) binds mainly with laminin of the basal lamina.[17]

Biological Activity

In-vitro studies have shown endostatin blocks the proliferation and organization of endothelial cells into new blood vessels.[18] In animal studies endostatin inhibited angiogenesis and growth of both primary tumors and secondary metastasis.[2]

Mechanism

Endostatin suppresses angiogenesis through many pathways affecting both cell viability and movement. Endostatin represses cell cycle control and anti-apoptosis genes in proliferating endothelial cells, resulting in cell death.[19] Endostatin blocks pro-angiogenic gene expression controlled by c-Jun N terminal kinase (JNK) by interfering with TNFα activation of JNK.[20] It reduces the growth of new cells by inhibiting cyclin D1. As a result, cells arrest during G1 phase and enter apoptosis.[21][22] Alteration of FGF signal transduction by endostatin inhibits the migration of endothelial cells through disruption of cell-matrix adhesions, cell-cell adhesions, and cytoskeletal reorganization.[23] By binding integrin α5β1 on endothelia cells it inhibits the signaling pathways of Ras and Raf kinases and decreases ERK-1 and p38 activity.[24] Endostatin binding and clustering of integrins causes co-localization with caveolin-1 and activates non-receptor tyrosine kinases of the Src family involved in the regulation of cell proliferation, differentiation, and mobility.[25][26][27][28] Other receptor interactions include the VEGF-R2/KDR/Flk-1 receptor on human umbilical vein endothelial cells.[29]

Endostatin may prevent activity from certain metalloproteinase.[30] Several studies have focused on the downstream effects of endostatin reception. These studies have estimated that endostatin may significantly affect 12% of genes used by human endothelial cells. Although endostatin signaling may affect this vast number of genes, the downstream affects appear surprisingly limited. Endostatin reception seems to only affect angiogenesis that arrives from pathogenic sources, such as tumors. Processes associated with angiogenesis, such as wound healing and reproduction, are seemingly not affected by endostatin. The result is possible because pathogenic-derived angiogenesis usually involves signaling through integrins, which are directly affected by endostatin.[1]

Cancer

Although this process by which endostatin works is not fully understood, it involves metalloproteases and endopeptidases that digest components of the extracellular matrix. Several similar endogeneous angiogenic factors are produced from matrix components in this fashion. For example, perlecan degradation can yield endorepellin which functions as an anti-angiogenic factor. Collectively, these products are thought to balance regulation between pro-angiogenic and anti-angiogenic factors outside epithelial and endothelial layers.[31] Among anti-angiogenesis inhibitors, endostatin has a wide range of anti-cancer spectrum targets, increasing its significance since synthetic inhibitors usually have single targets and struggle with toxicity.[32] Endostatin has several characteristics that may be advantageous to cancer therapy. First of all, endogenous endostatin has been described as “the least toxic anti-cancer drug in mice”. Furthermore, neither resistance nor toxicity to endostatin occur in humans . Also, endostatin has been estimated to affect 12% of the human genome. This reveals a broad spectrum of activity focused on preventing angiogenesis. This is very different from single-molecule therapies, and may change how cancer therapies are designed: drugs may be designed to target a wide range of genes instead of one particular protein. However, endostatin does not affect all tumors. For example, cancers that may have extreme pro-angiogenic activity through VEGF may overcome the anti-angiogenic effects of endostatin.[1]

Possible cancer treatment

Endostatin is currently being studied as part of cancer research. Prior results indicated that endostatin can be beneficial in combinations with other medicines, but endostatin alone gave no significant improvements in tumor/disease progression.

Phase I

In a Phase I clinical trial of Endostatin, of the 19 patients treated, 12 were switched out of the trial by their physicians due to continued progression of their disease.[33] Two patients continued to be treated, and the remaining patients withdrew on their own. The trial, designed primarily to demonstrate safety, indeed showed that the drug was safe and well-tolerated (at the dosages used).

Phase II

In a Phase II clinical trial of Endostatin, forty-two (42) patients with pancreatic endocrine tumors or carcinoid tumors were treated.[34] Of the 40 patients which could be evaluated for a radiologic response, none experienced partial response to therapy, as defined by World Health Organization criteria.

The conclusion from the trial was that, "Treatment with Endostatin did not result in significant tumor regression in patients with advanced neuroendocrine tumors."

