Endostatin

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

Contents

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, e.g. in platelets. [2] [3] [4] 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. [5] 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. [3] Pro-angiogenic and anti-angiogenic factors can also be created by proteolysis during coagulation cascades. [6] [7] [8] Endogenous inhibitors of angiogenesis are present in both normal tissue and cancerous tissue. [9] Overall, endostatin down regulates many signaling cascades like ephrin, TNF-α, and NFκB signaling as well as coagulation and adhesion cascades. [10] Other collagen derived antiangiogenic factors include arresten, canstatin, tumstatin, α 6 collagen type IV antiangiogenic fragment, and restin. [11]

Structure

Human monomeric endostatin is a globular protein containing two disulfide bonds: Cys162−302 and Cys264−294. [12] 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. [13] [14] [15] Endostatin also binds all heparan sulfate proteoglycans with low affinity. [16] [17] Oligomeric endostatin (trimer or dimer) binds mainly with laminin of the basal lamina. [18]

Biological activity

In-vitro studies have shown endostatin blocks the proliferation and organization of endothelial cells into new blood vessels. [19] In animal studies endostatin inhibited angiogenesis and growth of both primary tumors and secondary metastasis. [3]

Mechanism of action

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. [20] Endostatin blocks pro-angiogenic gene expression controlled by c-Jun N terminal kinase (JNK) by interfering with TNFα activation of JNK. [21] It reduces the growth of new cells by inhibiting cyclin D1. As a result, cells arrest during G1 phase and enter apoptosis. [22] [23] 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. [24] By binding integrin α5β1 on endothelia cells it inhibits the signaling pathways of Ras and Raf kinases and decreases ERK-1 and p38 activity. [25] 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. [26] [27] [28] [29] Other receptor interactions include the VEGF-R2/KDR/Flk-1 receptor on human umbilical vein endothelial cells. [30]

Endostatin may prevent activity from certain metalloproteinase. [31] 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. [32]

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. [33] 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.[ citation needed ] 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. [34] 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, 42 patients with pancreatic endocrine tumors or carcinoid tumors were treated. [35] 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. [36]

Clinical significance

Endostatin may also be useful as a therapeutic for inflammatory diseases like rheumatoid arthritis as well as Crohn disease, diabetic retinopathy, psoriasis, and endometriosis by reducing the infiltration of inflammatory cells through invading angiogenesis. [37] Down syndrome patients seem to be protected from diabetic retinopathy due to an additional copy of chromosome 21, and elevated expression of endostatin. [38]

Related Research Articles

<span class="mw-page-title-main">Angiogenesis</span> Blood vessel formation, when new vessels emerge from existing vessels

Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature mainly by processes of sprouting and splitting, but processes such as coalescent angiogenesis, vessel elongation and vessel cooption also play a role. Vasculogenesis is the embryonic formation of endothelial cells from mesoderm cell precursors, and from neovascularization, although discussions are not always precise. The first vessels in the developing embryo form through vasculogenesis, after which angiogenesis is responsible for most, if not all, blood vessel growth during development and in disease.

Vascular endothelial growth factor, originally known as vascular permeability factor (VPF), is a signal protein produced by many cells that stimulates the formation of blood vessels. To be specific, VEGF is a sub-family of growth factors, the platelet-derived growth factor family of cystine-knot growth factors. They are important signaling proteins involved in both vasculogenesis and angiogenesis.

An angiogenesis inhibitor is a substance that inhibits the growth of new blood vessels (angiogenesis). Some angiogenesis inhibitors are endogenous and a normal part of the body's control and others are obtained exogenously through pharmaceutical drugs or diet.

Moses Judah Folkman was an American biologist and pediatric surgeon best known for his research on tumor angiogenesis, the process by which a tumor attracts blood vessels to nourish itself and sustain its existence. He founded the field of angiogenesis research, which has led to the discovery of a number of therapies based on inhibiting or stimulating neovascularization.

<span class="mw-page-title-main">Angiopoietin</span> Protein family

Angiopoietin is part of a family of vascular growth factors that play a role in embryonic and postnatal angiogenesis. Angiopoietin signaling most directly corresponds with angiogenesis, the process by which new arteries and veins form from preexisting blood vessels. Angiogenesis proceeds through sprouting, endothelial cell migration, proliferation, and vessel destabilization and stabilization. They are responsible for assembling and disassembling the endothelial lining of blood vessels. Angiopoietin cytokines are involved with controlling microvascular permeability, vasodilation, and vasoconstriction by signaling smooth muscle cells surrounding vessels. There are now four identified angiopoietins: ANGPT1, ANGPT2, ANGPTL3, ANGPT4.

<span class="mw-page-title-main">Thrombospondin 1</span> Protein-coding gene in the species Homo sapiens

Thrombospondin 1, abbreviated as THBS1, is a protein that in humans is encoded by the THBS1 gene.

