Abstract
Exosomes, belonging to the group of extracellular bodies, are released by healthy as well as cancerous cells and serve as a communication pathway. Tumor-derived exosomes (TEX) possess the capacity to reprogram the function of normal cells owing to their genetic and molecular cargo. Such exosomes target endothelial cells (among others) in the tumor microenvironment to promote angiogenesis. Blood supply is essential in solid tumor growth and metastasis. The potential of pro-angiogenic changes is enhanced by an increased amount of circulating tumor-derived exosomes in the body fluids of cancer patients. A vascular network is important, since the proliferation, as well as the metastatic spread of cancer cells depends on an adequate supply of oxygen and nutrients, and the removal of waste products. New blood vessels and lymphatic vessels are formed through processes called angiogenesis and lymphangiogenesis, respectively. Angiogenesis is regulated by both activator and inhibitor molecules. Thousands of patients have received anti-angiogenic therapy to date. Despite their theoretical efficacy, anti-angiogenic treatments have not proved beneficial in terms of long-term survival. Tumor-derived exosomes carrying pro-angiogenic factors might be a target for new anti-cancer therapy.
References
1. Zaborowski MP, Balaj L, Breakefield XO, Lai CP. Extracellular Vesicles: Composition, Biological Relevance, and Methods of Study. Bioscience. 2015;65(8):783-97.
2. Ribeiro MF, Zhu H, Millard RW, Fan GC. Exosomes Function in Pro- and Anti-Angiogenesis. Curr Angiogenes. 2013;2(1):54-9.
3. Escola JM, Kleijmeer MJ, Stoorvogel W, Griffith JM, Yoshie O, Geuze HJ. Selective enrichment of tetraspan proteins on the internal vesicles of multivesicular endosomes and on exosomes secreted by human B-lymphocytes. J Biol Chem. 1998;273(32):20121-7.
4. Heijnen HF, Schiel AE, Fijnheer R, Geuze HJ, Sixma JJ. Activated platelets release two types of membrane vesicles: microvesicles by surface shedding and exosomes derived from exocytosis of multivesicular bodies and alpha-granules. Blood. 1999;94(11):3791-9.
5. Lai RC, Arslan F, Lee MM, Sze NS, Choo A, Chen TS, et al. Exosome secreted by MSC reduces myocardial ischemia/reperfusion injury. Stem Cell Res. 2010;4(3):214-22.
6. Li QL, Bu N, Yu YC, Hua W, Xin XY. Exvivo experiments of human ovarian cancer ascites-derived exosomes presented by dendritic cells derived from umbilical cord blood for immunotherapy treatment. Clin Med Oncol. 2008;2:461-7.
7. Ma B, Ren J, Jiang HF, Jia J. [Antitumor activities against hepato-cellular carcinoma induced by bone marrow mesenchymal stem cells pulsed with tumor-derived exosomes]. Beijing Da Xue Xue Bao Yi Xue Ban. 2008;40(5):494-9.
8. Thery C, Regnault A, Garin J, Wolfers J, Zitvogel L, Ricciardi-Castagnoli P, et al. Molecular characterization of dendritic cell-derived exosomes. Selective accumulation of the heat shock protein hsc73. J Cell Biol. 1999;147(3):599-610.
9. Yu S, Liu C, Su K, Wang J, Liu Y, Zhang L, et al. Tumor exosomes inhibit differentiation of bone marrow dendritic cells. J Immunol. 2007;178(11):6867-75.
10. Zhang X, Wang X, Zhu H, Kranias EG, Tang Y, Peng T, et al. Hsp20 functions as a novel cardiokine in promoting angiogenesis via activation of VEGFR2. PLoS One. 2012;7(3):e32765.
11. Al-Nedawi K, Meehan B, Rak J. Microvesicles: messengers and mediators of tumor progression. Cell Cycle. 2009;8(13):2014-8.
12. Camussi G, Deregibus MC, Bruno S, Cantaluppi V, Biancone L. Exosomes/microvesicles as a mechanism of cell-to-cell communication. Kidney Int. 2010;78(9):838-48.
13. Wieckowski E, Whiteside TL. Human tumor-derived vs dendritic cell-derived exosomes have distinct biologic roles and molecular profiles. Immunol Res. 2006;36(1-3):247-54.
14. Zhu H, Fan GC. Extracellular/circulating microRNAs and their potential role in cardiovascular disease. Am J Cardiovasc Dis. 2011;1(2):138-49.
15. Burnier L, Fontana P, Kwak BR, Angelillo-Scherrer A. Cell-derived microparticles in haemostasis and vascular medicine. Thromb Haemost. 2009;101(3):439-51.
16. Dignat-George F, Boulanger CM. The many faces of endothelial microparticles. Arterioscler Thromb Vasc Biol. 2011;31(1):27-33.
17. Martinez MC, Andriantsitohaina R. Microparticles in angiogenesis: therapeutic potential. Circ Res. 2011;109(1):110-9.
18. Rajagopal C, Harikumar KB. The Origin and Functions of Exosomes in Cancer. Front Oncol. 2018;8:66.
19. Keller S, Ridinger J, Rupp AK, Janssen JW, Altevogt P. Body fluid derived exosomes as a novel template for clinical diagnostics. J Transl Med. 2011;9:86.