Phase III

A phase III clinical trial was carried out on 493 histology or cytology-confirmed stage IIIB and IV NSCLC patients with a life expectancy >3 months. Patients were treated with Endostar (rh-endostatin, YH-16), a recombinant endostatin product, in combination with vinorelbine and cisplatin (a standard chemotherapeutic regimen). The addition of Endostar to the standard chemotherapeutic regimen in these advanced NSCLC patients resulted in significant and clinically meaningful improvement in response rate, median time to progression, and clinical benefit rate compared with the chemotherapeutic regimen alone.[35]

Clinical significance

Endostatin may also be useful as a therapeutic for inflammatory diseases like rheumatoid arthritis as well as Crohn’s disease, diabetic retinopathy, psoriasis, and endometriosis by reducing the infiltration of inflammatory cells through invading angiogenesis.[36] Down's syndrome patients seem to be protected from diabetic retinopathy due to an additional copy of chromosome 21, and elevated expression of endostatin.[37]

References

  1. 1 2 3 Folkman, J. (2006). "Antiangiogenesis in cancer therapy--endostatin and its mechanisms of action". Exp. Cell. Res. 312 (5, part 2): 594–607. doi:10.1016/j.yexcr.2005.11.015. PMID 16376330.
  2. 1 2 3 OReilly, M.S.; Boehm, T.; Shing, Y.; Fukai, N.; Vasios, G.; Lane, W.W.; Flynn, E.; Birkhead, J.R.; Olsen, B.R.; Folkman, J. (1997). "Endostatin: an endogenous inhibitor of angiogenesis and tumor growth". Cell 88 (2): 277–85. doi:10.1016/S0092-8674(00)81848-6. PMID 9008168.
  3. ↑ Standker, L; Schrader, M.; Kanse, S.M.; Jurgens, M.; Forssmann, W.G.; Prissner, K.T. (1997). "Isolation and characterization of the circulating form of human endostatin". FEBS Lett 420 (2–3): 129–33. doi:10.1016/S0014-5793(97)01503-2. PMID 9459295.
  4. ↑ Felbor, U; et al. (2000). "Secreted cathepsin L generates endostatin from collagen XVIII". EMBO J 19 (6): 1187–94. doi:10.1093/emboj/19.6.1187. PMC 305660. PMID 10716919.
  5. ↑ Browder, T.; Folkman, J.; Pirie-Shepherd, S. (2000). "The hemostatic system as a regulator of angiogenesis". J. Biol. Chem. 275 (3): 1521–4. doi:10.1074/jbc.275.3.1521. PMID 10636838.
  6. ↑ Ma, L; Hollenberg, M.D.; Wallace, J.L. (2001). "Thrombin-induced platelet endostatin release is blocked by a proteinase activated receptor-4 (PAR4) antagonist". Br. J. Pharmacol 134 (4): 701–4. doi:10.1038/sj.bjp.0704312. PMC 1573005. PMID 11606309.
  7. ↑ Rhim, T.Y.; Park, C.S.; Kim, E.; Kim, S.S. (1998). "Human prothrombin fragment 1 and 2 inhibit bFGF-induced BCE cell growth". Biochem. Biophys. Res. Commun. 252 (2): 513–6. doi:10.1006/bbrc.1998.9682. PMID 9826562.
  8. ↑ Nyberg, P.; Xie, L.; Kalluri, R. (2005). "Endogenous inhibitors of angiogenesis". Cancer Res 65 (10): 3967–79. doi:10.1158/0008-5472.CAN-04-2427. PMID 15899784.
  9. ↑ Abdollahi, A.; Hahnfeldt, P.; Maercker, C.; Grone, H.; Debus, J.; Ansorge, W.; Folman, J.; Hlatky, L.; Huber, P.E. (2004). "Endostatin's antiangiogenic signaling network". Mol. Cell 13 (5): 649–63. doi:10.1016/S1097-2765(04)00102-9. PMID 15023336.
  10. ↑ Assadian, S.; Teodoro, J.G. (2008). "Regulation of collagen-derived antiangiogenic factors by p53". Expert Opin Biol Ther 8 (7): 941–50. doi:10.1517/14712598.8.7.941. PMID 18549324.