<span class="mw-page-title-main">CTGF</span> Protein found in humans

CTGF, also known as CCN2 or connective tissue growth factor, is a matricellular protein of the CCN family of extracellular matrix-associated heparin-binding proteins. CTGF has important roles in many biological processes, including cell adhesion, migration, proliferation, angiogenesis, skeletal development, and tissue wound repair, and is critically involved in fibrotic disease and several forms of cancers.

<span class="mw-page-title-main">MMP2</span> Protein-coding gene in the species Homo sapiens

72 kDa type IV collagenase also known as matrix metalloproteinase-2 (MMP-2) and gelatinase A is an enzyme that in humans is encoded by the MMP2 gene. The MMP2 gene is located on chromosome 16 at position 12.2.

<span class="mw-page-title-main">CYR61</span> Protein-coding gene in the species Homo sapiens

Cysteine-rich angiogenic inducer 61 (CYR61) or CCN family member 1 (CCN1), is a matricellular protein that in humans is encoded by the CYR61 gene.

<span class="mw-page-title-main">METAP2</span> Protein-coding gene in humans

Methionine aminopeptidase 2 is an enzyme that in humans is encoded by the METAP2 gene.

<span class="mw-page-title-main">Tenascin C</span> Human protein-coding gene

Tenascin C (TN-C) is a glycoprotein that in humans is encoded by the TNC gene. It is expressed in the extracellular matrix of various tissues during development, disease or injury, and in restricted neurogenic areas of the central nervous system. Tenascin-C is the founding member of the tenascin protein family. In the embryo it is made by migrating cells like the neural crest; it is also abundant in developing tendons, bone and cartilage.

<span class="mw-page-title-main">Collagen, type XVIII, alpha 1</span> Protein found in humans

Collagen alpha-1(XVIII) chain is a protein that in humans is encoded by the COL18A1 gene.

<span class="mw-page-title-main">PEDF</span> Protein-coding gene in the species Homo sapiens

Pigment epithelium-derived factor (PEDF) also known as serpin F1 (SERPINF1), is a multifunctional secreted protein that has anti-angiogenic, anti-tumorigenic, and neurotrophic functions. Found in vertebrates, this 50 kDa protein is being researched as a therapeutic candidate for treatment of such conditions as choroidal neovascularization, heart disease, and cancer. In humans, pigment epithelium-derived factor is encoded by the SERPINF1 gene.

<span class="mw-page-title-main">Vascular endothelial growth factor A</span> Protein involved in blood vessel growth

Vascular endothelial growth factor A (VEGF-A) is a protein that in humans is encoded by the VEGFA gene.

Angiogenesis is the process of forming new blood vessels from existing blood vessels, formed in vasculogenesis. It is a highly complex process involving extensive interplay between cells, soluble factors, and the extracellular matrix (ECM). Angiogenesis is critical during normal physiological development, but it also occurs in adults during inflammation, wound healing, ischemia, and in pathological conditions such as rheumatoid arthritis, hemangioma, and tumor growth. Proteolysis has been indicated as one of the first and most sustained activities involved in the formation of new blood vessels. Numerous proteases including matrix metalloproteinases (MMPs), a disintegrin and metalloproteinase domain (ADAM), a disintegrin and metalloproteinase domain with throbospondin motifs (ADAMTS), and cysteine and serine proteases are involved in angiogenesis. This article focuses on the important and diverse roles that these proteases play in the regulation of angiogenesis.

Tumstatin is a protein fragment cleaved from collagen that serves as both an antiangiogenic and proapoptotic agent. It has similar function to canstatin, endostatin, restin, and arresten, which also affect angiogenesis. Angiogenesis is the growth of new blood vessels from pre-existing blood vessels, and is important in tumor growth and metastasis. Angiogenesis is stimulated by many growth factors, the most prevalent of which is vascular endothelial growth factor (VEGF).

<span class="mw-page-title-main">AEE788</span> Chemical compound

AEE788 is a multitargeted human epidermal receptor (HER) 1/2 and vascular endothelial growth factor receptor (VEGFR) 1/2 receptor family tyrosine kinases inhibitor with IC50 of 2, 6, 77, 59 nM for EGFR, ErbB2, KDR, and Flt-1. In cells, growth factor-induced EGFR and ErbB2 phosphorylation was also efficiently inhibited with IC50s of 11 and 220 nM, respectively. It efficiently inhibited growth factor-induced EGFR and ErbB2 phosphorylation in tumors for >72 h, a phenomenon correlating with the antitumor efficacy of intermittent treatment schedules. It also inhibits VEGF-induced angiogenesis in a murine implant model. It has potential as an anticancer agent targeting deregulated tumor cell proliferation as well as angiogenic parameters.