20. Ludwig N, Yerneni SS, Razzo BM, Whiteside TL. Exosomes from HNSCC Promote Angiogenesis through Reprogramming of Endothelial Cells. Mol Cancer Res. 2018;16(11):1798-808.
21. Nishida N, Yano H, Nishida T, Kamura T, Kojiro M. Angiogenesis in cancer. Vasc Health Risk Manag. 2006;2(3):213-9.
22. Rajabi M, Mousa SA. The Role of Angiogenesis in Cancer Treatment. Biomedicines. 2017;5(2).
23. Koch AE, Distler O. Vasculopathy and disordered angiogenesis in selected rheumatic diseases: rheumatoid arthritis and systemic sclerosis. Arthritis Res Ther. 2007;9 Suppl 2:S3.
24. 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):3731-6.
25. Izumi Y, Xu L, di Tomaso E, Fukumura D, Jain RK. Tumour biology: herceptin acts as an anti-angiogenic cocktail. Nature. 2002;416(6878):279-80.
26. Winkler F, Kozin SV, Tong RT, Chae SS, Booth MF, Garkavtsev I, et al. 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):553-63.
27. Yuan F, Chen Y, Dellian M, Safabakhsh N, Ferrara N, Jain RK. Time-dependent vascular regression and permeability changes in established human tumor xenografts induced by an anti-vascular endothelial growth factor/vascular permeability factor antibody. Proc Natl Acad Sci U S A. 1996;93(25):14765-70.
28. Willett CG, Boucher Y, di Tomaso E, Duda DG, Munn LL, Tong RT, et al. Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Nat Med. 2004;10(2):145-7.
29. Inai T, Mancuso M, Hashizume H, Baffert F, Haskell A, Baluk P, et al. 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.
30. Lee Y, El Andaloussi S, Wood MJ. Exosomes and microvesicles: extracellular vesicles for genetic information transfer and gene therapy. Hum Mol Genet. 2012;21(R1):R125-34.
31. Padera TP, Stoll BR, Tooredman JB, Capen D, di Tomaso E, Jain RK. Pathology: cancer cells compress intratumour vessels. Nature. 2004;427(6976):695.
32. Denekamp J. Review article: angiogenesis, neovascular proliferation and vascular pathophysiology as targets for cancer therapy. Br J Radiol. 1993;66(783):181-96.
33. Dameron KM, Volpert OV, Tainsky MA, Bouck N. Control of angiogenesis in fibroblasts by p53 regulation of thrombospondin-1. Science. 1994;265(5178):1582-4.
34. Folkman J. What is the evidence that tumors are angiogenesis dependent? J Natl Cancer Inst. 1990;82(1):4-6.
35. Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med. 1995;1(1):27-31.
36. Folkman J. Seminars in Medicine of the Beth Israel Hospital, Boston. Clinical applications of research on angiogenesis. N Engl J Med. 1995;333(26):1757-63.
37. Bottaro DP, Liotta LA. Cancer: Out of air is not out of action. Nature. 2003;423(6940):593-5.
38. Mizejewski GJ. Role of integrins in cancer: survey of expression patterns. Proc Soc Exp Biol Med. 1999;222(2):124-38.
39. Nelson AR, Fingleton B, Rothenberg ML, Matrisian LM. Matrix metalloproteinases: biologic activity and clinical implications. J Clin Oncol. 2000;18(5):1135-49.
40. Maisonpierre PC, Suri C, Jones PF, Bartunkova S, Wiegand SJ, Radziejewski C, et al. Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science. 1997;277(5322):55-60.
41. Suri C, Jones PF, Patan S, Bartunkova S, Maisonpierre PC, Davis S, et al. Requisite role of angiopoietin-1, a ligand for the TIE2 receptor, during embryonic angiogenesis. Cell. 1996;87(7):1171-80.
42. Tournaire R, Simon MP, le Noble F, Eichmann A, England P, Pouyssegur J. A short synthetic peptide inhibits signal transduction, migration and angiogenesis mediated by Tie2 receptor. EMBO Rep. 2004;5(3):262-7.
43. Salven P, Lymboussaki A, Heikkila P, Jaaskela-Saari H, Enholm B, Aase K, et al. Vascular endothelial growth factors VEGF-B and VEGF-C are expressed in human tumors. Am J Pathol. 1998;153(1):103-8.
44. Amioka T, Kitadai Y, Tanaka S, Haruma K, Yoshihara M, Yasui W, et al. Vascular endothelial growth factor-C expression predicts lymph node metastasis of human gastric carcinomas invading the submucosa. Eur J Cancer. 2002;38(10):1413-9.
45. Andre T, Kotelevets L, Vaillant JC, Coudray AM, Weber L, Prevot S, et al. Vegf, Vegf-B, Vegf-C and their receptors KDR, FLT-1 and FLT-4 during the neoplastic progression of human colonic mucosa. Int J Cancer. 2000;86(2):174-81.
