Cancer Stem Cells as a Seed for Cancer Metastasis

  • L. Lizha Mary
  • M. Vasantha Kumar
  • R. Satish


Cancer is one of the leading causes of death worldwide. Recent report from the World Health Organization suggested that, globally, one in six deaths is owing to cancer. In 2018, it was accountable for nearly 9.6 million deaths, and it is expected to be 14.6 million by the year 2035. The worldwide burden of cancer increase is due to aging and growth of population. In addition, cancer-associated lifestyle choices like smoking, sedentary habits and westernized diets increases the risk. Metastasis is complex and multistep process that results in the spread of cancerous cells from the primary site of the tumor to the surrounding tissues and to distant organs. Metastatic cancer is the primary cause of cancer morbidity and mortality. Several studies suggest that tumor has heterogeneous cell population and have numerically less cancer stem cell (CSC) population with self-renewal characteristics. CSCs are shown to drive tumor initiation, progression, metastasis, recurrence, and resistance. In addition, acquisition of epithelial-mesenchymal transition, expression of aberrant RNA-binding proteins, dysregulated microRNA expression, and increase in intercellular transfer of molecules via exosome cargo have been correlated with tumor progression, invasion, metastasis, poor survival, and an increased risk of cancer recurrence. Given the tumor initiating capacity, resistance, migratory potential and invasiveness, CSCs are the seeds of metastasis. This review article attempts to provide the details of the critical importance of CSCs on metastatic process and to offer a basis for the investigation of novel targets to curtail this deadly disease.


MicroRNA Epithelial-mesenchymal transition Exosomes RNA-binding proteins 



The authors would like to thank the SRM Institute of Science and Technology for funding and providing the laboratory facility. We would also like to thank Science and Engineering Research Board (SERB)-EMR/2017/002874, Indian Council of Medical Research (ICMR)-2019-5526/CMB/BMS and Department of Biotechnology (DBT)-BT/PR26189/GET/119/226/2017 for the funding support provided.


  1. 1.
    Lazer LM, Sadhasivam B, Palaniyandi K, Muthuswamy T, Ramachandran I, Balakrishnan A, Pathak S, Narayan S, Ramalingam S (2018) Chitosan-based nano-formulation enhances the anticancer efficacy of hesperetin. Int J Biol Macromol 107:1988–1998CrossRefGoogle Scholar
  2. 2.
    Nguyen LV, Vanner R, Dirks P et al (2012) Cancer stem cells: an evolving concept. Nat Rev Cancer 12(2):133PubMedCrossRefGoogle Scholar
  3. 3.
    Mashouri L, Yousefi H, Aref AR, Mohammad Ahadi A, Molaei F, Alahari SK (2019) Exosomes: composition, biogenesis, and mechanisms in cancer metastasis and drug resistance. Mol Cancer 18(1):75PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Shibue T, Weinberg RA (2017) EMT, CSCs, and drug resistance: the mechanistic link and clinical implications. Nat Rev Clin Oncol 14(10):611–629PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Pang R, Law WL, Chu AC et al (2010) A subpopulation of CD26+ cancer stem cells with metastatic capacity in human colorectal cancer. Cell Stem Cell 6(6):603–615PubMedCrossRefGoogle Scholar
  6. 6.
    Chen C, Wei Y, Hummel M et al (2011) Evidence for epithelial-mesenchymal transition in cancer stem cells of head and neck squamous cell carcinoma. PLoS One 6(1):e16466PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Morel AP, Lièvre M, Thomas C et al (2008) Generation of breast cancer stem cells through epithelialmesenchymal transition. PLoS One 3(8):e2888PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Marjanovic ND, Weinberg RA, Chaffer CL (2013) Cell plasticity and heterogeneity in cancer. Clin Chem 59(1):168–179PubMedCrossRefGoogle Scholar
  9. 9.
    Kim WT, Ryu CJ (2017 Jun) Cancer stem cell surface markers on normal stem cells. BMB reports. 50(6):285PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Huang R, Rofstad EK (2017) Cancer stem cells (CSCs), cervical CSCs and targeted therapies. Oncotarget 8(21):35351PubMedCrossRefGoogle Scholar
  11. 11.
