Please wait a minute...
Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

Postal Subscription Code 80-967

2018 Impact Factor: 1.847

Front Med    2012, Vol. 6 Issue (1) : 67-78
Progress in tumor vascular normalization for anticancer therapy: challenges and perspectives
Bingxue Shang, Zhifei Cao, Quansheng Zhou()
Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, the First Affiliated Hospital of Soochow University, Suzhou 215123, China; Key Laboratory of Thrombosis and Hemostasis, Ministry of Health, Soochow University, Suzhou 215123, China
 Download: PDF(331 KB)   HTML
 Export: BibTeX | EndNote | Reference Manager | ProCite | RefWorks

Antitumor angiogenic therapy has been shown promising in the treatment of several advanced cancers since the approval of the first antiangiogenic drug Avastin in 2004. Although the current antiangiogenic drugs reduce the density of tumor blood vessels and result in tumor shrinkage at the early stage of treatment, recent studies have shown that antiangiogenic therapy has transient and insufficient efficacy, resulting in tumor recurrence in patients after several months of treatment. Blockage of blood and oxygen supplies creates a hypoxic and acidic microenvironment in the tumor tissues, which fosters tumor cells to become more aggressive and metastatic. In 2001, Jain proposed tumor vascular normalization as an alternative approach to treating cancers based on the pioneering work on tumor blood vessels by several other researchers. At present, normalizing the disorganized tumor vasculature, rather than disrupting or blocking them, has emerged as a new option for anticancer therapy. Preclinical and clinical data have shown that tumor vascular normalization using monoclonal antibodies, proteins, peptides, small molecules, and pericytes resulted in decreased tumor size and reduced metastasis. However, current tumor vascular normalizing drugs display moderate anticancer efficacy. Accumulated data have shown that a variety of vasculogenic/angiogenic tumor cells and genes play important roles in tumor neovascularization, growth, and metastasis. Therefore, multiple-targeting of vasculogenic tumor cells and genes may improve the efficacy of tumor vascular normalization. To this end, the combination of antiangiogenic drugs with tumor vascular normalizing therapeutics, as well as the integration of Western medicine with traditional Chinese medicine, may provide a good opportunity for discovering novel tumor vascular normalizing drugs for an effective anticancer therapy.

Keywords angiogenesis      vasculogenesis      neovascularization      tumor      vasculature      normalization      traditional Chinese medicine     
Corresponding Author(s): Zhou Quansheng,   
Issue Date: 05 March 2012
 Cite this article:   
Bingxue Shang,Zhifei Cao,Quansheng Zhou. Progress in tumor vascular normalization for anticancer therapy: challenges and perspectives[J]. Front Med, 2012, 6(1): 67-78.
Fig.1  Comparison of normal vasculature with tumor vasculature. (A) Normal blood vessels are organized in a hierarchy of evenly distributed arteries, capillaries, and veins. The vessels are covered by pericytes to maintain the integrity of the vessels. (B) Tumor blood vessels are heterogeneous and consist of irregular branches with arteriovenous shunts.
Fig.2  Normalization of disorganized tumor blood vessels for anticancer therapy. Malignant tumors may make their own blood vessels via a complex process of neovascularization through (1) VEGF and endothelial cell-mediated angiogenesis, (2) vessel co-option between endothelial cells and tumor cells, and (3) tumor cell-predominant vasculogenesis. The disorganized tumor blood vessels could be normalized using several options, including (1) anti-VEGF therapeutics, (2) PHD2 agonists, (3) VE-cadherin blocking agents, (4) targeting tumor-associated macrophages, (5) traditional Chinese medicinal herbal drugs, and (6) manipulation of pericytes.
1 Ebos JM, Kerbel RS. Antiangiogenic therapy: impact on invasion, disease progression, and metastasis. Nat Rev Clin Oncol 2011; 8(4): 210-221
doi: 10.1038/nrclinonc.2011.21 pmid:21364524
2 Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med 1971; 285(21): 1182-1186