46. Boocock CA, Charnock-Jones DS, Sharkey AM, McLaren J, Barker PJ, Wright KA, et al. Expression of vascular endothelial growth factor and its receptors flt and KDR in ovarian carcinoma. J Natl Cancer Inst. 1995;87(7):506-16.
47. Decaussin M, Sartelet H, Robert C, Moro D, Claraz C, Brambilla C, et al. Expression of vascular endothelial growth factor (VEGF) and its two receptors (VEGF-R1-Flt1 and VEGF-R2-Flk1/KDR) in non-small cell lung carcinomas (NSCLCs): correlation with angiogenesis and survival. J Pathol. 1999;188(4):369-77.
48. Furudoi A, Tanaka S, Haruma K, Kitadai Y, Yoshihara M, Chayama K, et al. Clinical significance of vascular endothelial growth factor C expression and angiogenesis at the deepest invasive site of advanced colorectal carcinoma. Oncology. 2002;62(2):157-66.
49. George ML, Tutton MG, Janssen F, Arnaout A, Abulafi AM, Eccles SA, et al. VEGF-A, VEGF-C, and VEGF-D in colorectal cancer progression. Neoplasia. 2001;3(5):420-7.
50. Gunningham SP, Currie MJ, Han C, Robinson BA, Scott PA, Harris AL, et al. The short form of the alternatively spliced flt-4 but not its ligand vascular endothelial growth factor C is related to lymph node metastasis in human breast cancers. Clin Cancer Res. 2000;6(11):4278-86.
51. Hashimoto I, Kodama J, Seki N, Hongo A, Yoshinouchi M, Okuda H, et al. Vascular endothelial growth factor-C expression and its relationship to pelvic lymph node status in invasive cervical cancer. Br J Cancer. 2001;85(1):93-7.
52. Hirai M, Nakagawara A, Oosaki T, Hayashi Y, Hirono M, Yoshihara T. Expression of vascular endothelial growth factors (VEGF-A/VEGF-1 and VEGF-C/VEGF-2) in postmenopausal uterine endometrial carcinoma. Gynecol Oncol. 2001;80(2):181-8.
53. Jussila L, Valtola R, Partanen TA, Salven P, Heikkila P, Matikainen MT, et al. Lymphatic endothelium and Kaposi’s sarcoma spindle cells detected by antibodies against the vascular endothelial growth factor receptor-3. Cancer Res. 1998;58(8):1599-604.
54. Kinoshita J, Kitamura K, Kabashima A, Saeki H, Tanaka S, Sugimachi K. Clinical significance of vascular endothelial growth factor-C (VEGF-C) in breast cancer. Breast Cancer Res Treat. 2001;66(2):159-64.
55. Kurebayashi J, Otsuki T, Kunisue H, Mikami Y, Tanaka K, Yamamoto S, et al. Expression of vascular endothelial growth factor (VEGF) family members in breast cancer. Jpn J Cancer Res. 1999;90(9):977-81.
56. Niki T, Iba S, Tokunou M, Yamada T, Matsuno Y, Hirohashi S. Expression of vascular endothelial growth factors A, B, C, and D and their relationships to lymph node status in lung adenocarcinoma. Clin Cancer Res. 2000;6(6):2431-9.
57. Nishida N, Yano H, Komai K, Nishida T, Kamura T, Kojiro M. Vascular endothelial growth factor C and vascular endothelial growth factor receptor 2 are related closely to the prognosis of patients with ovarian carcinoma. Cancer. 2004;101(6):1364-74.
58. Ohta Y, Shridhar V, Bright RK, Kalemkerian GP, Du W, Carbone M, et al. VEGF and VEGF type C play an important role in angiogenesis and lymphangiogenesis in human malignant mesothelioma tumours. Br J Cancer. 1999;81(1):54-61.
59. O-charoenrat P, Rhys-Evans P, Eccles SA. Expression of vascular endothelial growth factor family members in head and neck squamous cell carcinoma correlates with lymph node metastasis. Cancer. 2001;92(3):556-68.
60. Skobe M, Hawighorst T, Jackson DG, Prevo R, Janes L, Velasco P, et al. Induction of tumor lymphangiogenesis by VEGF-C promotes breast cancer metastasis. Nat Med. 2001;7(2):192-8.
61. Yokoyama Y, Charnock-Jones DS, Licence D, Yanaihara A, Hastings JM, Holland CM, et al. Vascular endothelial growth factor-D is an independent prognostic factor in epithelial ovarian carcinoma. Br J Cancer. 2003;88(2):237-44.
62. Yonemura Y, Endo Y, Fujita H, Fushida S, Ninomiya I, Bandou E, et al. Role of vascular endothelial growth factor C expression in the development of lymph node metastasis in gastric cancer. Clin Cancer Res. 1999;5(7):1823-9.
63. Kajita T, Ohta Y, Kimura K, Tamura M, Tanaka Y, Tsunezuka Y, et al. The expression of vascular endothelial growth factor C and its receptors in non-small cell lung cancer. Br J Cancer. 2001; 85(2):255-60.
64. Mousa SA, Lin HY, Tang HY, Hercbergs A, Luidens MK, Davis PJ. Modulation of angiogenesis by thyroid hormone and hormone analogues: implications for cancer management. Angiogenesis. 2014;17(3):463-9.