    Li Y, Lin K, Yang Z et al (2017) Bladder cancer stem cells: clonal origin and therapeutic perspectives. Oncotarget 8(39):66668–66679PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Lin W, Modiano JF, Ito D (2017) Stage-specific embryonic antigen: determining expression in canine glioblastoma, melanoma, and mammary cancer cells. J Vet Sci 18(1):101–104PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Yuan ZX, Mo J, Zhao G, Shu G, Fu HL, Zhao W (2016) Targeting strategies for renal cell carcinoma: from renal cancer cells to renal cancer stem cells. Front Pharmacol 7:423PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Govaere O, Wouters J, Petz M, Vandewynckel YP, Van den Eynde K, Verhulst S, Dollé L, Gremeaux L, Ceulemans A, Nevens F, van Grunsven LA (2016) Laminin-332 sustains chemoresistance and quiescence as part of the human hepatic cancer stem cell niche. J Hepatol 64(3):609–617PubMedCrossRefGoogle Scholar
  15. 15.
    Sun JH, Luo Q, Liu LL, Song GB (2016) Liver cancer stem cell markers: progression and therapeutic implications. World J Gastroenterol 22(13):3547PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Ming XY, Fu L, Zhang LY, Qin YR, Cao TT, Chan KW, Ma S, Xie D, Guan XY (2016) Integrin α7 is a functional cancer stem cell surface marker in oesophageal squamous cell carcinoma. Nat Commun 7(1):1–4CrossRefGoogle Scholar
  17. 17.
    Sahlberg SH, Spiegelberg D, Glimelius B, Stenerlöw B, Nestor M (2014) Evaluation of cancer stem cell markers CD133, CD44, CD24: association with AKT isoforms and radiation resistance in colon cancer cells. PLoS One 9(4):e94621PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Dawood S, Austin L, Cristofanilli M (2014) Cancer stem cells: implications for cancer therapy. Oncology 28(12):1101–1107, 1110PubMedGoogle Scholar
  19. 19.
    Guo Z, Hardin H, Lloyd RV (2014) Cancer stem-like cells and thyroid cancer. Endocr Relat Cancer 21(5):T285–T300PubMedCrossRefGoogle Scholar
  20. 20.
    Bao B, Ahmad A, Azmi AS, Ali S, Sarkar FH (2013) Overview of cancer stem cells (CSCs) and mechanisms of their regulation: implications for cancer therapy. Curr Protoc Pharmacol 61(1):14–25CrossRefGoogle Scholar
  21. 21.
    Gao MQ, Choi YP, Kang S, Youn JH, Cho NH (2010) CD24+ cells from hierarchically organized ovarian cancer are enriched in cancer stem cells. Oncogene 29(18):2672–2680PubMedCrossRefGoogle Scholar
  22. 22.
    Saikawa Y, Fukuda K, Takahashi T, Nakamura R, Takeuchi H, Kitagawa Y (2010) Gastric carcinogenesis and the cancer stem cell hypothesis. Gastric Cancer 13(1):11–24PubMedCrossRefGoogle Scholar
  23. 23.
    Li C, Heidt DG, Dalerba P, Burant CF, Zhang L, Adsay V, Wicha M, Clarke MF, Simeone DM (2007) Identification of pancreatic cancer stem cells. Cancer Res 67(3):1030–1037PubMedCrossRefGoogle Scholar
  24. 24.
    Bao S, Wu Q, Sathornsumetee S, Hao Y, Li Z, Hjelmeland AB, Shi Q, McLendon RE, Bigner DD, Rich JN (2006) Stem cell–like glioma cells promote tumor angiogenesis through vascular endothelial growth factor. Cancer Res 66(16):7843–7848PubMedCrossRefGoogle Scholar
  25. 25.
    Fang D, Leishear K, Nguyen TK, Finko R, Cai K, Fukunaga M, Li L, Brafford PA, Kulp AN, Xu X, Smalley KS (2006) Defining the conditions for the generation of melanocytes from human embryonic stem cells. Stem Cells 24(7):1668–1677PubMedCrossRefGoogle Scholar
  26. 26.
    Yun EJ, Lo UG, Hsieh JT (2016) The evolving landscape of prostate cancer stem cell: therapeutic implications and future challenges. Asian J Urol 3(4):203–210PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T, Henkelman RM, Cusimano MD, Dirks PB (2004) Identification of human brain tumour initiating cells. Nature 432(7015):396–401PubMedCrossRefGoogle Scholar
  28. 28.
    García de Herreros A (2014) Epithelial to mesenchymal transition in tumor cells as consequence of phenotypic instability. Front Cell Dev Biol 12(2):71Google Scholar
  29. 29.
    Kim DH, Xing T, Yang Z, Dudek R, Lu Q, Chen YH (2018) Epithelial mesenchymal transition in embryonic development, tissue repair and cancer: a comprehensive overview. J Clin Med 7(1):1CrossRefGoogle Scholar
  30. 30.