doi: 10.1056/NEJM197111182852108 pmid:4938153
3 Heath VL, Bicknell R. Anticancer strategies involving the vasculature. Nat Rev Clin Oncol 2009; 6(7): 395-404
doi: 10.1038/nrclinonc.2009.52 pmid:19424102
4 Ribatti D. Endogenous inhibitors of angiogenesis: a historical review. Leuk Res 2009; 33(5): 638-644
doi: 10.1016/j.leukres.2008.11.019 pmid:19117606
5 Ribatti D. The discovery of antiangiogenic molecules: a historical review. Curr Pharm Des 2009; 15(4): 345-352
doi: 10.2174/138161209787315855 pmid:19199962
6 Van Cutsem E, Lambrechts D, Prenen H, Jain RK, Carmeliet P. Lessons from the adjuvant bevacizumab trial on colon cancer: what next? J Clin Oncol 2011; 29(1): 1-4
doi: 10.1200/JCO.2010.32.2701 pmid:21115866
7 Miles D, Harbeck N, Escudier B, Hurwitz H, Saltz L, Van Cutsem E, Cassidy J, Mueller B, Sirzén F. Disease course patterns after discontinuation of bevacizumab: pooled analysis of randomized phase III trials. J Clin Oncol 2011; 29(1): 83-88
doi: 10.1200/JCO.2010.30.2794 pmid:21098326
8 Otrock ZK, Hatoum HA, Awada AH, Ishak RS, Shamseddine AI. Hypoxia-inducible factor in cancer angiogenesis: structure, regulation and clinical perspectives. Crit Rev Oncol Hematol 2009; 70(2): 93-102
doi: 10.1016/j.critrevonc.2009.01.001 pmid:19186072
9 Osinsky S, Zavelevich M, Vaupel P. Tumor hypoxia and malignant progression. Exp Oncol 2009; 31(2): 80-86
10 Jain RK. Normalizing tumor vasculature with anti-angiogenic therapy: a new paradigm for combination therapy. Nat Med 2001; 7(9): 987-989
doi: 10.1038/nm0901-987 pmid:11533692
11 Jain RK. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 2005; 307(5706): 58-62
doi: 10.1126/science.1104819 pmid:15637262
12 Carmeliet P, Jain RK. Principles and mechanisms of vessel normalization for cancer and other angiogenic diseases. Nat Rev Drug Discov 2011; 10(6): 417-427
doi: 10.1038/nrd3455 pmid:21629292
13 Goel S, Duda DG, Xu L, Munn LL, Boucher Y, Fukumura D, Jain RK. Normalization of the vasculature for treatment of cancer and other diseases. Physiol Rev 2011; 91(3): 1071-1121
doi: 10.1152/physrev.00038.2010 pmid:21742796
14 Sato Y. Persistent vascular normalization as an alternative goal of anti-angiogenic cancer therapy. Cancer Sci 2011; 102(7): 1253-1256
doi: 10.1111/j.1349-7006.2011.01929.x pmid:21401807
15 Fukumura D, Jain RK. Tumor microvasculature and microenvironment: targets for anti-angiogenesis and normalization. Microvasc Res 2007; 74(2-3): 72-84
doi: 10.1016/j.mvr.2007.05.003 pmid:17560615
16 Hess AR, Margaryan NV, Seftor EA, Hendrix MJ. Deciphering the signaling events that promote melanoma tumor cell vasculogenic mimicry and their link to embryonic vasculogenesis: role of the Eph receptors. Dev Dyn 2007; 236(12): 3283-3296
doi: 10.1002/dvdy.21190 pmid:17557303
17 Ku?era T, Lammert E. Ancestral vascular tube formation and its adoption by tumors. Biol Chem 2009; 390(10): 985-994
doi: 10.1515/BC.2009.115 pmid:19642872
18 Carmeliet P, Jain RK. Molecular mechanisms and clinical applications of angiogenesis. Nature 2011; 473(7347): 298-307
doi: 10.1038/nature10144 pmid:21593862
19 Potente M, Gerhardt H, Carmeliet P. Basic and therapeutic aspects of angiogenesis. Cell 2011; 146(6): 873-887
doi: 10.1016/j.cell.2011.08.039 pmid:21925313
20 Shen R, Ye Y, Chen L, Yan Q, Barsky SH, Gao JX. Precancerous stem cells can serve as tumor vasculogenic progenitors. PLoS One , 2008; 3(2): e1652
21 Menakuru SR, Brown NJ, Staton CA, Reed MW. Angiogenesis in pre-malignant conditions. Br J Cancer 2008; 99(12): 1961-1966
doi: 10.1038/sj.bjc.6604733 pmid:18941463
22 Hong D, Gupta R, Ancliff P, Atzberger A, Brown J, Soneji S, Green J, Colman S, Piacibello W, Buckle V, Tsuzuki S, Greaves M, Enver T. Initiating and cancer-propagating cells in TEL-AML1-associated childhood leukemia. Science 2008; 319(5861): 336-339
doi: 10.1126/science.1150648 pmid:18202291
23 Hill RP, Marie-Egyptienne DT, Hedley DW. Cancer stem cells, hypoxia and metastasis. Semin Radiat Oncol 2009; 19(2): 106-111
doi: 10.1016/j.semradonc.2008.12.002 pmid:19249648
24 Zhao Y, Dong J, Huang Q, Lou M, Wang A, Lan Q. Endothelial cell transdifferentiation of human glioma stem progenitor cells in vitro. Brain Res Bull 2010; 82(5-6): 308-312
