Emerging insights into the biology of metastasis: A review article

Document Type: Review Article

Author

Dental Research Centre, Oral Pathology Department, Dental Faculty, Hamadan University of Medical Sciences, Hamadan,Iran, Lecturer at Griffith University,Gold Coast,Australia

Abstract

Metastasis means the dissemination of the cancer cells from one organ to another which is not directly connected to the primary site. Metastasis has a crucial role in the prognosis of cancer patients. A few theories, different types of cell and several molecular pathways have been proposed to explain the mechanism of metastasis. In this work, the related articles in the limited period of time, 2000–mid -2018 were reviewed, through search in PubMed, Google Scholar and Scopus database. The articles published in the last two decades related to the biology of cancer metastasis were selected and the most important factors were discussed. Metastasis is critical factor to predict survival in patients with advanced cancer and prognosis determines the treatment plan. Many different cell types and various signaling pathways control the metastatic process. Metastasis is a multistep process. Many signaling pathways and molecules are involved in metastasis. Increasing knowledge about the mechanism of metastasis can help in finding the promising targets of cancer therapy.

Keywords

Main Subjects


1.    Irani S. Pre-cancerous lesions in the oral and maxillofacial region: A literature review with special focus on etopathogenesis. Iran j pathol 2016;11:303-322.
2.    Irani S,  Bidari –Zerehpoush F, Sabti S. Prevalence of pathological entities in neck masses: A study of 1208 consecutive cases. Avicenna J Dent Res 2016;8:e25614.
3.    Irani S, Moshref M, Lotfi A. Metastasis of a gastric adenocarcinoma to the mandible:A case report. Oral Oncol extra 2004;40:85-87.
4.    Irani S. Metastasis to the Jawbones: A review of 453 cases. J Int Soc Prev Community Dent 2017;7:71-81.
5.    Irani S. Metastasis to the oral soft tissues: A review of 412 cases. J Int Soc Prev Community Dent 2016;6:393-401.
6.    Irani S. Metastasis to head and neck area: a 16-year retrospective study. Am J Otolaryngol. 2011;32:24-27.
7.    Irani S. Distant metastasis from oral cancer: A review and molecular biologic aspects. J Int Soc Prev Community Dent 2016;6:265-271.
8.    Pein M, Oskarsson T. Microenvironment in metastasis: roadblocks and supportive niches. Am J Physiol Cell Physiol 2015;309:C627-638.
9.    Quail DF, Joyce JA. Microenvironmental regulation of tumor progression and metastasis. J Nat Med 2013;19:1423-1437.
10. Qureshi-Baig K, Ullmann P, Haan S, Letellier E. Tumor-initiating cells: a critical review of isolation approaches and new challenges in targeting strategies. Mol Cancer 2017;16:40.
11. Irani S, Dehghan A. The expression and functional significance of vascular endothelial-cadherin, CD44, and vimentin in oral squamous cell carcinoma. J Int Soc Prev Community Dent 2018;8:408-417.
12. Irani S, Dehghan A. Expression of vascular endothelial-cadherin in mucoepidermoid carcinoma: role in cancer development. J Int Soc Prev Community Dent 2017;7:301-307.
13. Irani S,  Jafari B. Expression of vimentin and CD44 in mucoepidermoid carcinoma: A role in tumor growth. Indian J Dent Res 2018;29: 330-340.
14. Phi LTH, Sari IN, Yang YG, Lee SH, Jun N, Kim KS, et al. Cancer Stem Cells (CSCs) in Drug Resistance and their Therapeutic Implications in Cancer Treatment. Stem Cells int 2018;2018:5416923.
15. Roos A, Ding Z, Loftus JC, Tran NL. Molecular and microenvironmental determinants of glioma stem-like cell survival and invasion. Front Oncol 2017;7:120.
16. Kreso A, Dick JE. Evolution of the cancer stem cell model. Cell stem cell. 2014;14:275-291.
17. Fulda S. Regulation of apoptosis pathways in cancer stem cells. Cancer Lett. 2013;338:168-173.
18. Geng S, Guo Y, Wang Q, Li L, Wang J. Cancer stem-like cells enriched with CD29 and CD44 markers exhibit molecular characteristics with epithelial-mesenchymal transition in squamous cell carcinoma. Arch Dermatol Res 2013;305:35-47.
19. Kim WT, Ryu CJ. Cancer stem cell surface markers on normal stem cells. BMB Rep 2017;50:285-298.
20. Harris KS, Kerr BA. Prostate cancer stem cell markers drive progression, therapeutic resistance, and bone metastasis. Stem Cells int 2017;2017:8629234.
21. Jablonska-Trypuc A, Matejczyk M, Rosochacki S. Matrix metalloproteinases (MMPs), the main extracellular matrix (ECM) enzymes in collagen degradation, as a target for anticancer drugs. J Enzyme inhib Med Chem 2016;31:177-183.
22. Chetty C, Vanamala SK, Gondi CS, Dinh DH, Gujrati M, Rao JS. MMP-9 induces CD44 cleavage and CD44 mediated cell migration in glioblastoma xenograft cells. Cell Signal 2012;24:549-559.