    Clark DW, Palle K (2016) Aldehyde dehydrogenases in cancer stem cells: potential as therapeutic targets. Ann Transl Med 4(24):518PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Sikandar SS, Kuo AH, Kalisky T, Cai S, Zabala M, Hsieh RW, Lobo NA, Scheeren FA, Sim S, Qian D, Dirbas FM (2017) Role of epithelial to mesenchymal transition associated genes in mammary gland regeneration and breast tumorigenesis. Nat Commun 8(1):1–9CrossRefGoogle Scholar
  32. 32.
    Bhattacharya R, Mitra T, Ray Chaudhuri S, Roy SS (2018) Mesenchymal splice isoform of CD44 (CD44s) promotes EMT/invasion and imparts stem‐like properties to ovarian cancer cells. J Cell Biochem 119(4):3373–3383PubMedCrossRefGoogle Scholar
  33. 33.
    Fan D, Lin X, Zhang F, Zhong W, Hu J, Chen Y, Cai Z, Zou Y, He X, Chen X, Lan P (2018) Micro RNA 26b promotes colorectal cancer metastasis by downregulating phosphatase and tensin homolog and wingless‐type MMTV integration site family member 5A. Cancer Sci 109(2):354–362PubMedCrossRefGoogle Scholar
  34. 34.
    Chen DL, Chen LZ, Lu YX, Zhang DS, Zeng ZL, Pan ZZ, Huang P, Wang FH, Li YH, Ju HQ, Xu RH (2017) Long noncoding RNA XIST expedites metastasis and modulates epithelial–mesenchymal transition in colorectal cancer. Cell Death Dis 8(8):e3011PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Hudis CA, Gianni L (2011) Triple-negative breast cancer: an unmet medical need. Oncologist 16(Suppl 1):1–11PubMedCrossRefGoogle Scholar
  36. 36.
    Carey JP, Karakas C, Bui T, Chen X, Vijayaraghavan S, Zhao Y, Wang J, Mikule K, Litton JK, Hunt KK, Keyomarsi K (2018) Synthetic lethality of PARP inhibitors in combination with MYC blockade is independent of BRCA status in triple-negative breast cancer. Cancer Res 78(3):742–757PubMedCrossRefGoogle Scholar
  37. 37.
    Yang M, Li Y, Shen X, Ruan Y, Lu Y, Jin X, Song P, Guo Y, Zhang X, Qu H, Shao Y (2017) CLDN6 promotes chemoresistance through GSTP1 in human breast cancer. J Exp Clin Cancer Res 36(1):1–5CrossRefGoogle Scholar
  38. 38.
    Jiang P, Chen A, Wu X, Zhou M, ul Haq I, Mariyam Z, Feng Q (2018) NEAT1 acts as an inducer of cancer stem cell‐like phenotypes in NSCLC by inhibiting EGCG‐upregulated CTR1. J Cell Physiol 233(6):4852–4863PubMedCrossRefGoogle Scholar
  39. 39.
    Mayoral-Varo V, Calcabrini A, Sánchez-Bailón MP, Martín-Pérez J (2017) miR205 inhibits stem cell renewal in SUM159PT breast cancer cells. PLoS One 12(11):e0188637PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Kim YJ, Jeong SH, Kim EK, Kim EJ, Cho JH (2017) Ursodeoxycholic acid suppresses epithelial-mesenchymal transition and cancer stem cell formation by reducing the levels of peroxiredoxin II and reactive oxygen species in pancreatic cancer cells. Oncol Rep 38(6):3632–3638PubMedGoogle Scholar
  41. 41.
    Giacomelli C, Daniele S, Natali L, Iofrida C, Flamini G, Braca A, Trincavelli ML, Martini C (2017) Carnosol controls the human glioblastoma stemness features through the epithelial-mesenchymal transition modulation and the induction of cancer stem cell apoptosis. Sci Rep 7(1):1–7CrossRefGoogle Scholar
  42. 42.
    Lagunas AM, Wu J, Crowe DL (2017) Telomere DNA damage signaling regulates cancer stem cell evolution, epithelial mesenchymal transition, and metastasis. Oncotarget 8(46):80139PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Kang HM, Son HS, Cui YH, Youn B, Son B, Kaushik NK, Uddin N, Lee JS, Song JY, Kaushik N, Lee SJ (2017) Phytosphingosine exhibits an anti-epithelial–mesenchymal transition function by the inhibition of EGFR signaling in human breast cancer cells. Oncotarget 8(44):77794PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Lin Y, Wang Y, Shi Q, Yu Q, Liu C, Feng J, Deng J, Evers BM, Zhou BP, Wu Y (2017) Stabilization of the transcription factors slug and twist by the deubiquitinase dub3 is a key requirement for tumor metastasis. Oncotarget 8(43):75127PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Yan X, Liu L, Li H, Qin H, Sun Z (2017) Clinical significance of Fusobacterium nucleatum, epithelial–mesenchymal transition, and cancer stem cell markers in stage III/IV colorectal cancer patients. Onco Targets Ther 10:5031PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Xie SL, Fan S, Zhang SY, Chen WX, Li QX, Pan GK, Zhang HQ, Wang WW, Weng B, Zhang Z, Li JS (2018) SOX8 regulates cancer stem‐like properties and cisplatin‐induced EMT in tongue squamous cell carcinoma by acting on the Wnt/β‐catenin pathway. Int J Cancer 142(6):1252–1265PubMedCrossRefGoogle Scholar
  47. 47.