doi: 10.1016/j.brainresbull.2010.06.006 pmid:20599593
25 Wang R, Chadalavada K, Wilshire J, Kowalik U, Hovinga KE, Geber A, Fligelman B, Leversha M, Brennan C, Tabar V. Glioblastoma stem-like cells give rise to tumour endothelium. Nature 2010; 468(7325): 829-833
doi: 10.1038/nature09624 pmid:21102433
26 Ricci-Vitiani L, Pallini R, Biffoni M, Todaro M, Invernici G, Cenci T, Maira G, Parati EA, Stassi G, Larocca LM, De Maria R. Tumour vascularization via endothelial differentiation of glioblastoma stem-like cells. Nature 2010; 468(7325): 824-828
doi: 10.1038/nature09557 pmid:21102434
27 Soda Y, Marumoto T, Friedmann-Morvinski D, Soda M, Liu F, Michiue H, Pastorino S, Yang M, Hoffman RM, Kesari S, Verma IM. Transdifferentiation of glioblastoma cells into vascular endothelial cells. Proc Natl Acad Sci USA 2011; 108(11): 4274-4280
doi: 10.1073/pnas.1016030108 pmid:21262804
28 Chiao MT, Yang YC, Cheng WY, Shen CC, Ko JL. CD133+ glioblastoma stem-like cells induce vascular mimicry in vivo. Curr Neurovasc Res 2011; 8(3): 210-219
doi: 10.2174/156720211796558023 pmid:21675958
29 Ping YF, Bian XW. Consice review: contribution of cancer stem cells to neovascularization. Stem Cells 2011; 29(6): 888-894
doi: 10.1002/stem.650 pmid:21557392
30 Ahn GO, Brown JM. Role of endothelial progenitors and other bone marrow-derived cells in the development of the tumor vasculature. Angiogenesis 2009; 12(2): 159-164
doi: 10.1007/s10456-009-9135-7 pmid:19221886
31 Ria R, Piccoli C, Cirulli T, Falzetti F, Mangialardi G, Guidolin D, Tabilio A, Di Renzo N, Guarini A, Ribatti D, Dammacco F, Vacca A. Endothelial differentiation of hematopoietic stem and progenitor cells from patients with multiple myeloma. Clin Cancer Res 2008; 14(6): 1678-1685
doi: 10.1158/1078-0432.CCR-07-4071 pmid:18347168
32 Vacca A, Ribatti D. Bone marrow angiogenesis in multiple myeloma. Leukemia 2006; 20(2): 193-199
doi: 10.1038/sj.leu.2404067 pmid:16357836
33 Chen H, Campbell RA, Chang Y, Li M, Wang CS, Li J, Sanchez E, Share M, Steinberg J, Berenson A, Shalitin D, Zeng Z, Gui D, Perez-Pinera P, Berenson RJ, Said J, Bonavida B, Deuel TF, Berenson JR. Pleiotrophin produced by multiple myeloma induces transdifferentiation of monocytes into vascular endothelial cells: a novel mechanism of tumor-induced vasculogenesis. Blood 2009; 113(9): 1992-2002
doi: 10.1182/blood-2008-02-133751 pmid:19060246
34 Scavelli C, Nico B, Cirulli T, Ria R, Di Pietro G, Mangieri D, Bacigalupo A, Mangialardi G, Coluccia AM, Caravita T, Molica S, Ribatti D, Dammacco F, Vacca A. Vasculogenic mimicry by bone marrow macrophages in patients with multiple myeloma. Oncogene 2008; 27(5): 663-674
doi: 10.1038/sj.onc.1210691 pmid:17667938
35 Maltby S, Khazaie K, McNagny KM. Mast cells in tumor growth: angiogenesis, tissue remodelling and immune-modulation. Biochim Biophys Acta 2009; 1796(1): 19-26
36 Ball SG, Shuttleworth CA, Kielty CM. Mesenchymal stem cells and neovascularization: role of platelet-derived growth factor receptors. J Cell Mol Med 2007; 11(5): 1012-1030
doi: 10.1111/j.1582-4934.2007.00120.x pmid:17979880
37 Chen MY, Lie PC, Li ZL, Wei X. Endothelial differentiation of Wharton’s jelly-derived mesenchymal stem cells in comparison with bone marrow-derived mesenchymal stem cells. Exp Hematol 2009; 37(5): 629-640
doi: 10.1016/j.exphem.2009.02.003 pmid:19375653
38 Siveen KS, Kuttan G. Role of macrophages in tumour progression. Immunol Lett 2009; 123(2): 97-102
doi: 10.1016/j.imlet.2009.02.011 pmid:19428556
39 Coffelt SB, Hughes R, Lewis CE. Tumor-associated macrophages: effectors of angiogenesis and tumor progression. Biochim Biophys Acta 2009; 1796(1): 11-18
40 Maniotis AJ, Folberg R, Hess A, Seftor EA, Gardner LM, Pe’er J, Trent JM, Meltzer PS, Hendrix MJ. Vascular channel formation by human melanoma cells in vivo and in vitro: vasculogenic mimicry. Am J Pathol 1999; 155(3): 739-752
doi: 10.1016/S0002-9440(10)65173-5 pmid:10487832
41 Folberg R, Hendrix MJ, Maniotis AJ. Vasculogenic mimicry and tumor angiogenesis. Am J Pathol 2000; 156(2): 361-381
doi: 10.1016/S0002-9440(10)64739-6 pmid:10666364