  11. ↑ John, H.; Forssmann, W.G. (2001). "Determination of the disulfide bond pattern of the endogenous and recombinant angiogenesis inhibitor endostatin by mass spectrometry". Rapid Commun Mass Spectrom 15 (14): 1222–8. doi:10.1002/rcm.367. PMID 11445906.
  12. ↑ Hohenester, E.; Sasaki, T.; Olsen, B.R.; Timpl, R. (1998). "Crystal structure of the angiogenesis inhibitor endostatin at 1.5 A resolution". EMBO J 17 (6): 1656–64. doi:10.1093/emboj/17.6.1656. PMC 1170513. PMID 9501087.
  13. ↑ Ding, Y.H.; Javaherian, K.; Lo, K.M.; Chopra, R.; Boehm, T.; Lanciotti, J.; Harris, B.A.; Li, Y.; Shapiro, R.; Hohenester, E.; et al. (1998). "Zinc-dependent dimers observed in crystals of human endostatin". Proc Natl Acad Sci U.S.A. 95 (18): 10443–8. doi:10.1073/pnas.95.18.10443. PMC 27913. PMID 9724722.
  14. ↑ Dixelius, J.; Cross, M.; Matsumoto, T.; Sasaki, T.; Timpl, R.; Claesson-Welsh, L. (2002). "Endostatin regulates endothelial cell adhesion and cytoskeletal organization". Cancer Res 62 (7): 1944–7. PMID 11929807.
  15. ↑ Karumanchi, S.A.; Jha, V.; Ramchandran, R.; Karihaloo, A.; Tsiokas, L.; Chan, B.; Dhanabal, M.; Hanai, J.I.; Venkataraman, G.; Shriver, Z.; et al. (2001). "Cell surface glypicans are low-affinity endostatin receptors". Mol Cell 7 (4): 811–22. doi:10.1016/S1097-2765(01)00225-8. PMID 11336704.
  16. ↑ Sasaki, T; Larsson, H.; Kreuger, J.; Salmivirta, M.; Claesson-Welsh, L.; Lindahl, U.; Hohenester, E.; Timpl, R. (1999). "Structural basis and potential role of heparin/heparan sulfate binding to the angiogenesis inhibitor endostatin". EMBO J 18 (22): 6240–8. doi:10.1093/emboj/18.22.6240. PMC 1171687. PMID 10562536.
  17. ↑ Javaherian, K.; Park, S.Y.; Pickl, W.F.; LaMontagne, K.R.; Sjin, R.T.T.; Gillies, S.; Lo, K. (2002). "Laminin modulates morphogenic properties of the collagen XVIII endostatin domain". J. Biol. Chem. 277 (47): 45211–8. doi:10.1074/jbc.M206358200. PMID 12237301.
  18. ↑ Folkman, J.; Kalluri, R. (2004). "Cancer without disease". Nature 427 (6977): 787. doi:10.1038/427787a. PMID 14985739.
  19. ↑ Shichiri, M.; Hirata (2001). "Y". FASEB J 15 (6): 1044–53. doi:10.1096/fj.99-1083com. PMID 11292666.
  20. ↑ Yin, G; Liu, W.; An, P.; Li, P.; Ding, I.; Planelles, V.; Schwarz, E.M.; Min, W. (2002). "Endostatin gene transfer inhibits joint angiogenesis and pannus formation in inflammatory arthritis". Mol Ther 5 (5 Pt 1): 547–54. doi:10.1006/mthe.2002.0590. PMID 11991745.
  21. ↑ Dhanabal, M.; Volk, R.; Ramchandran, R.; Simons, M.; Sukhatme, V.P. (1999). "Cloning, expression, and in vitro activity of human endostatin". Biochem Biophys Res Commun 258 (2): 345–52. doi:10.1006/bbrc.1999.0595. PMID 10329390.
  22. ↑ Hanai, J.; Dhanabal, M.; Karumanchi, S.A.; Albanese, C.; Waterman, M.; Chan, B.; Ramchandran, R.; Pestell, R.; Sukhatme, V.P. (2002). "Endostatin causes G1 arrest of endothelial cells through inhibition of cyclin D1". J. Biol. Chem. 277 (19): 16464–9. doi:10.1074/jbc.M112274200. PMID 11815623.
  23. ↑ Dixelius, J; Larsson, H.; Sasaki, T.; Holmqvist, K.; Lu, L.; Engstrom, A.; Timpl, R.; Welsh, M.; Claesson-Welsh, L. (2000). "Endostatin-induced tyrosin kinase signaling through the Shb adaptor protein regulates endothelial cell apoptosis". Blood 95 (11): 3403–11. PMID 10828022.