65. Finetti F, Solito R, Morbidelli L, Giachetti A, Ziche M, Donnini S. Prostaglandin E2 regulates angiogenesis via activation of fibroblast growth factor receptor-1. J Biol Chem. 2008;283(4):2139-46.
66. Xu L, Stevens J, Hilton MB, Seaman S, Conrads TP, Veenstra TD, et al. COX-2 inhibition potentiates antiangiogenic cancer therapy and prevents metastasis in preclinical models. Sci Transl Med. 2014; 6(242):242ra84.
67. Butler GS, Connor AR, Sounni NE, Eckhard U, Morrison CJ, Noel A, et al. Degradomic and yeast 2-hybrid inactive catalytic domain substrate trapping identifies new membrane-type 1 matrix metalloproteinase (MMP14) substrates: CCN3 (Nov) and CCN5 (WISP2). Matrix Biol. 2017;59:23-38.
68. Chen PC, Cheng HC, Wang J, Wang SW, Tai HC, Lin CW, et al. Prostate cancer-derived CCN3 induces M2 macrophage infiltration and contributes to angiogenesis in prostate cancer microenvironment. Oncotarget. 2014;5(6):1595-608.
69. Lin Z, Natesan V, Shi H, Hamik A, Kawanami D, Hao C, et al. A novel role of CCN3 in regulating endothelial inflammation. J Cell Commun Signal. 2010;4(3):141-53.
70. Zhang C, van der Voort D, Shi H, Zhang R, Qing Y, Hiraoka S, et al. Matricellular protein CCN3 mitigates abdominal aortic aneurysm. J Clin Invest. 2016;126(4):1282-99.
71. Andreuzzi E, Colladel R, Pellicani R, Tarticchio G, Cannizzaro R, Spessotto P, et al. The angiostatic molecule Multimerin 2 is processed by MMP-9 to allow sprouting angiogenesis. Matrix Biol. 2017;64:40-53.
72. Colladel R, Pellicani R, Andreuzzi E, Paulitti A, Tarticchio G, Todaro F, et al. MULTIMERIN2 binds VEGF-A primarily via the carbohydrate chains exerting an angiostatic function and impairing tumor growth. Oncotarget. 2016;7(2):2022-37.
73. Ali SH, O’Donnell AL, Balu D, Pohl MB, Seyler MJ, Mohamed S, et al. Estrogen receptor-alpha in the inhibition of cancer growth and angiogenesis. Cancer Res. 2000;60(24):7094-8.
74. Kerbel RS. Tumor angiogenesis. N Engl J Med. 2008;358(19):2039-49.
75. Pavlakovic H, Havers W, Schweigerer L. Multiple angiogenesis stimulators in a single malignancy: implications for anti-angiogenic tumour therapy. Angiogenesis. 2001;4(4):259-62.
76. Stack MS, Gately S, Bafetti LM, Enghild JJ, Soff GA. Angiostatin inhibits endothelial and melanoma cellular invasion by blocking matrix-enhanced plasminogen activation. Biochem J. 1999;340(Pt 1):77-84.
77. Claesson-Welsh L, Welsh M, Ito N, Anand-Apte B, Soker S, Zetter B, et al. Angiostatin induces endothelial cell apoptosis and activation of focal adhesion kinase independently of the integrin-binding motif RGD. Proc Natl Acad Sci U S A. 1998;95(10):5579-83.
78. Lucas R, Holmgren L, Garcia I, Jimenez B, Mandriota SJ, Borlat F, et al. Multiple forms of angiostatin induce apoptosis in endothelial cells. Blood. 1998;92(12):4730-41.
79. Kirsch M, Strasser J, Allende R, Bello L, Zhang J, Black PM. Angiostatin suppresses malignant glioma growth in vivo. Cancer Res. 1998;58(20):4654-9.
80. Rehn M, Veikkola T, Kukk-Valdre E, Nakamura H, Ilmonen M, Lombardo C, et al. Interaction of endostatin with integrins implicated in angiogenesis. Proc Natl Acad Sci U S A. 2001;98(3): 1024-9.
81. Wickstrom SA, Alitalo K, Keski-Oja J. Endostatin associates with integrin alpha5beta1 and caveolin-1, and activates Src via a tyrosyl phosphatase-dependent pathway in human endothelial cells. Cancer Res. 2002;62(19):5580-9.
82. Dhanabal M, Ramchandran R, Volk R, Stillman IE, Lombardo M, Iruela-Arispe ML, et al. Endostatin: yeast production, mutants, and antitumor effect in renal cell carcinoma. Cancer Res. 1999;59(1):189-97.
83. Olsson AK, Johansson I, Akerud H, Einarsson B, Christofferson R, Sasaki T, et al. The minimal active domain of endostatin is a heparin-binding motif that mediates inhibition of tumor vascularization. Cancer Res. 2004;64(24):9012-7.
84. O’Reilly MS, Boehm T, Shing Y, Fukai N, Vasios G, Lane WS, et al. Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell. 1997;88(2):277-85.