42 Seftor RE, Seftor EA, Koshikawa N, Meltzer PS, Gardner LM, Bilban M, Stetler-Stevenson WG, Quaranta V, Hendrix MJ. Cooperative interactions of laminin 5 gamma2 chain, matrix metalloproteinase-2, and membrane type-1-matrix/metalloproteinase are required for mimicry of embryonic vasculogenesis by aggressive melanoma. Cancer Res 2001; 61(17): 6322-6327
43 Sood AK, Fletcher MS, Zahn CM, Gruman LM, Coffin JE, Seftor EA, Hendrix MJ. The clinical significance of tumor cell-lined vasculature in ovarian carcinoma: implications for anti-vasculogenic therapy. Cancer Biol Ther 2002; 1(6): 661-664
44 Hendrix MJ, Seftor EA, Hess AR, Seftor RE. Vasculogenic mimicry and tumour-cell plasticity: lessons from melanoma. Nat Rev Cancer 2003; 3(6): 411-421
doi: 10.1038/nrc1092 pmid:12778131
45 Folberg R, Maniotis AJ. Vasculogenic mimicry. APMIS 2004; 112(7-8): 508-525
doi: 10.1111/j.1600-0463.2004.apm11207-0810.x pmid:15563313
46 Zhang S, Zhang D, Sun B. Vasculogenic mimicry: current status and future prospects. Cancer Lett 2007; 254(2): 157-164
doi: 10.1016/j.canlet.2006.12.036 pmid:17306454
47 Rak J, Milsom C, Yu J. Vascular determinants of cancer stem cell dormancy—do age and coagulation system play a role? APMIS 2008; 116(7-8): 660-676
doi: 10.1111/j.1600-0463.2008.01058.x pmid:18834410
48 Begg AC, Stewart FA, Vens C. Strategies to improve radiotherapy with targeted drugs. Nat Rev Cancer 2011;11(4):239-253
doi: 10.1038/nrc3007 pmid:21430696
49 Chiarugi V, Magnelli L, Cinelli M, Ruggiero M. Oncogenes, p53, and tumor angiogenesis. J Cancer Res Clin Oncol 1998; 124(9): 523-525
doi: 10.1007/s004320050209 pmid:9808428
50 Giri D, Ittmann M. Inactivation of the PTEN tumor suppressor gene is associated with increased angiogenesis in clinically localized prostate carcinoma. Hum Pathol 1999; 30(4): 419-424
doi: 10.1016/S0046-8177(99)90117-X pmid:10208463
51 Bohonowych JE,Gopal U, Isaacs JS. Hsp90 as a gatekeeper of tumor angiogenesis: clinical promise and potential pitfalls. J Oncol 2010; 2010: 412985
52 Gao JX. Cancer stem cells: the lessons from pre-cancerous stem cells. J Cell Mol Med 2008; 12(1): 67-96
doi: 10.1111/j.1582-4934.2007.00170.x pmid:18053092
53 Midulla M, Verma R, Pignatelli M, Ritter MA, Courtenay-Luck NS, George AJ. Source of oncofetal ED-B-containing fibronectin: implications of production by both tumor and endothelial cells. Cancer Res 2000; 60(1): 164-169
54 Ye Y, Yin DT, Chen L, Zhou Q, Shen R, He G, Yan Q, Tong Z, Issekutz AC, Shapiro CL, Barsky SH, Lin H, Li JJ, Gao JX. Identification of Piwil2-like (PL2L) proteins that promote tumorigenesis. PLoS ONE 2010; 5(10): e13406
doi: 10.1371/journal.pone.0013406 pmid:20975993
55 Oike Y, Ito Y, Hamada K, Zhang XQ, Miyata K, Arai F, Inada T, Araki K, Nakagata N, Takeya M, Kisanuki YY, Yanagisawa M, Gale NW, Suda T. Regulation of vasculogenesis and angiogenesis by EphB/ephrin-B2 signaling between endothelial cells and surrounding mesenchymal cells. Blood 2002; 100(4): 1326-1333
56 Djokovic D, Trindade A, Gigante J, Badenes M, Silva L, Liu R, Li X, Gong M, Krasnoperov V, Gill PS, Duarte A. Combination of Dll4/Notch and Ephrin-B2/EphB4 targeted therapy is highly effective in disrupting tumor angiogenesis. BMC Cancer 2010; 10(1): 641-652
doi: 10.1186/1471-2407-10-641 pmid:21092311
57 McColgan P, Sharma P. Polymorphisms of matrix metalloproteinases 1, 2, 3 and 9 and susceptibility to lung, breast and colorectal cancer in over 30,000 subjects. Int J Cancer 2009; 125(6): 1473-1478
doi: 10.1002/ijc.24441 pmid:19507256
58 Taveau JC, Dubois M, Le Bihan O, Trépout S, Almagro S, Hewat E, Durmort C, Heyraud S, Gulino-Debrac D, Lambert O. Structure of artificial and natural VE-cadherin-based adherens junctions. Biochem Soc Trans 2008; 36(2): 189-193
doi: 10.1042/BST0360189 pmid:18363560
59 Sun Q, Zhou H, Binmadi NO, Basile JR. Hypoxia-inducible factor-1-mediated regulation of semaphorin 4D affects tumor growth and vascularity. J Biol Chem 2009; 284(46): 32066-32074
doi: 10.1074/jbc.M109.057166 pmid:19762474
60 Suri C, Jones PF, Patan S, Bartunkova S, Maisonpierre PC, Davis S, Sato TN, Yancopoulos GD. Requisite role of angiopoietin-1, a ligand for the TIE2 receptor, during embryonic angiogenesis. Cell 1996; 87(7): 1171-1180
doi: 10.1016/S0092-8674(00)81813-9 pmid:8980224