    Garg M (2015) Emerging role of microRNAs in cancer stem cells: implications in cancer therapy. World J Stem Cells 7(8):1078PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Takahashi RU, Miyazaki H, Ochiya T (2014) The role of microRNAs in the regulation of cancer stem cells. Front Genet 4:295PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Zhou L, Liu F, Wang X, Ouyang G (2015) The roles of microRNAs in the regulation of tumor metastasis. Cell Biosci 5(1):32PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    El Helou R, Pinna G, Cabaud O, Wicinski J, Bhajun R, Guyon L, Rioualen C, Finetti P, Gros A, Mari B, Barbry P (2017) miR-600 acts as a bimodal switch that regulates breast cancer stem cell fate through WNT signaling. Cell Rep 18(9):2256–2268PubMedCrossRefGoogle Scholar
  51. 51.
    Wang ZM, Du WJ, Piazza GA, Xi Y (2013) MicroRNAs are involved in the self-renewal and differentiation of cancer stem cells. Acta Pharmacol Sin 34(11):1374–1380PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Shimono Y, Mukohyama J, Nakamura SI, Minami H (2016) MicroRNA regulation of human breast cancer stem cells. J Clin Med 5(1):2CrossRefGoogle Scholar
  53. 53.
    Xiao Y, Humphries B, Yang C, Wang Z (2019) MiR-205 dysregulations in breast cancer: the complexity and opportunities. Non-coding RNA 5(4):53PubMedCentralCrossRefPubMedGoogle Scholar
  54. 54.
    Bimonte S, Barbieri A, Leongito M, Palma G, Del Vecchio V, Falco M, Palaia R, Albino V, Piccirillo M, Amore A, Petrillo A (2016) The role of miRNAs in the regulation of pancreatic cancer stem cells. Stem Cells Int 2016:8352684PubMedPubMedCentralGoogle Scholar
  55. 55.
    Hu J, Qiu M, Jiang F, Zhang S, Yang X, Wang J, Xu L, Yin R (2014) MiR-145 regulates cancer stem-like properties and epithelial-to-mesenchymal transition in lung adenocarcinoma-initiating cells. Tumor Biol 35(9):8953–8961CrossRefGoogle Scholar
  56. 56.
    Fan X, Chen X, Deng W, Zhong G, Cai Q, Lin T (2013) Up-regulated microRNA-143 in cancer stem cells differentiation promotes prostate cancer cells metastasis by modulating FNDC3B expression. BMC Cancer 13(1):61PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Liu C, Liu R, Zhang D, Deng Q, Liu B, Chao HP, Rycaj K, Takata Y, Lin K, Lu Y, Zhong Y (2017) MicroRNA-141 suppresses prostate cancer stem cells and metastasis by targeting a cohort of pro-metastasis genes. Nat Commun 8(1):1–4CrossRefGoogle Scholar
  58. 58.
    Bao B, Li Y, Ahmad A, Azmi AS, Bao G, Ali S, Banerjee S, Kong D, H Sarkar F (2012) Targeting CSC-related miRNAs for cancer therapy by natural agents. Curr Drug Targets 13(14):1858–1868PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Yu CC, Lo WL, Chen YW, Huang PI, Hsu HS, Tseng LM, Hung SC, Kao SY, Chang CJ, Chiou SH (2011) Bmi-1 regulates snail expression and promotes metastasis ability in head and neck squamous cancer-derived ALDH1 positive cells. J Oncol 2011:609259PubMedCrossRefGoogle Scholar
  60. 60.