85. Hansen-Algenstaedt N, Stoll BR, Padera TP, Dolmans DE, Hicklin DJ, Fukumura D, et al. Tumor oxygenation in hormone-dependent tumors during vascular endothelial growth factor receptor-2 blockade, hormone ablation, and chemotherapy. Cancer Res. 2000;60(16):4556-60.
86. Helmlinger G, Endo M, Ferrara N, Hlatky L, Jain RK. Formation of endothelial cell networks. Nature. 2000;405(6783):139-41.
87. McKeown SR. Defining normoxia, physoxia and hypoxia in tumours-implications for treatment response. Br J Radiol. 2014;87(1035):20130676.
88. Eales KL, Hollinshead KE, Tennant DA. Hypoxia and metabolic adaptation of cancer cells. Oncogenesis. 2016;5:e190.
89. Ayob AZ, Ramasamy TS. Cancer stem cells as key drivers of tumour progression. J Biomed Sci. 2018;25(1):20.
90. Brahimi-Horn MC, Chiche J, Pouyssegur J. Hypoxia and cancer. J Mol Med (Berl). 2007;85(12):1301-7.
91. Harris AL. Hypoxia--a key regulatory factor in tumour growth. Nat Rev Cancer. 2002;2(1):38-47.
92. Ward JP. Oxygen sensors in context. Biochim Biophys Acta. 2008; 1777(1):1-14.
93. Semenza GL. Hypoxia-inducible factors in physiology and medicine. Cell. 2012;148(3):399-408.
94. Harada H, Inoue M, Itasaka S, Hirota K, Morinibu A, Shinomiya K, et al. Cancer cells that survive radiation therapy acquire HIF-1 activity and translocate towards tumour blood vessels. Nat Commun. 2012;3:783.
95. Semenza GL. The hypoxic tumor microenvironment: A driving force for breast cancer progression. Biochim Biophys Acta. 2016;1863(3): 382-91.
96. Semenza GL. Targeting HIF-1 for cancer therapy. Nat Rev Cancer. 2003;3(10):721-32.
97. Lu X, Kang Y. Hypoxia and hypoxia-inducible factors: master regulators of metastasis. Clin Cancer Res. 2010;16(24):5928-35.
98. King HW, Michael MZ, Gleadle JM. Hypoxic enhancement of exosome release by breast cancer cells. BMC Cancer. 2012;12:421.
99. Shao C, Yang F, Miao S, Liu W, Wang C, Shu Y, et al. Role of hypoxia-induced exosomes in tumor biology. Mol Cancer. 2018;17(1):120.
100. Kosaka N, Iguchi H, Hagiwara K, Yoshioka Y, Takeshita F, Ochiya T. Neutral sphingomyelinase 2 (nSMase2)-dependent exosomal transfer of angiogenic microRNAs regulate cancer cell metastasis. J Biol Chem. 2013;288(15):10849-59.
101. Tadokoro H, Umezu T, Ohyashiki K, Hirano T, Ohyashiki JH. Exosomes derived from hypoxic leukemia cells enhance tube formation in endothelial cells. J Biol Chem. 2013;288(48):34343-51.
102. Umezu T, Tadokoro H, Azuma K, Yoshizawa S, Ohyashiki K, Ohyashiki JH. Exosomal miR-135b shed from hypoxic multiple myeloma cells enhances angiogenesis by targeting factor-inhibiting HIF-1. Blood. 2014;124(25):3748-57.
103. Hsu YL, Hung JY, Chang WA, Lin YS, Pan YC, Tsai PH, et al. Hypoxic lung cancer-secreted exosomal miR-23a increased angiogenesis and vascular permeability by targeting prolyl hydroxylase and tight junction protein ZO-1. Oncogene. 2017;36(34):4929-42.
104. Mao G, Liu Y, Fang X, Liu Y, Fang L, Lin L, et al. Tumor-derived microRNA-494 promotes angiogenesis in non-small cell lung cancer. Angiogenesis. 2015;18(3):373-82.
105. Park JE, Tan HS, Datta A, Lai RC, Zhang H, Meng W, et al. Hypoxic tumor cell modulates its microenvironment to enhance angiogenic and metastatic potential by secretion of proteins and exosomes. Mol Cell Proteomics. 2010;9(6):1085-99.
106. Kore RA, Edmondson JL, Jenkins SV, Jamshidi-Parsian A, Dings RPM, Reyna NS, et al. Hypoxia-derived exosomes induce putative altered pathways in biosynthesis and ion regulatory channels in glioblastoma cells. Biochem Biophys Rep. 2018;14:104-13.
107. Skog J, Wurdinger T, van Rijn S, Meijer DH, Gainche L, Sena-Esteves M, et al. Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nat Cell Biol. 2008;10(12):1470-6.
108. Kucharzewska P, Christianson HC, Welch JE, Svensson KJ, Fredlund E, Ringner M, et al. Exosomes reflect the hypoxic status of glioma cells and mediate hypoxia-dependent activation of vascular cells during tumor development. Proc Natl Acad Sci U S A. 2013;110(18):7312-7.