  24. ↑ Sudhakar, A.; Sugimoto, H.; Yang, C.; Lively, J.; Zeisberg, M.; Kalluri, R. (2003). "Human tumstatin and human endostatin exhibit distinct antiangiogenic activities mediated by alpha v beta 3 and alpha 5 beta 1 integrins". Proc Natl Acad Sci U.S.A. 100 (8): 4766–71. doi:10.1073/pnas.0730882100. PMC 153630. PMID 12682293.
  25. ↑ Tatosyan, A.G; Mizenina, O.A. (2000). "Kinases of the Src family: structure and functions". Biochemistry Mosc 65 (1): 49–58. PMID 10702640.
  26. ↑ Thomas, S.M.; Brugge, J.S. (1997). "Cellular functions regulated by Src family kinases". Annu Rev Cell Dev Biol 13: 513–609. doi:10.1146/annurev.cellbio.13.1.513. PMID 9442882.
  27. ↑ Wary, K.K.; Mariotti, A.; Zurzolo, C.; Giancotti, F.G. (1998). "A requirement for caveolin-1 and associated kinase Fyn in integrin signaling and anchorage-dependent cell growth". Cell 94 (5): 625–34. doi:10.1016/S0092-8674(00)81604-9. PMID 9741627.
  28. ↑ Wickstrom, S.A.; Alitalo, K.; Keski-Oja, J. (2002). "Endostatin associates with integrin alpha5beta1 and caveolin-1, and activates Src via a tyrosyl phosphatase-dependent pathway in human endothelial cells". Cancer Res 62 (19): 5580–9. PMID 12359771.
  29. ↑ Kim, Y.; Hwang, S.; Kim, Y.; Pyun, B.; Kim, T.; Lee, S.; Gho, Y.S.; Kwon, Y. (2002). "Endostatin blocks vascular endothelial growth factor-mediated signaling via direct interaction with KDR/Flk-1". J. Biol. Chem. 277 (31): 27872–9. doi:10.1074/jbc.M202771200. PMID 12029087.
  30. ↑ Felbor, U.; et al. (2000). "Secreted cathepsin L generates endostatin from collagen XVIII". EMBO J 19 (6): 1187–94. doi:10.1093/emboj/19.6.1187. PMC 305660. PMID 10716919.
  31. ↑ Marneros, A.G.; Olsen, B.R. (2005). "Physiological role of collagen XVIII and endostatin". The FASEB Journal 19 (7): 716–28. doi:10.1096/fj.04-2134rev. PMID 15857886.
  32. ↑ Karamouzis, M.V.; Moschos, S.J. (2009). "The use of endostatin in the treatment of solid tumors". Expert Opin Biol Ther 9 (5): 641–8. doi:10.1517/14712590902882118. PMID 19368526.
  33. ↑ "Boston hospitals report early results of Endostatin clinical trial" (Press release). ScienceDaily.com: Dana-Farber Cancer Institute. November 13, 2000. Retrieved 2006-07-12.
  34. ↑ Kulke M H; et al. (2006). "Phase II study of recombinant human endostatin in patients with advanced neuroendocrine tumors". J. Clin. Oncol. 24 (22): 3555–3561. doi:10.1200/JCO.2006.05.6762. PMID 16877721.
  35. ↑ Results of phase III trial of rh-endostatin (YH-16) in advanced non-small cell lung cancer (NSCLC) patients (Y. Sun, J. Wang, Y. Liu, X. Song, Y. Zhang, K. Li, Y. Zhu, Q. Zhou, L. You and C. Yao)
  36. ↑ Yin, G.; Liu, W.; An, P.; Li, P.; ding, I.; Planelles, V.; Schwarz, E.M.; Min, W. (2002). "Endostatin gene transfer inhibits joint angiogenesis and pannus formation in inflammatory arthritis". Mol Ther 5 (5 Pt 1): 547–54. doi:10.1006/mthe.2002.0590. PMID 11991745.
  37. ↑ Ryeom S, Folkman J (March 2009). "Role of endogenous angiogenesis inhibitors in Down syndrome". J Craniofac Surg. 20 Suppl 1: 595–6. doi:10.1097/SCS.0b013e3181927f47. PMID 19795527.

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