    Li XJ, Ren ZJ, Tang JH (2014) MicroRNA-34a: a potential therapeutic target in human cancer. Cell Death Dis 5(7):e1327PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Wang Y, Kim S, Kim IM (2014) Regulation of metastasis by microRNAs in ovarian cancer. Front Oncol 4:143PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Liu C, Tang DG (2011) MicroRNA regulation of cancer stem cells. Cancer Res 71(18):5950–5954PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Pencheva N, Tavazoie SF (2013) Control of metastatic progression by microRNA regulatory networks. Nat Cell Biol 15(6):546–554PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Lim YY, Wright JA, Attema JL, Gregory PA, Bert AG, Smith E, Thomas D, Lopez AF, Drew PA, Khew-Goodall Y, Goodall GJ (2013) Epigenetic modulation of the miR-200 family is associated with transition to a breast cancer stem-cell-like state. J Cell Sci 126(10):2256–2266PubMedCrossRefGoogle Scholar
  65. 65.
    Wu M-J, Chen Y-S, Kim MR, Chang C-J (2016) Regulation of epithelial plasticity and cancer stemness via microRNAs. J Mol Genet Med 10:2. ISSN: 1747-0862Google Scholar
  66. 66.
    Ju SY, Chiou SH, Su Y (2014) Maintenance of the stemness in CD44+ HCT-15 and HCT-116 human colon cancer cells requires miR-203 suppression. Stem Cell Res 12(1):86–100PubMedCrossRefGoogle Scholar
  67. 67.
    Taube JH, Malouf GG, Lu E, Sphyris N, Vijay V, Ramachandran PP, Ueno KR, Gaur S, Nicoloso MS, Rossi S, Herschkowitz JI (2013) Epigenetic silencing of microRNA-203 is required for EMT and cancer stem cell properties. Sci Rep 3:2687PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Zhang Y, Zhou SY, Yan HZ, Xu DD, Chen HX, Wang XY, Wang X, Liu YT, Zhang L, Wang S, Zhou PJ (2016) miR-203 inhibits proliferation and self-renewal of leukemia stem cells by targeting survivin and Bmi-1. Sci Rep 6(1):1–2CrossRefGoogle Scholar
  69. 69.
    Yu G, Yao W, Xiao W, Li H, Xu H, Lang B (2014) MicroRNA-34a functions as an anti-metastatic microRNA and suppresses angiogenesis in bladder cancer by directly targeting CD44. J Exp Clin Cancer Res 33(1):779PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Kumar B, Yadav A, Lang J, Teknos TN, Kumar P (2012) Dysregulation of microRNA-34a expression in head and neck squamous cell carcinoma promotes tumor growth and tumor angiogenesis. PLoS One 7(5):e37601PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Liu C, Kelnar K, Liu B, Chen X, Calhoun-Davis T, Li H, Patrawala L, Yan H, Jeter C, Honorio S, Wiggins JF, Bader AG, Fagin R, Brown D, Tang DG (2011) The microRNA miR-34a inhibits prostate cancer stem cells and metastasis by directly repressing CD44. Nat Med 17:211–215PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Zhang X, Ai F, Li X, Tian L, Wang X, Shen S, Liu F (2017) MicroRNA‑34a suppresses colorectal cancer metastasis by regulating Notch signaling. Oncol Lett 14(2):2325–2333PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Gao Y, Luo LH, Li S, Yang C (2014) miR-17 inhibitor suppressed osteosarcoma tumor growth and metastasis via increasing PTEN expression. Biochem Biophys Res Commun 444(2):230–234PubMedCrossRefGoogle Scholar
  74. 74.
    Schubbert S, Jiao J, Ruscetti M, Nakashima J, Wu S, Lei H, Xu Q, Yi W, Zhu H, Wu H (2016) Methods for PTEN in stem cells and cancer stem cells. In: PTEN. Humana Press, New York, pp 233–285CrossRefGoogle Scholar
  75. 75.
    Jiang Z, Yin J, Fu W, Mo Y, Pan Y, Dai L, Huang H, Li S, Zhao J (2014) MiRNA 17 family regulates cisplatin-resistant and metastasis by targeting TGFbetaR2 in NSCLC. PLoS One 9(4):e94639PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Ajani JA, Song S, Hochster HS, Steinberg IB (2015) Cancer stem cells: the promise and the potential. In: Seminars in oncology, vol 42. WB Saunders, pp S3–S17Google Scholar
  77. 77.
    Zhang J, Xiao Z, Lai D, Sun J, He C, Chu Z, Ye H, Chen S, Wang J (2012) miR-21, miR-17 and miR-19a induced by phosphatase of regenerating liver-3 promote the proliferation and metastasis of colon cancer. Br J Cancer 107(2):352–359PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Gong C, Yang Z, Wu F, Han L, Liu Y, Gong W (2016) miR-17 inhibits ovarian cancer cell peritoneal metastasis by targeting ITGA5 and ITGB1. Oncol Rep 36(4):2177–2183PubMedCrossRefGoogle Scholar
  79. 79.