109. Milia AF, Salis MB, Stacca T, Pinna A, Madeddu P, Trevisani M, et al. Protease-activated receptor-2 stimulates angiogenesis and accelerates hemodynamic recovery in a mouse model of hindlimb ischemia. Circ Res. 2002;91(4):346-52.
110. Svensson KJ, Kucharzewska P, Christianson HC, Skold S, Lofstedt T, Johansson MC, et al. Hypoxia triggers a proangiogenic pathway involving cancer cell microvesicles and PAR-2-mediated heparin-binding EGF signaling in endothelial cells. Proc Natl Acad Sci U S A. 2011;108(32):13147-52.
111. Huang Z, Feng Y. Exosomes Derived From Hypoxic Colorectal Cancer Cells Promote Angiogenesis Through Wnt4-Induced beta-Catenin Signaling in Endothelial Cells. Oncol Res. 2017;25(5):651-61.
112. Sruthi TV, Edatt L, Raji GR, Kunhiraman H, Shankar SS, Shankar V, et al. Horizontal transfer of miR-23a from hypoxic tumor cell colonies can induce angiogenesis. J Cell Physiol. 2018;233(4):3498-514.
113. Grange C, Tapparo M, Collino F, Vitillo L, Damasco C, Deregibus MC, et al. Microvesicles released from human renal cancer stem cells stimulate angiogenesis and formation of lung premetastatic niche. Cancer Res. 2011;71(15):5346-56.
114. Burnley-Hall N, Willis G, Davis J, Rees DA, James PE. Nitrite-derived nitric oxide reduces hypoxia-inducible factor 1alpha-mediated extracellular vesicle production by endothelial cells. Nitric Oxide. 2017;63:1-12.
115. Zhang G, Zhang Y, Cheng S, Wu Z, Liu F, Zhang J. CD133 positive U87 glioblastoma cells-derived exosomal microRNAs in hypoxia- versus normoxia-microenviroment. J Neurooncol. 2017;135(1):37-46.
116. Luga V, Zhang L, Viloria-Petit AM, Ogunjimi AA, Inanlou MR, Chiu E, et al. Exosomes mediate stromal mobilization of autocrine Wnt-PCP signaling in breast cancer cell migration. Cell. 2012;151(7):1542-56.
117. Alvarez-Teijeiro S, Garcia-Inclan C, Villaronga MA, Casado P, Hermida-Prado F, Granda-Diaz R, et al. Factors Secreted by Cancer-Associated Fibroblasts that Sustain Cancer Stem Properties in Head and Neck Squamous Carcinoma Cells as Potential Therapeutic Targets. Cancers (Basel). 2018;10(9).
118. Calvo F, Ege N, Grande-Garcia A, Hooper S, Jenkins RP, Chaudhry SI, et al. Mechanotransduction and YAP-dependent matrix remodelling is required for the generation and maintenance of cancer-associated fibroblasts. Nat Cell Biol. 2013;15(6):637-46.
119. Koczorowska MM, Tholen S, Bucher F, Lutz L, Kizhakkedathu JN, De Wever O, et al. Fibroblast activation protein-alpha, a stromal cell surface protease, shapes key features of cancer associated fibroblasts through proteome and degradome alterations. Mol Oncol. 2016;10(1):40-58.
120. Ramteke A, Ting H, Agarwal C, Mateen S, Somasagara R, Hussain A, et al. Exosomes secreted under hypoxia enhance invasiveness and stemness of prostate cancer cells by targeting adherens junction molecules. Mol Carcinog. 2015;54(7):554-65.
121. Fiaschi T, Giannoni E, Taddei ML, Cirri P, Marini A, Pintus G, et al. Carbonic anhydrase IX from cancer-associated fibroblasts drives epithelial-mesenchymal transition in prostate carcinoma cells. Cell Cycle. 2013;12(11):1791-801.
122. Giannoni E, Bianchini F, Masieri L, Serni S, Torre E, Calorini L, et al. Reciprocal activation of prostate cancer cells and cancer-associated fibroblasts stimulates epithelial-mesenchymal transition and cancer stemness. Cancer Res. 2010;70(17):6945-56.
123. Maia J, Caja S, Strano Moraes MC, Couto N, Costa-Silva B. Exosome-Based Cell-Cell Communication in the Tumor Microenvironment. Front Cell Dev Biol. 2018;6:18.
124. Carmeliet P, Jain RK. Angiogenesis in cancer and other diseases. Nature. 2000;407(6801):249-57.
125. Yoon YJ, Kim DK, Yoon CM, Park J, Kim YK, Roh TY, et al. Egr-1 activation by cancer-derived extracellular vesicles promotes endothelial cell migration via ERK1/2 and JNK signaling pathways. PLoS One. 2014;9(12):e115170.
126. Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med. 1971;285(21):1182-6.
127. Song YH, Warncke C, Choi SJ, Choi S, Chiou AE, Ling L, et al. Breast cancer-derived extracellular vesicles stimulate myofibroblast differentiation and pro-angiogenic behavior of adipose stem cells. Matrix Biol. 2017;60-61:190-205.