61 Suri C, McClain J, Thurston G, McDonald DM, Zhou H, Oldmixon EH, Sato TN, Yancopoulos GD. Increased vascularization in mice overexpressing angiopoietin-1. Science 1998; 282(5388): 468-471
doi: 10.1126/science.282.5388.468 pmid:9774272
62 Thurston G, Suri C, Smith K, McClain J, Sato TN, Yancopoulos GD, McDonald DM. Leakage-resistant blood vessels in mice transgenically overexpressing angiopoietin-1. Science 1999; 286(5449): 2511-2514
doi: 10.1126/science.286.5449.2511 pmid:10617467
63 Hayes AJ, Huang WQ, Yu J, Maisonpierre PC, Liu A, Kern FG, Lippman ME, McLeskey SW, Li LY. Expression and function of angiopoietin-1 in breast cancer. Br J Cancer 2000; 83(9): 1154-1160
doi: 10.1054/bjoc.2000.1437 pmid:11027428
64 Willett CG, Boucher Y, di Tomaso E, Duda DG, Munn LL, Tong RT, Chung DC, Sahani DV, Kalva SP, Kozin SV, Mino M, Cohen KS, Scadden DT, Hartford AC, Fischman AJ, Clark JW, Ryan DP, Zhu AX, Blaszkowsky LS, Chen HX, Shellito PC, Lauwers GY, Jain RK. Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Nat Med 2004; 10(2): 145-147
doi: 10.1038/nm988 pmid:14745444
65 Ferrara N, Hillan KJ, Novotny W. Bevacizumab (Avastin), a humanized anti-VEGF monoclonal antibody for cancer therapy. Biochem Biophys Res Commun 2005; 333(2): 328-335
doi: 10.1016/j.bbrc.2005.05.132 pmid:15961063
66 Jain RK, Duda DG, Willett CG, Sahani DV, Zhu AX, Loeffler JS, Batchelor TT, Sorensen AG. Biomarkers of response and resistance to antiangiogenic therapy. Nat Rev Clin Oncol 2009; 6(6): 327-338
doi: 10.1038/nrclinonc.2009.63 pmid:19483739
67 Greenberg JI, Cheresh DA. VEGF as an inhibitor of tumor vessel maturation: implications for cancer therapy. Expert Opin Biol Ther 2009; 9(11): 1347-1356
doi: 10.1517/14712590903208883 pmid:19761418
68 Tong RT, Boucher Y, Kozin SV, Winkler F, Hicklin DJ, Jain RK. Vascular normalization by vascular endothelial growth factor receptor 2 blockade induces a pressure gradient across the vasculature and improves drug penetration in tumors. Cancer Res 2004; 64(11): 3731-3736
doi: 10.1158/0008-5472.CAN-04-0074 pmid:15172975
69 Winkler F, Kozin SV, Tong RT, Chae SS, Booth MF, Garkavtsev I, Xu L, Hicklin DJ, Fukumura D, di Tomaso E, Munn LL, Jain RK. Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: role of oxygenation, angiopoietin-1, and matrix metalloproteinases. Cancer Cell 2004; 6(6): 553-563
70 Ladroue C, Carcenac R, Leporrier M, Gad S, Le Hello C, Galateau-Salle F, Feunteun J, Pouysségur J, Richard S, Gardie B. PHD2 mutation and congenital erythrocytosis with paraganglioma. N Engl J Med 2008; 359(25): 2685-2692
doi: 10.1056/NEJMoa0806277 pmid:19092153
71 Mazzone M, Dettori D, Leite de Oliveira R, Loges S, Schmidt T, Jonckx B, Tian YM, Lanahan AA, Pollard P, Ruiz de Almodovar C, De Smet F, Vinckier S, Aragonés J, Debackere K, Luttun A, Wyns S, Jordan B, Pisacane A, Gallez B, Lampugnani MG, Dejana E, Simons M, Ratcliffe P, Maxwell P, Carmeliet P. Heterozygous deficiency of PHD2 restores tumor oxygenation and inhibits metastasis via endothelial normalization. Cell 2009; 136(5): 839-851
doi: 10.1016/j.cell.2009.01.020 pmid:19217150
72 Kim JW, Johnson RS. You don’t need a PHD to grow a tumor. Dev Cell 2009; 16(6): 781-782
doi: 10.1016/j.devcel.2009.06.001 pmid:19531349
73 Choi HJ, Song BJ, Gong YD, Gwak WJ, Soh Y. Rapid degradation of hypoxia-inducible factor-1alpha by KRH102053, a new activator of prolyl hydroxylase 2. Br J Pharmacol 2008; 154(1): 114-125
doi: 10.1038/bjp.2008.70 pmid:18332861
74 Nepal M, Gong YD, Park YR, Soh Y. An activator of PHD2, KRH102140, decreases angiogenesis via inhibition of HIF-1α. Cell Biochem Funct 2011; 29(2): 126-134
doi: 10.1002/cbf.1732 pmid:21287578
75 Vestweber D. VE-cadherin: the major endothelial adhesion molecule controlling cellular junctions and blood vessel formation. Arterioscler Thromb Vasc Biol 2008; 28(2): 223-232
doi: 10.1161/ATVBAHA.107.158014 pmid:18162609
76 Gavard J. Breaking the VE-cadherin bonds. FEBS Lett 2009; 583(1): 1-6
doi: 10.1016/j.febslet.2008.11.032 pmid:19059243
77 Dejana E, Orsenigo F, Lampugnani MG. The role of adherens junctions and VE-cadherin in the control of vascular permeability. J Cell Sci 2008; 121(13): 2115-2122
doi: 10.1242/jcs.017897 pmid:18565824
78 Zhang LZ, Mei J, Qian ZK, Cai XS, Jiang Y, Huang WD. The role of VE-cadherin in osteosarcoma cells. Pathol Oncol Res 2010; 16(1): 111-117