    Xia H, Cheung WK, Ng SS, Jiang X, Jiang S, Sze J, Leung GK, Lu G, Chan DT, Bian XW, Kung HF (2012) Loss of brain-enriched miR-124 microRNA enhances stem-like traits and invasiveness of glioma cells. J Biol Chem 287(13):9962–9971PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Wei J, Wang F, Kong LY, Xu S, Doucette T, Ferguson SD, Yang Y, McEnery K, Jethwa K, Gjyshi O, Qiao W (2013) MiR-124 inhibits STAT3 signaling to enhance T cell-mediated immune clearance of glioma. Cancer Res 73(13):3913–3926PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Lv XB, Jiao Y, Qing Y, Hu H, Cui X, Lin T, Song E, Yu F (2011) miR-124 suppresses multiple steps of breast cancer metastasis by targeting a cohort of pro-metastatic genes in vitro. Chin J Cancer 30(12):821PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Zhou XU, Qi L, Tong S, Cui YU, Chen J, Huang T, Chen Z, Zu XB (2015) miR-128 downregulation promotes growth and metastasis of bladder cancer cells and involves VEGF-C upregulation. Oncol Lett 10(5):3183–3190PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Zhao X, Wu Y, Lv Z (2015) miR-128 modulates hepatocellular carcinoma by inhibition of ITGA2 and ITGA5 expression. Am J Transl Res 7(9):1564PubMedPubMedCentralGoogle Scholar
  84. 84.
    Sun X, Li Y, Yu J, Pei H, Luo P, Zhang J (2015) miR-128 modulates chemosensitivity and invasion of prostate cancer cells through targeting ZEB1. Jpn J Clin Oncol 45(5):474–482PubMedCrossRefGoogle Scholar
  85. 85.
    Zeng H, Zhang Z, Dai X, Chen Y, Ye J, Jin Z (2016) Increased expression of microRNA-199b-5p associates with poor prognosis through promoting cell proliferation, invasion and migration abilities of human osteosarcoma. Pathol Oncol Res 22(2):253–260PubMedCrossRefGoogle Scholar
  86. 86.
    Fang C, Zhao Y, Guo B (2013) MiR‐199b‐5p targets HER2 in breast cancer cells. J Cell Biochem 114(7):1457–1463PubMedCrossRefGoogle Scholar
  87. 87.
    Zhou SJ, Liu FY, Zhang AH, Liang HF, Wang Y, Ma R, Jiang YH, Sun NF (2017) MicroRNA-199b-5p attenuates TGF-β1-induced epithelial–mesenchymal transition in hepatocellular carcinoma. Br J Cancer 117(2):233–244PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Wang Z, Zhang H, Zhang P, Li J, Shan Z, Teng W (2013) Upregulation of miR-2861 and miR-451 expression in papillary thyroid carcinoma with lymph node metastasis. Med Oncol 30(2):577PubMedCrossRefGoogle Scholar
  89. 89.
    Zhang J, Qin X, Sun Q, Guo H, Wu X, Xie F, Xu Q, Yan M, Liu J, Han Z, Chen W (2015) Transcriptional control of PAX4-regulated miR-144/451 modulates metastasis by suppressing ADAMs expression. Oncogene 34(25):3283–3295PubMedCrossRefGoogle Scholar
  90. 90.
    Zhang F, Huang W, Sheng M, Liu T (2015) MiR-451 inhibits cell growth and invasion by targeting CXCL16 and is associated with prognosis of osteosarcoma patients. Tumor Biol 36(3):2041–2048CrossRefGoogle Scholar
  91. 91.
    Huang JY, Zhang K, Chen DQ, Chen J, Feng B, Song H, Chen Y, Zhu Z, Lu L, De W, Wang R (2015) MicroRNA-451: epithelial-mesenchymal transition inhibitor and prognostic biomarker of hepatocelluar carcinoma. Oncotarget 6(21):18613PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Liu G, Xu Z, Hao D (2016) MicroRNA‑451 inhibits neuroblastoma proliferation, invasion and migration by targeting macrophage migration inhibitory factor. Mol Med Rep 13(3):2253–2260PubMedCrossRefGoogle Scholar
  93. 93.
    Yin P, Peng R, Peng H, Yao L, Sun Y, Wen L, Wu T, Zhou J, Zhang Z (2015) MiR-451 suppresses cell proliferation and metastasis in A549 lung cancer cells. Mol Biotechnol 57(1):1–11PubMedCrossRefGoogle Scholar
  94. 94.
    Lei T, Zhu Y, Jiang C, Wang Y, Fu J, Fan Z, Qin H (2016) MicroRNA-320 was downregulated in non-small cell lung cancer and inhibited cell proliferation, migration and invasion by targeting fatty acid synthase. Mol Med Rep 14(2):1255–1262PubMedCrossRefGoogle Scholar
  95. 95.