128. Al-Nedawi K, Meehan B, Kerbel RS, Allison AC, Rak J. Endothelial expression of autocrine VEGF upon the uptake of tumor-derived microvesicles containing oncogenic EGFR. Proc Natl Acad Sci U S A. 2009;106(10):3794-9.
129. Conigliaro A, Costa V, Lo Dico A, Saieva L, Buccheri S, Dieli F, et al. CD90+ liver cancer cells modulate endothelial cell phenotype through the release of exosomes containing H19 lncRNA. Mol Cancer. 2015;14:155.
130. Dickman CT, Lawson J, Jabalee J, MacLellan SA, LePard NE, Bennewith KL, et al. Selective extracellular vesicle exclusion of miR-142-3p by oral cancer cells promotes both internal and extracellular malignant phenotypes. Oncotarget. 2017;8(9):15252-66.
131. Lawson J, Dickman C, MacLellan S, Towle R, Jabalee J, Lam S, et al. Selective secretion of microRNAs from lung cancer cells via extracellular vesicles promotes CAMK1D-mediated tube formation in endothelial cells. Oncotarget. 2017;8(48):83913-24.
132. Schillaci O, Fontana S, Monteleone F, Taverna S, Di Bella MA, Di Vizio D, et al. Exosomes from metastatic cancer cells transfer amoeboid phenotype to non-metastatic cells and increase endothelial permeability: their emerging role in tumor heterogeneity. Sci Rep. 2017;7(1):4711.
133. Zhuang G, Wu X, Jiang Z, Kasman I, Yao J, Guan Y, et al. Tumour-secreted miR-9 promotes endothelial cell migration and angiogenesis by activating the JAK-STAT pathway. EMBO J. 2012;31(17):3513-23.
134. You B, Shan Y, Bao L, Chen J, Yang L, Zhang Q, et al. The biology and function of extracellular vesicles in nasopharyngeal carcinoma (Review). Int J Oncol. 2018;52(1):38-46.
135. Liu Y, Luo F, Wang B, Li H, Xu Y, Liu X, et al. STAT3-regulated exosomal miR-21 promotes angiogenesis and is involved in neoplastic processes of transformed human bronchial epithelial cells. Cancer Lett. 2016;370(1):125-35.
136. Zomer A, Maynard C, Verweij FJ, Kamermans A, Schafer R, Beerling E, et al. In Vivo imaging reveals extracellular vesicle-mediated phenocopying of metastatic behavior. Cell. 2015;161(5):1046-57.
137. Kosaka N. Decoding the Secret of Cancer by Means of Extracellular Vesicles. J Clin Med. 2016;5(2).
138. Abak A, Abhari A, Rahimzadeh S. Exosomes in cancer: small vesicular transporters for cancer progression and metastasis, biomarkers in cancer therapeutics. PeerJ. 2018;6:e4763.
139. Al-Nedawi K, Meehan B, Micallef J, Lhotak V, May L, Guha A, et al. Intercellular transfer of the oncogenic receptor EGFRvIII by microvesicles derived from tumour cells. Nat Cell Biol. 2008;10(5):619-24.
140. Nazarenko I, Rana S, Baumann A, McAlear J, Hellwig A, Trendelenburg M, et al. Cell surface tetraspanin Tspan8 contributes to molecular pathways of exosome-induced endothelial cell activation. Cancer Res. 2010;70(4):1668-78.
141. Deregibus MC, Cantaluppi V, Calogero R, Lo Iacono M, Tetta C, Biancone L, et al. Endothelial progenitor cell derived microvesicles activate an angiogenic program in endothelial cells by a horizontal transfer of mRNA. Blood. 2007;110(7):2440-8.
142. Gesierich S, Berezovskiy I, Ryschich E, Zoller M. Systemic induction of the angiogenesis switch by the tetraspanin D6.1A/CO-029. Cancer Res. 2006;66(14):7083-94.
143. Thompson CA, Purushothaman A, Ramani VC, Vlodavsky I, Sanderson RD. Heparanase regulates secretion, composition, and function of tumor cell-derived exosomes. J Biol Chem. 2013;288(14):10093-9.
144. Hood JL, San RS, Wickline SA. Exosomes released by melanoma cells prepare sentinel lymph nodes for tumor metastasis. Cancer Res. 2011;71(11):3792-801.
145. Gajos-Michniewicz A, Duechler M, Czyz M. MiRNA in melanoma-derived exosomes. Cancer Lett. 2014;347(1):29-37.
146. Umezu T, Ohyashiki K, Kuroda M, Ohyashiki JH. Leukemia cell to endothelial cell communication via exosomal miRNAs. Oncogene. 2013;32(22):2747-55.
147. Zhou W, Fong MY, Min Y, Somlo G, Liu L, Palomares MR, et al. Cancer-secreted miR-105 destroys vascular endothelial barriers to promote metastasis. Cancer Cell. 2014;25(4):501-15.
148. Zitvogel L, Regnault A, Lozier A, Wolfers J, Flament C, Tenza D, et al. Eradication of established murine tumors using a novel cell-free vaccine: dendritic cell-derived exosomes. Nat Med. 1998;4(5):594-600.