23. Yu Q, Stamenkovic I. Cell surface-localized matrix metalloproteinase-9 proteolytically activates TGF-beta and promotes tumor invasion and angiogenesis. Genes Dev 2000;14:163-176.
24. Krstic J, Santibanez JF. Transforming growth factor-beta and matrix metalloproteinases: functional interactions in tumor stroma-infiltrating myeloid cells. ScientificWorldJournal. 2014;2014:521754.
25. Judd NP, Winkler AE, Murillo-Sauca O, Brotman JJ, Law JH, Lewis JS, Jr., et al. ERK1/2 regulation of CD44 modulates oral cancer aggressiveness. Cancer Res 2012;72:365-374.
26. Shiozawa Y, Taichman RS. Cancer stem cells and the bone marrow microenvironment. Bonekey Rep 2012;1:48
27. Kazama S, Kishikawa J, Kiyomatsu T, Kawai K, Nozawa H, Ishihara S, et al. Expression of the stem cell marker CD133 is related to tumor development in colorectal carcinogenesis. Asian J Surg 2018;41:274-278.
28. Nomura A, Banerjee S, Chugh R, Dudeja V, Yamamoto M, Vickers SM, et al. CD133 initiates tumors, induces epithelial-mesenchymal transition and increases metastasis in pancreatic cancer. Oncotarget 2015;6:8313-8322.
29. Chen S, Song X, Chen Z, Li X, Li M, Liu H, et al. CD133 expression and the prognosis of colorectal cancer: a systematic review and meta-analysis. PloS One. 2013;8:e56380.
30. Nakamura M, Zhang X, Mizumoto Y, Maida Y, Bono Y, Takakura M, et al. Molecular characterization of CD133+ cancer stem-like cells in endometrial cancer. Int J Oncol 2014;44:669-677.
31. Baillie R, Tan ST, Itinteang T. Cancer stem cells in oral cavity squamous cell carcinoma: A review. Front Oncol 2017;7:112.
32. Yao J, Jin Q, Wang XD, Zhu HJ, Ni QC. Aldehyde dehydrogenase 1 expression is correlated with poor prognosis in breast cancer. Medicine 2017;96:e7171.
33. Rodriguez-Torres M, Allan AL. Aldehyde dehydrogenase as a marker and functional mediator of metastasis in solid tumors. Clin Exp Metastasis. 2016;33:97-113.
34. Jaggupilli A, Elkord E. Significance of CD44 and CD24 as cancer stem cell markers: an enduring ambiguity. Clin Dev Immunol 2012;2012:708036.
35. Taniuchi K, Nishimori I, Hollingsworth MA. Intracellular CD24 inhibits cell invasion by posttranscriptional regulation of BART through interaction with G3BP. Cancer Res 2011;71:895-905.
36. Hatano Y, Fukuda S, Hisamatsu K, Hirata A, Hara A, Tomita H. Multifaceted Interpretation of Colon Cancer Stem Cells. Int J Mol Sci 2017;18.
37. Jolly MK, Tripathi SC, Jia D, Mooney SM, Celiktas M, Hanash SM, et al. Stability of the hybrid epithelial/mesenchymal phenotype. Oncotarget 2016;7:27067-27084.
38. Da C, Wu K, Yue C, Bai P, Wang R, Wang G, et al. N-cadherin promotes thyroid tumorigenesis through modulating major signaling pathways. Oncotarget 2017;8:8131-8142.
39. Huang R, Zong X. Aberrant cancer metabolism in epithelial-mesenchymal transition and cancer metastasis: Mechanisms in cancer progression. Crit Rev Oncol Hematol 2017;115:13-22.
40. Pradella D, Naro C, Sette C, Ghigna C. EMT and stemness: flexible processes tuned by alternative splicing in development and cancer progression. Mol cancer. 2017;16:8.
41. Sommers CL, Heckford SE, Skerker JM, Worland P, Torri JA, Thompson EW, et al. Loss of epithelial markers and acquisition of vimentin expression in adriamycin- and vinblastine-resistant human breast cancer cell lines. Cancer Res 1992;52:5190-5197.
42. Ishiwata T. Cancer stem cells and epithelial-mesenchymal transition: Novel therapeutic targets for cancer. Pathol Int 2016;66:601-608.
43. Liu S, Ye D, Guo W, Yu W, He Y, Hu J, et al. G9a is essential for EMT-mediated metastasis and maintenance of cancer stem cell-like characters in head and neck squamous cell carcinoma. Oncotarget 2015;6:6887-6901.
44. Clark AG, Vignjevic DM. Modes of cancer cell invasion and the role of the microenvironment. Curr Opin Cell Biol 2015;36:13-22.
45. Shiga K, Hara M, Nagasaki T, Sato T, Takahashi H, Takeyama H. Cancer-associated fibroblasts: Their characteristics and their roles in tumor growth. cancers 2015;7:2443-2458.
46. Lee SK, Hwang JH, Choi KY. Interaction of the Wnt/beta-catenin and RAS-ERK pathways involving co-stabilization of both beta-catenin and RAS plays important roles in the colorectal tumorigenesis. Advances in biological regulation. Adv Biol Regul 2018;68: 46-54
47. Lu P, Weaver VM, Werb Z. The extracellular matrix: a dynamic niche in cancer progression. Journal Cell Biol 2012;196:395-406.