doi: 10.1007/s12253-009-9198-1 pmid:19760520
79 Cavallaro U, Liebner S, Dejana E. Endothelial cadherins and tumor angiogenesis. Exp Cell Res 2006; 312(5): 659-667
doi: 10.1016/j.yexcr.2005.09.019 pmid:16256984
80 Labelle M, Schnittler HJ, Aust DE, Friedrich K, Baretton G, Vestweber D, Breier G. Vascular endothelial cadherin promotes breast cancer progression via transforming growth factor beta signaling. Cancer Res 2008; 68(5): 1388-1397
doi: 10.1158/0008-5472.CAN-07-2706 pmid:18316602
81 Otani A, Slike BM, Dorrell MI, Hood J, Kinder K, Ewalt KL, Cheresh D, Schimmel P, Friedlander M. A fragment of human TrpRS as a potent antagonist of ocular angiogenesis. Proc Natl Acad Sci USA 2002; 99(1): 178-183
doi: 10.1073/pnas.012601899 pmid:11773625
82 Banin E, Dorrell MI, Aguilar E, Ritter MR, Aderman CM, Smith AC, Friedlander J, Friedlander M. T2-TrpRS inhibits preretinal neovascularization and enhances physiological vascular regrowth in OIR as assessed by a new method of quantification. Invest Ophthalmol Vis Sci 2006; 47(5): 2125-2134
doi: 10.1167/iovs.05-1096 pmid:16639024
83 Zhou Q, Kiosses WB, Liu J, Schimmel P. Tumor endothelial cell tube formation model for determining anti-angiogenic activity of a tRNA synthetase cytokine. Methods 2008; 44(2): 190-195
doi: 10.1016/j.ymeth.2007.10.004 pmid:18241800
84 Zhou Q, Kapoor M, Guo M, Belani R, Xu X, Kiosses WB, Hanan M, Park C, Armour E, Do MH, Nangle LA, Schimmel P, Yang XL. Orthogonal use of a human tRNA synthetase active site to achieve multifunctionality. Nat Struct Mol Biol 2010; 17(1): 57-61
doi: 10.1038/nsmb.1706 pmid:20010843
85 Jaggi JS, Henke E, Seshan SV, Kappel BJ, Chattopadhyay D, May C, McDevitt MR, Nolan D, Mittal V, Benezra R, Scheinberg DA. Selective alpha-particle mediated depletion of tumor vasculature with vascular normalization. PLoS ONE 2007; 2(3): e267
doi: 10.1371/journal.pone.0000267 pmid:17342201
86 Rolny C, Mazzone M, Tugues S, Laoui D, Johansson I, Coulon C, Squadrito ML, Segura I, Li X, Knevels E, Costa S, Vinckier S, Dresselaer T, ?kerud P, De Mol M, Salom?ki H, Phillipson M, Wyns S, Larsson E, Buysschaert I, Botling J, Himmelreich U, Van Ginderachter JA, De Palma M, Dewerchin M, Claesson-Welsh L, Carmeliet P. HRG inhibits tumor growth and metastasis by inducing macrophage polarization and vessel normalization through downregulation of PlGF. Cancer Cell 2011; 19(1): 31-44
doi: 10.1016/j.ccr.2010.11.009 pmid:21215706
87 Wang L, Zhou GB, Liu P, Song JH, Liang Y, Yan XJ, Xu F, Wang BS, Mao JH, Shen ZX, Chen SJ, Chen Z. Dissection of mechanisms of Chinese medicinal formula Realgar-Indigo naturalis as an effective treatment for promyelocytic leukemia. Proc Natl Acad Sci USA 2008; 105(12): 4826-4831
doi: 10.1073/pnas.0712365105 pmid:18344322
88 Xiong L, Tian SX. A concept of regulating tumor microenvironment immune and normalizing angiogenesis by Chinese medicine drug therapy for supporting zheng-qi to prop up root. Chin J Integr Traidt West Med (Zhongguo Zhong Xi Yi Jie He Za Zhi) 2010; 30(2): 201-204 (in Chinese)
89 Pang X, Yi Z, Zhang J, Lu B, Sung B, Qu W, Aggarwal BB, Liu M. Celastrol suppresses angiogenesis-mediated tumor growth through inhibition of AKT/mammalian target of rapamycin pathway. Cancer Res 2010; 70(5): 1951-1959
doi: 10.1158/0008-5472.CAN-09-3201 pmid:20160026
90 Pang X, Yi T, Yi Z, Cho SG, Qu W, Pinkaew D, Fujise K, Liu M. Morelloflavone, a biflavonoid, inhibits tumor angiogenesis by targeting rho GTPases and extracellular signal-regulated kinase signaling pathways. Cancer Res 2009; 69(2): 518-525
doi: 10.1158/0008-5472.CAN-08-2531 pmid:19147565
91 Qiang L, Yang Y, You QD, Ma YJ, Yang L, Nie FF, Gu HY, Zhao L, Lu N, Qi Q, Liu W, Wang XT, Guo QL. Inhibition of glioblastoma growth and angiogenesis by gambogic acid: an in vitro and in vivo study. Biochem Pharmacol 2008; 75(5): 1083-1092
doi: 10.1016/j.bcp.2007.10.033 pmid:18070617
92 Pang X, Yi Z, Zhang X, Sung B, Qu W, Lian X, Aggarwal BB, Liu M. Acetyl-11-keto-beta-boswellic acid inhibits prostate tumor growth by suppressing vascular endothelial growth factor receptor 2-mediated angiogenesis. Cancer Res 2009; 69(14): 5893-5900