    Shi C, Zhang Z (2017) MicroRNA‑320 suppresses cervical cancer cell viability, migration and invasion via directly targeting FOXM1. Oncol Lett 14(3):3809–3816PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Pereira B, Billaud M, Almeida R (2017) RNA-binding proteins in cancer: old players and new actors. Trends Cancer 3(7):506–528PubMedCrossRefGoogle Scholar
  97. 97.
    Denkert C, Koch I, von Keyserlingk N, Noske A, Niesporek S, Dietel M, Weichert W (2006) Expression of the ELAV-like protein HuR in human colon cancer: association with tumor stage and cyclooxygenase-2. Modern Pathol 19(9):1261–1269CrossRefGoogle Scholar
  98. 98.
    Hong S (2017) RNA binding protein as an emerging therapeutic target for cancer prevention and treatment. J Cancer Prev 22(4):203PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Sureban SM, Ramalingam S, Natarajan G, May R, Subramaniam D, Bishnupuri KS, Morrison AR, Dieckgraefe BK, Brackett DJ, Postier RG, Houchen CW (2008) Translation regulatory factor RBM3 is a proto-oncogene that prevents mitotic catastrophe. Oncogene 27(33):4544–4556PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Venugopal A, Subramaniam D, Balmaceda J, Roy B, Dixon DA, Umar S, Weir SJ, Anant S (2016) RNA binding protein RBM3 increases β‐catenin signaling to increase stem cell characteristics in colorectal cancer cells. Mol Carcinog 55(11):1503–1516PubMedCrossRefGoogle Scholar
  101. 101.
    Hou P, Li L, Chen F, Chen Y, Liu H, Li J, Bai J, Zheng J (2018) PTBP3-mediated regulation of ZEB1 mRNA stability promotes epithelial–mesenchymal transition in breast cancer. Cancer Res 78(2):387–398PubMedCrossRefGoogle Scholar
  102. 102.
    Mukohyama J, Shimono Y, Minami H, Kakeji Y, Suzuki A (2017) Roles of microRNAs and RNA-binding proteins in the regulation of colorectal cancer stem cells. Cancers 9(10):143PubMedCentralCrossRefPubMedGoogle Scholar
  103. 103.
    Pastò A, Serafin V, Pilotto G, Lago C, Bellio C, Trusolino L, Bertotti A, Hoey T, Plateroti M, Esposito G, Pinazza M (2014) NOTCH3 signaling regulates MUSASHI-1 expression in metastatic colorectal cancer cells. Cancer Res 74(7):2106–2118PubMedCrossRefGoogle Scholar
  104. 104.
    Shou Z, Jin X, He X, Zhao Z, Chen Y, Ye M, Yao J (2017) Overexpression of Musashi-1 protein is associated with progression and poor prognosis of gastric cancer. Oncol Lett 13(5):3556–3566PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Kudinov AE, Deneka A, Nikonova AS, Beck TN, Ahn YH, Liu X, Martinez CF, Schultz FA, Reynolds S, Yang DH, Cai KQ (2016) Musashi-2 (MSI2) supports TGF-β signaling and inhibits claudins to promote non-small cell lung cancer (NSCLC) metastasis. Proc Natl Acad Sci U S A 113(25):6955–6960PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Codony-Servat J, Rosell R (2015) Cancer stem cells and immunoresistance: clinical implications and solutions. Transl Lung Cancer Res 4(6):689PubMedPubMedCentralGoogle Scholar
  107. 107.
    Jachetti E, Caputo S, Mazzoleni S, Brambillasca CS, Parigi SM, Grioni M, Piras IS, Restuccia U, Calcinotto A, Freschi M, Bachi A (2015) Tenascin-C protects cancer stem–like cells from immune surveillance by arresting T-cell activation. Cancer Res 75(10):2095–2108PubMedCrossRefGoogle Scholar
  108. 108.
    Kitamura T, Qian BZ, Soong D, Cassetta L, Noy R, Sugano G, Kato Y, Li J, Pollard JW (2015) CCL2-induced chemokine cascade promotes breast cancer metastasis by enhancing retention of metastasis-associated macrophages. J Exp Med 212(7):1043–1059PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Zhao D, Pan C, Sun J, Gilbert C, Drews-Elger K, Azzam DJ, Picon-Ruiz M, Kim M, Ullmer W, El-Ashry D, Creighton CJ (2015) VEGF drives cancer-initiating stem cells through VEGFR-2/Stat3 signaling to upregulate Myc and Sox2. Oncogene 34(24):3107–3119PubMedCrossRefGoogle Scholar
  110. 110.