48. Theocharis AD, Skandalis SS, Gialeli C, Karamanos NK. Extracellular matrix structure. Adv Drug Deliv Rev 2016;97:4-27.
49. Jiang WG, Sanders AJ, Katoh M, Ungefroren H, Gieseler F, Prince M, et al. Tissue invasion and metastasis: Molecular, biological and clinical perspectives. Semin Cancer Biol. 2015;35 Suppl:S244-S275.
50. Gattazzo F, Urciuolo A, Bonaldo P. Extracellular matrix: a dynamic microenvironment for stem cell niche. Biochim Biophys Acta. 2014;1840:2506-2519.
51. Plaks V, Kong N, Werb Z. The cancer stem cell niche: how essential is the niche in regulating stemness of tumor cells? Cell Stem Cell. 2015;16:225-238.
52. Paoli P, Giannoni E, Chiarugi P. Anoikis molecular pathways and its role in cancer progression. Biochim Biophys Acta. 2013;1833:3481-3498.
53. Zhao J, Li J, Schlosser HA, Popp F, Popp MC, Alakus H, Jauch KW, et al. Targeting cancer stem cells and their niche: Current therapeutic implications and challenges in pancreatic cancer. stem cells Int 2017;2017:6012810.
54. Sangaletti S, Chiodoni C, Tripodo C, Colombo MP. The good and bad of targeting cancer-associated extracellular matrix. Curr  Opin Pharmacol 2017;35:75-82.
55. Webb AH, Gao BT, Goldsmith ZK, Irvine AS, Saleh N, Lee RP, et al. Inhibition of MMP-2 and MMP-9 decreases cellular migration, and angiogenesis in in vitro models of retinoblastoma. BMC Cancer. 2017;17:434.
56. Markwell SM, Weed SA. Tumor and stromal-based contributions to head and neck squamous cell carcinoma invasion. Cancers. 2015;7:382-406.
57. Pietruszewska W, Bojanowska-Pozniak K, Kobos J. Matrix metalloproteinases MMP1, MMP2, MMP9 and their tissue inhibitors TIMP1, TIMP2, TIMP3 in head and neck cancer: an immunohistochemical study. Otolaryngol Pol  2016;70(3):32-43.
58. Wood SL, Pernemalm M, Crosbie PA, Whetton AD. The role of the tumor-microenvironment in lung cancer-metastasis and its relationship to potential therapeutic targets. Cancer Treat Rev 2014;40:558-566.
59. Jenning S, Pham T, Ireland SK, Ruoslahti E, Biliran H. Bit1 in anoikis resistance and tumor metastasis. Cancer Lett. 2013;333:147-151.
60. Sun B, Hu C, Yang Z, Zhang X, Zhao L, Xiong J, et al. Midkine promotes hepatocellular carcinoma metastasis by elevating anoikis resistance of circulating tumor cells. Oncotarget 2017;8:32523-32535.
61. Piyush T, Rhodes JM, Yu LG. MUC1 O-glycosylation contributes to anoikis resistance in epithelial cancer cells. Cell Death Discov 2017;3:17044.
62. Frisch SM, Schaller M, Cieply B. Mechanisms that link the oncogenic epithelial-mesenchymal transition to suppression of anoikis. J Cell Sci 2013;126:21-29.
63. Yao X, Gray S, Pham T, Delgardo M, Nguyen A, Do S, et al. Downregulation of Bit1 expression promotes growth, anoikis resistance, and transformation of immortalized human bronchial epithelial cells via Erk activation-dependent suppression of E-cadherin. Biochem  Biophys Res Commun 2018;495:1240-1248.
64. Haemmerle M, Taylor ML, Gutschner T, Pradeep S, Cho MS, Sheng J, et al. Platelets reduce anoikis and promote metastasis by activating YAP1 signaling. Nat Commun 2017;8:310.
65. Kaplan RN, Riba RD, Zacharoulis S, Bramley AH, Vincent L, Costa C, et al. VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature. 2005;438:820-827.
66. Jablonska J, Lang S, Sionov RV, Granot Z. The regulation of pre-metastatic niche formation by neutrophils. Oncotarget 2017;8:112132-112144.
67. Qian JJ, Akcay E. Competition and niche construction in a model of cancer metastasis. PloS One. 2018;13:e0198163.
68. Hoye AM, Erler JT. Structural ECM components in the premetastatic and metastatic niche. Am J Physiol Cell Physiol 2016;310:C955-967.
69. Chen W, Hoffmann AD, Liu H, Liu X. Organotropism: new insights into molecular mechanisms of breast cancer metastasis. NPJ Precis oncol 2018;2:4.
70. Aguado BA, Bushnell GG, Rao SS, Jeruss JS, Shea LD. Engineering the pre-metastatic niche. Nat Biomed Eng 2017;1.
71. Wang W, Lin P, Han C, Cai W, Zhao X, Sun B. Vasculogenic mimicry contributes to lymph node metastasis of laryngeal squamous cell carcinoma. J Exp Clin Cancer Res  2010;29:60.