doi: 10.1158/0008-5472.CAN-09-0755 pmid:19567671
93 Park B, Sung B, Yadav VR, Cho SG, Liu M, Aggarwal BB. Acetyl-11-keto-β-boswellic acid suppresses invasion of pancreatic cancer cells through the downregulation of CXCR4 chemokine receptor expression. Int J Cancer 2011; 129(1): 23-33
doi: 10.1002/ijc.25966 pmid:21448932
94 Pang X, Zhang L, Lai L, Chen J, Wu Y, Yi Z, Zhang J, Qu W, Aggarwal BB, Liu M. 1′-Acetoxychavicol acetate suppresses angiogenesis-mediated human prostate tumor growth by targeting VEGF-mediated Src-FAK-Rho GTPase-signaling pathway. Carcinogenesis 2011; 32(6): 904-912
doi: 10.1093/carcin/bgr052 pmid:21427164
95 Kuang L, Wang L, Wang Q, Zhao Q, Du B, Li D, Luo J, Liu M, Hou A, Qian M. Cudratricusxanthone G inhibits human colorectal carcinoma cell invasion by MMP-2 down-regulation through suppressing activator protein-1 activity. Biochem Pharmacol 2011; 81(10): 1192-1200
doi: 10.1016/j.bcp.2011.02.017 pmid:21377450
96 Liu XD, Fan RF, Zhang Y, Yang HZ, Fang ZG, Guan WB, Lin DJ, Xiao RZ, Huang RW, Huang HQ, Liu PQ, Liu JJ. Down-regulation of telomerase activity and activation of caspase-3 are responsible for tanshinone I-induced apoptosis in monocyte leukemia cells in vitro. Int J Mol Sci 2010; 11(6): 2267-2280
doi: 10.3390/ijms11062267 pmid:20640151
97 Wu Y, Fan Q, Lu N, Tao L, Gao Y, Qi Q, Guo Q. Breviscapine-induced apoptosis of human hepatocellular carcinoma cell line HepG2 was involved in its antitumor activity. Phytother Res 2010; 24(8): 1188-1194
98 Lin J, Wei L, Xu W, Hong Z, Liu X, Peng J. Effect of Hedyotis diffusa Willd extract on tumor angiogenesis. Mol Med Report 2011; 4(6): 1283-1288
99 You J. Study on the tumor microenvironment and tumor vascular normalization in integrative treatment of tumor by Chinese medicine and western medicine.Chin J Integr Traidt West Med (Zhongguo Zhong Xi Yi Jie He Za Zhi) 2011; 31(8): 1127-1131 (in Chinese)
100 Hida K, Hida Y, Amin DN, Flint AF, Panigrahy D, Morton CC, Klagsbrun M. Tumor-associated endothelial cells with cytogenetic abnormalities. Cancer Res 2004; 64(22): 8249-8255
doi: 10.1158/0008-5472.CAN-04-1567 pmid:15548691
101 Tian S, Hayes AJ, Metheny-Barlow LJ, Li LY. Stabilization of breast cancer xenograft tumour neovasculature by angiopoietin-1. Br J Cancer 2002; 86(4): 645-651
doi: 10.1038/sj.bjc.6600082 pmid:11870550
102 Metheny-Barlow LJ, Li LY. The enigmatic role of angiopoietin-1 in tumor angiogenesis. Cell Res 2003; 13(5): 309-317
doi: 10.1038/ pmid:14672554
103 Inai T, Mancuso M, Hashizume H, Baffert F, Haskell A, Baluk P, Hu-Lowe DD, Shalinsky DR, Thurston G, Yancopoulos GD, McDonald DM. 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 2004; 165(1): 35-52
doi: 10.1016/S0002-9440(10)63273-7 pmid:15215160
104 Coulon C, Georgiadou M, Roncal C, De Bock K, Langenberg T, Carmeliet P. From vessel sprouting to normalization: role of the prolyl hydroxylase domain protein/hypoxia-inducible factor oxygen-sensing machinery. Arterioscler Thromb Vasc Biol 2010; 30(12): 2331-2336
doi: 10.1161/ATVBAHA.110.214106 pmid:20966400
105 Sorensen AG, Batchelor TT, Zhang WT, Chen PJ, Yeo P, Wang M, Jennings D, Wen PY, Lahdenranta J, Ancukiewicz M, di Tomaso E, Duda DG, Jain RK. A “vascular normalization index” as potential mechanistic biomarker to predict survival after a single dose of cediranib in recurrent glioblastoma patients. Cancer Res 2009; 69(13): 5296-5300
doi: 10.1158/0008-5472.CAN-09-0814 pmid:19549889
106 Zhang Q, Bindokas V, Shen J, Fan H, Hoffman RM, Xing HR. Time-course imaging of therapeutic functional tumor vascular normalization by antiangiogenic agents. Mol Cancer Ther 2011; 10(7): 1173-1184
doi: 10.1158/1535-7163.MCT-11-0008 pmid:21586628
107 Hormigo A, Gutin PH, Rafii S. Tracking normalization of brain tumor vasculature by magnetic imaging and proangiogenic biomarkers. Cancer Cell 2007; 11(1): 6-8
doi: 10.1016/j.ccr.2006.12.008 pmid:17222788
[1] Zixin Shu, Yana Zhou, Kai Chang, Jifen Liu, Xiaojun Min, Qing Zhang, Jing Sun, Yajuan Xiong, Qunsheng Zou, Qiguang Zheng, Jinghui Ji, Josiah Poon, Baoyan Liu, Xuezhong Zhou, Xiaodong Li. Clinical features and the traditional Chinese medicine therapeutic characteristics of 293 COVID-19 inpatient cases[J]. Front. Med., 2020, 14(6): 760-775.