    Li YL, Zhao H, Ren XB (2016) Relationship of VEGF/VEGFR with immune and cancer cells: staggering or forward? Cancer Biol Med 13(2):206PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    Hsu YL, Hung JY, Tsai YM, Tsai EM, Huang MS, Hou MF, Kuo PL (2015) 6-Shogaol, an active constituent of dietary ginger, impairs cancer development and lung metastasis by inhibiting the secretion of CC-chemokine ligand 2 (CCL2) in tumor-associated dendritic cells. J Agric Food Chem 63(6):1730–1738PubMedCrossRefGoogle Scholar
  112. 112.
    Xiang ZL, Zeng ZC, Fan J, Wu WZ, He J, Zeng HY, Tang ZY (2011) A clinicopathological model to predict bone metastasis in hepatocellular carcinoma. J Cancer Res Clin Oncol 137(12):1791PubMedCrossRefGoogle Scholar
  113. 113.
    Kim SW, Kim HY, Song IC, Jin SA, Lee HJ, Yun HJ, Kim S, Jo DY (2008) Cytoplasmic trapping of CXCR4 in hepatocellular carcinoma cell lines. Cancer Res Treat 40(2):53PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Jeng KS, Jeng CJ, Jeng WJ, Chang CF, Sheen I (2017) Role of CXC chemokine ligand 12/CXC chemokine receptor 4 in the progression of hepatocellular carcinoma. Oncol Lett 14(2):1905–1910PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Geiger P, Mayer B, Wiest I, Schulze S, Jeschke U, Weissenbacher T (2016) Binding of galectin-1 to breast cancer cells MCF7 induces apoptosis and inhibition of proliferation in vitro in a 2D-and 3D-cell culture model. BMC Cancer 16(1):1–9CrossRefGoogle Scholar
  116. 116.
    Zhou X, Li D, Wang X, Zhang B, Zhu H, Zhao J (2015) Galectin-1 is overexpressed in CD133+ human lung adenocarcinoma cells and promotes their growth and invasiveness. Oncotarget 6(5):3111PubMedCrossRefGoogle Scholar
  117. 117.
    Kitamura T, Qian B-Z, Pollard JW (2015) Immune cell promotion of metastasis. Nat Rev Immunol 15(2):73–86PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Syn N, Wang L, Sethi G et al (2016) Exosome-mediated metastasis: from epithelial–mesenchymal transition to escape from immunosurveillance. Trends Pharmacol Sci 37(7):606–617PubMedCrossRefGoogle Scholar
  119. 119.
    Desgrosellier JS, Cheresh DA (2010) Integrins in cancer: biological implications and therapeutic opportunities. Nat Rev Cancer 10(1):9–22PubMedPubMedCentralCrossRefGoogle Scholar
  120. 120.
    Peinado H, Alečković M, Lavotshkin S, Matei I, Costa-Silva B, Moreno-Bueno G, Hergueta-Redondo M, Williams C, García-Santos G, Ghajar CM, Nitadori-Hoshino A (2012) Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. Nat Med 18(6):883–891PubMedPubMedCentralCrossRefGoogle Scholar
  121. 121.
    Parfejevs V, Sagini K, Buss A, Sobolevska K, Llorente A, Riekstina U, Abols A (2020) Adult stem cell-derived extracellular vesicles in cancer treatment: opportunities and challenges. Cells 9(5):1171PubMedCentralCrossRefPubMedGoogle Scholar
  122. 122.
    Hannafon BN, Ding WQ (2015) Cancer stem cells and exosome signaling. Stem Cell Invest 2:11Google Scholar
  123. 123.
    O’Brien K, Rani S, Corcoran C, Wallace R, Hughes L, Friel AM, McDonnell S, Crown J, Radomski MW, O’Driscoll L (2013) Exosomes from triple-negative breast cancer cells can transfer phenotypic traits representing their cells of origin to secondary cells. Eur J Cancer 49(8):1845–1859PubMedPubMedCentralCrossRefGoogle Scholar
  124. 124.
    Lowry MC, Gallagher WM, O’Driscoll L (2015) The role of exosomes in breast cancer. Clin Chem 61(12):1457–1465PubMedCrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2020

Authors and Affiliations

  • L. Lizha Mary
    • 1
  • M. Vasantha Kumar
    • 2
  • R. Satish
    • 2
  1. 1.Department of Biotechnology, School of Bio-EngineeringSRM Institute of Science and TechnologyKanchipuramIndia
  2. 2.Department of Genetic Engineering, School of Bio-EngineeringSRM Institute of Science and TechnologyKanchipuramIndia

Personalised recommendations