72. Maniotis AJ, Folberg R, Hess A, Seftor EA, Gardner LM, Pe’er J, et al. Vascular channel formation by human melanoma cells in vivo and in vitro: vasculogenic mimicry.  Am J Pathol 1999;155:739-752.
73. Ping YF, Bian XW. Consice review: Contribution of cancer stem cells to neovascularization. Stem Cells 2011;29:888-894.
74. Chen YS, Chen ZP. Vasculogenic mimicry: a novel target for glioma therapy. Chin J Cancer. 2014;33:74-79.
75. Angara K, Borin TF, Arbab AS. Vascular Mimicry: A novel neovascularization mechanism driving anti-angiogenic therapy (AAT) resistance in glioblastoma. Transl Oncol 2017;10:650-660.
76. Irani S, Salajegheh A, Gopalan V, Smith RA, Lam AK. Expression profile of endothelin 1 and its receptor endothelin receptor A in papillary thyroid carcinoma and their correlations with clinicopathologic characteristics. Ann Diagn Pathol 2014;18:43-48.
77. Irani S, Salajegheh A, Smith RA, Lam AK. A review of the profile of endothelin axis in cancer and its management. Crit Rev Oncol Hematol 2014;89:314-321.
78. Burkholder B, Huang RY, Burgess R, Luo S, Jones VS, Zhang W, et al. Tumor-induced perturbations of cytokines and immune cell networks. Biochim Biophys Acta. 2014;1845:182-201.
79. Smith A, Teknos TN, Pan Q. Epithelial to mesenchymal transition in head and neck squamous cell carcinoma. Oral Oncol 2013;49:287-292.
80. Torigata M, Yamakawa D, Takakura N. Elevated expression of Tie1 is accompanied by acquisition of cancer stemness properties in colorectal cancer. Cancer Med 2017;6:1378-1388.
81. Yao X, Ping Y, Liu Y, Chen K, Yoshimura T, Liu M, et al. Vascular endothelial growth factor receptor 2 (VEGFR-2) plays a key role in vasculogenic mimicry formation, neovascularization and tumor initiation by Glioma stem-like cells. PloS One. 2013;8:e57188.
82. Alshammari A, Eldeib OJ, Eldeib AJ, Saleh W. Adenoid cystic carcinoma of the submandibular gland with rare metastasis to the sternum in a 52-year-old male. Ann Thorac Med 2016;11:82-84.
83. Malgieri A, Kantzari E, Patrizi MP, Gambardella S. Bone marrow and umbilical cord blood human mesenchymal stem cells: state of the art. Int  J Clinc Exp Med 2010;3:248-269.
84. T LR, Sanchez-Abarca LI, Muntion S, Preciado S, Puig N, Lopez-Ruano G, et al. MSC surface markers (CD44, CD73, and CD90) can identify human MSC-derived extracellular vesicles by conventional flow cytometry. Cell Commu Signal  2016;14:2.
85. Togarrati PP, Sasaki RT, Abdel-Mohsen M, Dinglasan N, Deng X, Desai S, et al. Identification and characterization of a rich population of CD34(+) mesenchymal stem/stromal cells in human parotid, sublingual and submandibular glands. Sci Rep 2017;7:3484.
86. Marofi F, Vahedi G, Biglari A, Esmaeilzadeh A, Athari SS. Mesenchymal stromal/stem cells: A new era in the cell-based targeted gene therapy of Cancer. Front Immunol 2017;8:1770.
87. Ma S, Xie N, Li W, Yuan B, Shi Y, Wang Y. Immunobiology of mesenchymal stem cells. Cell Death Differ 2014;21:216-225.
88. Fan L, Hu C, Chen J, Cen P, Wang J, Li L. Interaction between mesenchymal stem cells and B-cells. Int J Mol Sci 2016;17.E650
89. Ishihara S, Ponik SM, Haga H. Mesenchymal stem cells in breast cancer: response to chemical and mechanical stimuli. Oncoscience 2017;4:158-159.
90. Chang AI, Schwertschkow AH, Nolta JA, Wu J. Involvement of mesenchymal stem cells in cancer progression and metastases. Curr Vancer Drug Targets 2015;15:88-98.
91. Ridge SM, Sullivan FJ, Glynn SA. Mesenchymal stem cells: key players in cancer progression. Mol Cancer. 2017;16:31.
92. Kudo-Saito C. Cancer-associated mesenchymal stem cells aggravate tumor progression. Front Cell Dev Biol 2015;3:23.
93. Kubo N, Araki K, Kuwano H, Shirabe K. Cancer-associated fibroblasts in hepatocellular carcinoma. World J Gastroenterol 2016;22:6841-6850.
94. Quante M, Tu SP, Tomita H, Gonda T, Wang SS, Takashi S, et al. Bone marrow-derived myofibroblasts contribute to the mesenchymal stem cell niche and promote tumor growth. Cancer Cell. 2011;19:257-272.
95. Hanley CJ, Noble F, Ward M, Bullock M, Drifka C, Mellone M, et al. A subset of myofibroblastic cancer-associated fibroblasts regulate collagen fiber elongation, which is prognostic in multiple cancers. Oncotarget 2016;7:6159-6174.