149. Tominaga N, Kosaka N, Ono M, Katsuda T, Yoshioka Y, Tamura K, et al. Brain metastatic cancer cells release microRNA-181c-containing extracellular vesicles capable of destructing blood-brain barrier. Nat Commun. 2015;6:6716.
150. Treps L, Perret R, Edmond S, Ricard D, Gavard J. Glioblastoma stem-like cells secrete the pro-angiogenic VEGF-A factor in extracellular vesicles. J Extracell Vesicles. 2017;6(1):1359479.
151. Peinado H, Aleckovic M, Lavotshkin S, Matei I, Costa-Silva B, Moreno-Bueno G, et al. Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. Nat Med. 2012;18(6):883-91.
152. Fabbri M, Paone A, Calore F, Galli R, Gaudio E, Santhanam R, et al. MicroRNAs bind to Toll-like receptors to induce prometastatic inflammatory response. Proc Natl Acad Sci U S A. 2012;109(31): E2110-6.
153. Jabalee J, Towle R, Garnis C. The Role of Extracellular Vesicles in Cancer: Cargo, Function, and Therapeutic Implications. Cells. 2018;7(8).
154. McCready J, Sims JD, Chan D, Jay DG. Secretion of extracellular hsp90alpha via exosomes increases cancer cell motility: a role for plasminogen activation. BMC Cancer. 2010;10:294.
155. Gopal SK, Greening DW, Hanssen EG, Zhu HJ, Simpson RJ, Mathias RA. Oncogenic epithelial cell-derived exosomes containing Rac1 and PAK2 induce angiogenesis in recipient endothelial cells. Oncotarget. 2016;7(15):19709-22.
156. Hood JL, Pan H, Lanza GM, Wickline SA, Consortium for Translational Research in Advanced I, Nanomedicine. Paracrine induction of endothelium by tumor exosomes. Lab Invest. 2009; 89(11):1317-28.
157. El-Kenawi AE, El-Remessy AB. Angiogenesis inhibitors in cancer therapy: mechanistic perspective on classification and treatment rationales. Br J Pharmacol. 2013;170(4):712-29.
158. Teicher BA. A systems approach to cancer therapy. (Antioncogenics + standard cytotoxics-->mechanism(s) of interaction). Cancer Metastasis Rev. 1996;15(2):247-72.
159. Kamba T, McDonald DM. Mechanisms of adverse effects of anti-VEGF therapy for cancer. Br J Cancer. 2007;96(12):1788-95.
160. Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med. 2003;9(6):669-76.
161. Gelinas DS, Bernatchez PN, Rollin S, Bazan NG, Sirois MG. Immediate and delayed VEGF-mediated NO synthesis in endothelial cells: role of PI3K, PKC and PLC pathways. Br J Pharmacol. 2002;137(7):1021-30.
162. Hood JD, Meininger CJ, Ziche M, Granger HJ. VEGF upregulates ecNOS message, protein, and NO production in human endothelial cells. Am J Physiol. 1998;274(3 Pt 2):H1054-8.
163. Sane DC, Anton L, Brosnihan KB. Angiogenic growth factors and hypertension. Angiogenesis. 2004;7(3):193-201.
164. Bobrie A, Krumeich S, Reyal F, Recchi C, Moita LF, Seabra MC, et al. Rab27a supports exosome-dependent and -independent mechanisms that modify the tumor microenvironment and can promote tumor progression. Cancer Res. 2012;72(19):4920-30.
165. Nishida-Aoki N, Tominaga N, Takeshita F, Sonoda H, Yoshioka Y, Ochiya T. Disruption of Circulating Extracellular Vesicles as a Novel Therapeutic Strategy against Cancer Metastasis. Mol Ther. 2017;25(1):181-91.
166. Richards KE, Zeleniak AE, Fishel ML, Wu J, Littlepage LE, Hill R. Cancer-associated fibroblast exosomes regulate survival and proliferation of pancreatic cancer cells. Oncogene. 2017;36(13):1770-8.
167. Agarwal S, Muniyandi P, Maekawa T, Kumar DS. Vesicular systems employing natural substances as promising drug candidates for MMP inhibition in glioblastoma: A nanotechnological approach. Int J Pharm. 2018;551(1-2):339-61.
168. Keller S, Sanderson MP, Stoeck A, Altevogt P. Exosomes: from biogenesis and secretion to biological function. Immunol Lett. 2006; 107(2):102-8.
169. Krause M, Samoylenko A, Vainio SJ. Exosomes as renal inductive signals in health and disease, and their application as diagnostic markers and therapeutic agents. Front Cell Dev Biol. 2015;3:65.
170. Raposo G, Stoorvogel W. Extracellular vesicles: exosomes, microvesicles, and friends. J Cell Biol. 2013;200(4):373-83.
171. Simons M, Raposo G. Exosomes--vesicular carriers for intercellular communication. Curr Opin Cell Biol. 2009;21(4):575-81.
172. Zhang X, Yuan X, Shi H, Wu L, Qian H, Xu W. Exosomes in cancer: small particle, big player. J Hematol Oncol. 2015;8:83.
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 Unported License.
Copyright (c) 2019 Authors