<span class="mw-page-title-main">Yihai Cao</span> Chinese-born Swedish scientist and professor

Yihai Cao, M.D., hM. D., Ph.D., is a Chinese-born Swedish scientist and a professor at the Karolinska Institute, Sweden. He is also an honorary professor/guest professor in Copenhagen University, Denmark; Linköping University, Sweden; Leicester University, UK; Shinshu University, Japan; Shandong University, China; and Peking University, China. He is an internationally recognized and cited researcher in cancer, obesity, diabetes, cardiovascular disease, and eye disease research. His publications have been cited more than 35,000 times and his h-index is 92. Cao received the Fernström research prize, the Karolinska distinguished professor award, and the Axel Hirsch Prize in medicine. Cao received an ERC-advanced research grant award, and a Novo Nordisk-advanced grant award. From 2018, Cao was elected to Academia Europaea, the European Academy of Sciences and Arts, the Chinese Academy of Engineering, the National Academy of Inventors, and The World Academy of Sciences. His research findings received broad public attentions including New York Times, Reuters and Swedish National TV broad casting.

<span class="mw-page-title-main">Tumor-associated endothelial cell</span>

Tumor-associated endothelial cells or tumor endothelial cells (TECs) refers to cells lining the tumor-associated blood vessels that control the passage of nutrients into surrounding tumor tissue. Across different cancer types, tumor-associated blood vessels have been discovered to differ significantly from normal blood vessels in morphology, gene expression, and functionality in ways that promote cancer progression. There has been notable interest in developing cancer therapeutics that capitalize on these abnormalities of the tumor-associated endothelium to destroy tumors.

<span class="mw-page-title-main">Endothelial cell anergy</span> Defense mechanism of tumors against immunity

Endothelial cell anergy is a condition during the process of angiogenesis, where endothelial cells, the cells that line the inside of blood vessels, can no longer respond to inflammatory cytokines. These cytokines are necessary to induce the expression of cell adhesion molecules to allow leukocyte infiltration from the blood into the tissue at places of inflammation, such as a tumor. This condition, which protects the tumor from the immune system, is the result of exposure to angiogenic growth factors.

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. ↑ Custo, S; Baron, B; Felice, A; Seria, E (5 July 2022). "A comparative profile of total protein and six angiogenically-active growth factors in three platelet products". GMS Interdisciplinary Plastic and Reconstructive Surgery DGPW. 11 (Doc06): Doc06. doi:10.3205/iprs000167. PMC   9284722 . PMID   35909816.
  3. 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.
  4. ↑ 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. Bibcode:1997FEBSL.420..129S. doi:10.1016/S0014-5793(97)01503-2. PMID   9459295. S2CID   9852143.
  5. ↑ 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.
  6. ↑ 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.
  7. ↑ 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.
  8. ↑ 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.
  9. ↑ 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.
  10. ↑ 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.
  11. ↑ 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. S2CID   72058014.
  12. ↑ 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. Bibcode:2001RCMS...15.1222J. doi:10.1002/rcm.367. PMID   11445906.
  13. ↑ 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.
  14. ↑ 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. Bibcode:1998PNAS...9510443D. doi: 10.1073/pnas.95.18.10443 . PMC   27913 . PMID   9724722.
  15. ↑ 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.
  16. ↑ 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" (PDF). Mol. Cell. 7 (4): 811–22. doi:10.1016/S1097-2765(01)00225-8. PMID   11336704. S2CID   43358048.
  17. ↑ 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.
  18. ↑ 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.
  19. ↑ Folkman, J.; Kalluri, R. (2004). "Cancer without disease". Nature. 427 (6977): 787. Bibcode:2004Natur.427..787F. doi: 10.1038/427787a . PMID   14985739.
  20. ↑ Shichiri, M.; Hirata (2001). "Y". FASEB J. 15 (6): 1044–53. doi: 10.1096/fj.99-1083com . PMID   11292666.
  21. ↑ 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.
  22. ↑ 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.
  23. ↑ 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.
  24. ↑ 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. doi:10.1182/blood.V95.11.3403. PMID   10828022.
  25. ↑ 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. Bibcode:2003PNAS..100.4766S. doi: 10.1073/pnas.0730882100 . PMC   153630 . PMID   12682293.
  26. ↑ Tatosyan, A.G; Mizenina, O.A. (2000). "Kinases of the Src family: structure and functions". Biochemistry. 65 (1): 49–58. PMID   10702640.
  27. ↑ 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.
  28. ↑ 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.
  29. ↑ 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.
  30. ↑ 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.
  31. ↑ 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.
  32. ↑ 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. S2CID   24259395.
  33. ↑ 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. S2CID   73212482.
  34. ↑ "Boston hospitals report early results of Endostatin clinical trial" (Press release). ScienceDaily.com: Dana-Farber Cancer Institute. November 13, 2000. Retrieved 2006-07-12.
  35. ↑ 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.
  36. ↑ 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)
  37. ↑ 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.
  38. ↑ 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. S2CID   21576950.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.