96. Yang TS, Yang XH, Chen X, Wang XD, Hua J, Zhou DL, et al. MicroRNA-106b in cancer-associated fibroblasts from gastric cancer promotes cell migration and invasion by targeting PTEN. FEBS Lett 2014;588:2162-2169.
97. Zhang Q, Peng C. Cancer-associated fibroblasts regulate the biological behavior of cancer cells and stroma in gastric cancer. Oncol Lett 2018;15:691-698.
98. Guo J, Hsu H, Tyan S, Li F, Shew J, Lee W, et al. Serglycin in tumor microenvironment promotes non-small cell lung cancer aggressiveness in a CD44-dependent manner. Oncogene  2017;36:2457-2471.
99. Nair N, Calle AS, Zahra MH, Prieto-Vila M, Oo AKK, Hurley L, et al. A cancer stem cell model as the point of origin of cancer-associated fibroblasts in tumor microenvironment. Sci Rep 2017;7:6838.
100. Celia-Terrassa T, Kang Y. Distinctive properties of metastasis-initiating cells. Genes  Dev 2016;30:892-908.
101. Liao WT, Ye YP, Deng YJ, Bian XW, Ding YQ. Metastatic cancer stem cells: from the concept to therapeutics. Am J Stem Cells. 2014;3:46-62.
102. Nio K, Yamashita T, Kaneko S. The evolving concept of liver cancer stem cells. Mol Cancer. 2017;16:4.
103. Onstenk W, Sieuwerts AM, Mostert B, Lalmahomed Z, Bolt-de Vries JB, van Galen A, et al. Molecular characteristics of circulating tumor cells resemble the liver metastasis more closely than the primary tumor in metastatic colorectal cancer. Oncotarget 2016;7:59058-59069.
104. Umer M, Vaidyanathan R, Nguyen NT, Shiddiky MJA. Circulating tumor microemboli: Progress in molecular understanding and enrichment technologies. Biotechnol Adv 2018;36:1367-1389.
105. Li N. Platelets in cancer metastasis: To help the “villain” to do evil. Int J Cancer  2016;138:2078-2087.
106. Leblanc R, Peyruchaud O. The role of platelets and megakaryocytes in bone metastasis. J Bone Oncol 2016;5:109-111.
107. Elaskalani O, Berndt MC, Falasca M, Metharom P. Targeting platelets for the treatment of cancer. Cancers. 2017;9.E94
108. Qin L, Zhao D, Xu J, Ren X, Terwilliger EF, Parangi S, et al. The vascular permeabilizing factors histamine and serotonin induce angiogenesis through TR3/Nur77 and subsequently truncate it through thrombospondin-1. Blood. 2013;121:2154-2164.
109. Kizer NT, Hatem H, Nugent EK, Zhou G, Moore K, Heller P, et al. Chemotherapy response rates among patients with endometrial cancer who have elevated serum platelets. Int J Gynecol Cancer 2015;25:1015-1022.
110. Elaskalani O, Falasca M. The role of platelet-derived ADP and ATP in promoting pancreatic cancer cell survival and gemcitabine resistance. Cancers 2017;9.
111. Dasgupta A, Lim AR, Ghajar CM. Circulating and disseminated tumor cells: harbingers or initiators of metastasis? Mol Oncol 2017;11:40-61.
112. Lou XL, Sun J, Gong SQ, Yu XF, Gong R, Deng H. Interaction between circulating cancer cells and platelets: clinical implication. Chin J Cancer Res 2015;27:450-460.
113. Coussens LM, Zitvoge L, Palucka AK. Neutralizing tumor-promoting Chronic Inflammation: A Magic Bullet? Sci 2013;339:286-291.
114. Dionne LK, Driver ER, Wang XJ. Head and neck cancer stem cells: From identification to tumor immune network. J Dent Res 2015;94:1524-1531.
115. Hanahan D, Coussens LM. Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell. 2012;21:309-322.
116. Liu JY, Peng CW, Yang GF, Hu WQ, Yang XJ, Huang CQ, et al. Distribution pattern of tumor associated macrophages predicts the prognosis of gastric cancer. Oncotarget 2017;8:92757-92769.
117. Zhang Y, Zhou N, Yu X, Zhang X, Li S, Lei Z, et al. Tumacrophage: macrophages transformed into tumor stem-like cells by virulent genetic material from tumor cells. Oncotarget 2017;8:82326-82343.
118. Goswami KK, Ghosh T, Ghosh S, Sarkar M, Bose A, Baral R. Tumor promoting role of anti-tumor macrophages in tumor microenvironment. Cell Immunol 2017;316:1-10.
119. Di Tomaso T, Mazzoleni S, Wang E, Sovena G, Clavenna D, Franzin A, et al. Immunobiological characterization of cancer stem cells isolated from glioblastoma patients. Clin Cancer Res 2010;16:800-813.
120. Varricchi G, Galdiero MR, Loffredo S, Marone G, Iannone R, Marone G, et al. Are Mast Cells MASTers in Cancer? Front Immunol 2017;8:424.