[2] Qingwei Li, Han Wang, Xiuyang Li, Yujiao Zheng, Yu Wei, Pei Zhang, Qiyou Ding, Jiaran Lin, Shuang Tang, Yikun Zhao, Linhua Zhao, Xiaolin Tong. The role played by traditional Chinese medicine in preventing and treating COVID-19 in China[J]. Front. Med., 2020, 14(5): 681-688.
[3] Mengxue Huang, Jingjing Wang, Runshun Zhang, Zhuying Ni, Xiaoying Liu, Wenwen Liu, Weilian Kong, Yao Chen, Tiantian Huang, Guihua Li, Dan Wei, Jianzhong Liu, Xuezhong Zhou. Symptom network topological features predict the effectiveness of herbal treatment for pediatric cough[J]. Front. Med., 2020, 14(3): 357-367.
[4] Qiqi Zhao, Xin Gao, Guangli Yan, Aihua Zhang, Hui Sun, Ying Han, Wenxiu Li, Liang Liu, Xijun Wang. Chinmedomics facilitated quality-marker discovery of Sijunzi decoction to treat spleen qi deficiency syndrome[J]. Front. Med., 2020, 14(3): 335-356.
[5] Xiaojing Jiao, Dong Zhang, Quan Hong, Lei Yan, Qiuxia Han, Fengmin Shao, Guangyan Cai, Xiangmei Chen, Hanyu Zhu. Netrin-1 works with UNC5B to regulate angiogenesis in diabetic kidney disease[J]. Front. Med., 2020, 14(3): 293-304.
[6] Amy Lee, Fa-Chyi Lee. Medical oncology management of advanced hepatocellular carcinoma 2019: a reality check[J]. Front. Med., 2020, 14(3): 273-283.
[7] Anqi Chen, Suhua Zhang, Jixi Li, Chaoneng Ji, Jinzhong Chen, Chengtao Li. Detecting genetic hypermutability of gastrointestinal tumor by using a forensic STR kit[J]. Front. Med., 2020, 14(1): 101-111.
[8] Yuan Gao, Zhilei Wang, Jinfa Tang, Xiaoyi Liu, Wei Shi, Nan Qin, Xiaoyan Wang, Yu Pang, Ruisheng Li, Yaming Zhang, Jiabo Wang, Ming Niu, Zhaofang Bai, Xiaohe Xiao. New incompatible pair of TCM: Epimedii Folium combined with Psoraleae Fructus induces idiosyncratic hepatotoxicity under immunological stress conditions[J]. Front. Med., 2020, 14(1): 68-80.
[9] Rui Zhou, Yuanshu Liu, Wenjun Huang, Xitong Dang. Potential functions of esophageal cancer-related gene-4 in the cardiovascular system[J]. Front. Med., 2019, 13(6): 639-645.
[10] Xin Qin, Ping Zhang. ECRG4: a new potential target in precision medicine[J]. Front. Med., 2019, 13(5): 540-546.
[11] Hudan Pan, Yanfang Zheng, Zhongqiu Liu, Zhongwen Yuan, Rutong Ren, Hua Zhou, Ying Xie, Liang Liu. Deciphering the pharmacological mechanism of Guan-Jie-Kang in treating rat adjuvant-induced arthritis using omics analysis[J]. Front. Med., 2019, 13(5): 564-574.
[12] Zhao Zhang, Jun Jiang, Xiaodong Wu, Mengyao Zhang, Dan Luo, Renyu Zhang, Shiyou Li, Youwen He, Huijie Bian, Zhinan Chen. Chimeric antigen receptor T cell targeting EGFRvIII for metastatic lung cancer therapy[J]. Front. Med., 2019, 13(1): 57-68.
[13] Min Zhang, Jingwen Yang, Wenjing Hua, Zhong Li, Zenghui Xu, Qijun Qian. Monitoring checkpoint inhibitors: predictive biomarkers in immunotherapy[J]. Front. Med., 2019, 13(1): 32-44.
[14] Yinlong Zhang, Guangna Liu, Jingyan Wei, Guangjun Nie. Platelet membrane-based and tumor-associated platelet- targeted drug delivery systems for cancer therapy[J]. Front. Med., 2018, 12(6): 667-677.
[15] Bin Yang, Yan Yu, Jing Chen, Yan Zhang, Ye Yin, Nan Yu, Ge Chen, Shifei Zhu, Haiyan Huang, Yongqun Yuan, Jihui Ai, Xinyu Wang, Kezhen Li. Possibility of women treated with fertility-sparing surgery for non-epithelial ovarian tumors to safely and successfully become pregnant---a Chinese retrospective cohort study among 148 cases[J]. Front. Med., 2018, 12(5): 509-517.
Full text