121. Siiskonen H, Poukka M, Bykachev A, Tyynela-Korhonen K, Sironen R, Pasonen-Seppanen S, et al. Low numbers of tryptase+ and chymase+ mast cells associated with reduced survival and advanced tumor stage in melanoma. Melanoma Res 2015;25:479-485.
122. Pittoni P, Tripodo C, Piconese S, Mauri G, Parenza M, Rigoni A, et al. Mast cell targeting hampers prostate adenocarcinoma development but promotes the occurrence of highly malignant neuroendocrine cancers. Cancer Res 2011;71:5987-5997.
123. Zaidi M, Mallick A. A study on assessment of mast cells in oral squamous cell carcinoma. Ann Med Health Sci Res 2014;4:457-460.
124. Gudiseva S, Santosh ABR, Chitturi R, Anumula V, Poosarla C, Baddam VRR. The role of mast cells in oral squamous cell carcinoma. Contemp Oncol 2017;21:21-29.
125. Laishram D, Rao K, Devi HSU, Priya NS, Smitha T, Sheethal HS. Mast cells and angiogenesis in malignant and premalignant oral lesions: An immunohistochemical study. J Oral Maxillofac Pathol. 2017;21:229-238.
126. Ma P, Pan Y, Li W, Sun C, Liu J, Xu T, et al. Extracellular vesicles-mediated noncoding RNAs transfer in cancer. J Hematol Oncol 2017;10:57.
127. Plebanek MP, Angeloni NL, Vinokour E, Li J, Henkin A, Martinez-Marin D, et al. Pre-metastatic cancer exosomes induce immune surveillance by patrolling monocytes at the metastatic niche. Nat Commun 2017;8:1319.
128. Sun F, Wang JZ, Luo JJ, Wang YQ, Pan Q. Exosomes in the Oncobiology, Diagnosis, and Therapy of Hepatic Carcinoma: A New Player of an Old Game. BioMed Res Int 2018;2018:2747461.
129. Santos JC, Lima NDS, Sarian LO, Matheu A, Ribeiro ML. Exosome-mediated breast cancer chemoresistance via miR-155 transfer. Sci Rep 2018;8:829.
130. Hon KW, Abu N, Ab Mutalib NS, Jamal R. Exosomes As Potential Biomarkers and Targeted Therapy in Colorectal Cancer: A Mini-Review. Front Pharmacol 2017;8:583.
131. Blackwell RH, Foreman KE, Gupta GN. The Role of Cancer-Derived Exosomes in Tumorigenicity & Epithelial-to-Mesenchymal Transition. Cancers. 2017;9.
132. Weidle UH, Birzele F, Kollmorgen G, Ruger R. The Multiple Roles of Exosomes in Metastasis. Cancer Genomics Proteomics. 2017;14:1-15.
133. Armstrong D, Wildman DE. Extracellular Vesicles and the Promise of Continuous Liquid Biopsies. J Pathol Transl Med 2018;52:1-8.
134. Irani S. miRNAs signature in head and neck squamous cell carcinoma metastasis: A literature review. J Dent 2016;17:71-83.
135. Maroof H, Irani S, Ariana A, Vider J, Gopalan V, Lam AK. Interactions of vascular endothelial growth factor and p53 with miR-195 in thyroid carcinoma: possible therapeutic targets in aggressive thyroid cancers. Curr Cancer Drug Targets 2018.
136. Qu W, Chen X, Wang J, Lv J, Yan D. MicroRNA-1 inhibits ovarian cancer cell proliferation and migration through c-Met pathway. Clin Chim Acta 2017;473:237-244.
137. Lei L, Chen C, Zhao J, Wang H, Guo M, Zhou Y, et al. Targeted Expression of miR-7 Operated by TTF-1 Promoter Inhibited the Growth of Human Lung Cancer through the NDUFA4 Pathway. Mol Ther Nucleic Acids. 2017;6:183-197.
138. Wu W, Liu S, Liang Y, Zhou Z, Liu X. MiR-7 inhibits progression of hepatocarcinoma by targeting KLF-4 and promises a novel diagnostic biomarker. Cancer Cell Int 2017;17:31.
139. Ding Y, Pan Y, Liu S, Jiang F, Jiao J. Elevation of MiR-9-3p suppresses the epithelial-mesenchymal transition of nasopharyngeal carcinoma cells via down-regulating FN1, ITGB1 and ITGAV. Cancer Biol Ther 2017;18:414-424.
140. Li H, Zhou H, Luo J, Huang J. MicroRNA-17-5p inhibits proliferation and triggers apoptosis in non-small cell lung cancer by targeting transforming growth factor beta receptor 2. Exp Ther Med 2017;13:2715-2722.
141. Shi C, Ren L, Sun C, Yu L, Bian X, Zhou X, et al. miR-29a/b/c function as invasion suppressors for gliomas by targeting CDC42 and predict the prognosis of patients. Br J Cancer. 2017;117:1036-1047.
142. Fan MJ, Zhong YH, Shen W, Yuan KF, Zhao GH, Zhang Y, et al. MiR-30 suppresses lung cancer cell 95D epithelial mesenchymal transition and invasion through targeted regulating Snail. Eur  Rev Med  Pharmacol Sci 2017;21:2642-2649.
143. Ge F, Wang C, Wang W, Liu W, Wu B. MicroRNA-31 inhibits tumor invasion and metastasis by targeting RhoA in human gastric cancer. Oncol Rep 2017;38:1133-1139.
144. Zhou J, Xu D, Xie H, Tang J, Liu R, Li J, et al. miR-33a functions as a tumor suppressor in melanoma by targeting HIF-1α. Cancer Biol Ther 2015;16:846-855.
145. Sun H, Tian J, Xian W, Xie T, Yang X. miR-34a inhibits proliferation and invasion of bladder cancer cells by targeting orphan nuclear receptor HNF4G. Dis Markers. 2015;2015:879254.
146. Xin J, Yue Z, Zhang S, Jiang Z, Wang P, Li Y, et al. miR-99 inhibits cervical carcinoma cell proliferation by targeting TRIB2. Oncol Lett 2013;6:1025-1030.
147. Zhou SM, Zhang F, Chen XB, Jun CM, Jing X, Wei DX, et al. miR-100 suppresses the proliferation and tumor growth of esophageal squamous cancer cells via targeting CXCR7. Oncol Rep 2016;35:3453-3459.
148. Wang P, Liu X, Shao Y, Wang H, Liang C, Han B, et al. MicroRNA-107-5p suppresses non-small cell lung cancer by directly targeting oncogene epidermal growth factor receptor. Oncotarget 2017;8:57012-57023.
149. Kong R, Ma Y, Feng J, Li S, Zhang W, Jiang J, et al. The crucial role of miR-126 on suppressing progression of esophageal cancer by targeting VEGF-A. Cell Mol Biol Lett 2016;21:3.
150. Huang S, Wa Q, Pan J, Peng X, Ren D, Huang Y, et al. Downregulation of miR-141-3p promotes bone metastasis via activating NF-κB signaling in prostate cancer. J Exp Clin Cancer Res 2017;36.
151. Zhou LL, Dong JL, Huang G, Sun ZL, Wu J. MicroRNA-143 inhibits cell growth by targeting ERK5 and MAP3K7 in breast cancer. Braz J Med Biol Res 2017;50:e5891.
152. Chen GM, Zheng AJ, Cai J, Han P, Ji HB, Wang LL. microRNA-145-3p inhibits non-small cell lung cancer cell migration and invasion by targeting PDK1 via the mTOR signaling pathway. J Cell Biochem 2018;119:885-895.
153. Cao H, Liu Z, Wang R, Zhang X, Yi W, Nie G, et al. miR-148a suppresses human renal cell carcinoma malignancy by targeting AKT2. Oncol Rep 2017;37:147-154.
154. Shuang Y, Li C, Zhou X, Huang Y, Zhang L. MicroRNA-195 inhibits growth and invasion of laryngeal carcinoma cells by directly targeting DCUN1D1. Oncol Rep 2017;38:2155-2165.
155. Fang JF, Zhao HP, Wang ZF, Zheng SS. Upregulation of RASAL2 promotes proliferation and metastasis, and is targeted by miR-203 in hepatocellular carcinoma. Mol Med Rep 2017;15:2720-2726.
156. Wang L, Shen YF, Shi ZM, Shang XJ, Jin DL, Xi F. Overexpression miR-211-5p hinders the proliferation, migration, and invasion of thyroid tumor cells by downregulating SOX11. J Clin Lab Anal 2017;32.
157. Guo C, Zhao D, Zhang Q, Liu S, Sun MZ. miR-429 suppresses tumor migration and invasion by targeting CRKL in hepatocellular carcinoma via inhibiting Raf/MEK/ERK pathway and epithelial-mesenchymal transition. Sci Rep 2018;8:2375
158. Song G, Zhang H, Chen C, Gong L, Chen B, Zhao S, et al. miR-551b regulates epithelial-mesenchymal transition and metastasis of gastric cancer by inhibiting ERBB4 expression. Oncotarget 2017;8:45725-45735.
159. Zhang L, Sun J, Wang B, Ren JC, Su W, Zhang T. MicroRNA-10b Triggers the Epithelial-Mesenchymal Transition (EMT) of Laryngeal Carcinoma Hep-2 Cells by Directly Targeting the E-cadherin. Appl Biochem Biotechnol 2015;176:33-44.
160. Wang Z, Yao W, Li K, Zheng N, Zheng C, Zhao X, et al. Reduction of miR-21 induces SK-N-SH cell apoptosis and inhibits proliferation via PTEN/PDCD4. Oncol Lett 2017;13:4727-4733.
161. Cui S, Liao X, Ye C, Yin X, Liu M, Hong Y, et al. ING5 suppresses breast cancer progression and is regulated by miR-24. Mol Cancer. 2017;16:89.
162. Ji C, Liu H, Yin Q, Li H, Gao H. miR-93 enhances hepatocellular carcinoma invasion and metastasis by EMT via targeting PDCD4. Biotechnol Lett 2017;39:1621-169.
163. Han X, Saiyin H, Zhao J, Fang Y, Rong Y, Shi C, et al. Overexpression of miR-135b-5p promotes unfavorable clinical characteristics and poor prognosis via the repression of SFRP4 in pancreatic cancer. Oncotarget 2017;8:62195-62207.
164. Ji H, Tian D, Zhang B, Zhang Y, Yan D, Wu S. Overexpression of miR-155 in clear-cell renal cell carcinoma and its oncogenic effect through targeting FOXO3a. Exp Ther Med 2017;13:2286-2292.
165. Liu J, Xing Y, Rong L. miR-181 regulates cisplatin-resistant non-small cell lung cancer via downregulation of autophagy through the PTEN/PI3K/AKT pathway. Oncol Rep 2018;39:1631-1639.
166. Polioudakis D, Abell NS, Iyer VR. MiR-191 Regulates Primary Human Fibroblast Proliferation and Directly Targets Multiple Oncogenes. PloS One. 2015;10: e0126535.
167. Liang H, Yan X, Pan Y, Wang Y, Wang N, Li L, et al. MicroRNA-223 delivered by platelet-derived microvesicles promotes lung cancer cell invasion via targeting tumor suppressor EPB41L3. Mol Cancer. 2015;14:58
168. Yao S. MicroRNA biogenesis and their functions in regulating stem cell potency and differentiation. Biol Proced Online. 2016;18:8.
169. Fu S, Chen HH, Cheng P, Zhang CB, Wu Y. MiR-155 regulates oral squamous cell carcinoma Tca8113 cell proliferation, cycle, and apoptosis via regulating p27Kip1. Eur Rev Med pharmacol Sci 2017;21:937-944.
170. Henson BJ, Bhattacharjee S, O’Dee DM, Feingold E, Gollin SM. Decreased expression of miR-125b and miR-100 in oral cancer cells contributes to malignancy. Genes Chromosomes Cancer. 2009;48:569-582.
171. Wei Z, Liu Y, Wang Y, Zhang Y, Luo Q, Man X, et al. Downregulation of Foxo3 and TRIM31 by miR-551b in side population promotes cell proliferation, invasion, and drug resistance of ovarian cancer. Med Oncol 2016;33:126.
172. Hung PS, Tu HF, Kao SY, Yang CC, Liu CJ, Huang TY, et al. miR-31 is upregulated in oral premalignant epithelium and contributes to the immortalization of normal oral keratinocytes. Carcinogenesis. 2014;35:1162-1171.
173. Chen H, Li L, Wang S, Lei Y, Ge Q, Lv N, et al. Reduced miR-126 expression facilitates angiogenesis of gastric cancer through its regulation on VEGF-A. Oncotarget 2014;5:11873-1185.
174. Sasahira T, Kurihara M, Bhawal UK, Ueda N, Shimomoto T, Yamamoto K, et al. Downregulation of miR-126 induces angiogenesis and lymphangiogenesis by activation of VEGF-A in oral cancer. Br J Cancer. 2012;107:700-706.
175. Zhu Y, Wang J, Meng X, Xie H, Tan J, Guo X, et al. A positive feedback loop promotes HIF-1alpha stability through miR-210-mediated suppression of RUNX3 in paraquat-induced EMT. J Cell Mol Med 2017;21:3529-3539.
176. Gong M, Yu B, Wang J, Wang Y, Liu M, Paul C, et al. Mesenchymal stem cells release exosomes that transfer miRNAs to endothelial cells and promote angiogenesis. Oncotarget 2017;8:45200-45212.
177. Wang M, Zhao C, Shi H, Zhang B, Zhang L, Zhang X, et al. Deregulated microRNAs in gastric cancer tissue-derived mesenchymal stem cells: novel biomarkers and a mechanism for gastric cancer. Br J Cancer. 2014;110:1199-1210.
178. Wang Z, Tan Y, Yu W, Zheng S, Zhang S, Sun L, et al. Small role with big impact: miRNAs as communicators in the cross-talk between cancer-associated fibroblasts and cancer cells. Int J Biol Sci 2017;13:339-348.
179. Zhang Z, Xie Q, He D, Ling Y, Li Y, Li J, et al. Circular RNA: new star, new hope in cancer. BMC Cancer. 2018;18:834.
180. Huang YK, Yu JC. Circulating microRNAs and long non-coding RNAs in gastric cancer diagnosis: An update and review. World J Gastroenterol 2015;21:9863-9886.
181. Agliano A, Calvo A, Box C. The challenge of targeting cancer stem cells to halt metastasis. Semin Cancer Biol 2017;44:25-42.
182. Schneck H, Gierke B, Uppenkamp F, Behrens B, Niederacher D, Stoecklein NH, et al. EpCAM-Independent Enrichment of Circulating Tumor Cells in Metastatic Breast Cancer. PloS One. 2015;10: e0144535.
183. Andreu Z, Yanez-Mo M. Tetraspanins in extracellular vesicle formation and function. Front Iimmunol 2014;5:442.
184. Montazerian M, Yasari F, Aghaalikhani N. Ovarian extracellular MicroRNAs as the potential non-invasive biomarkers: An update. Biomed Pharmacother 2018;106:1633-1640.
185. Irani S. New insights into Oral Cancer Prevention: A review article. Int J Prev Med 2019 (In press).
186. Irani S, Meschi M, Goodarzi A. J Dent Res Dent Clin Dent Prospects. 2009; 3:56-59.