Molecular Mechanisms of Lymph Node Metastasis

  • Naohide Oue
  • Yasuhiko Kitadai
  • Wataru YasuiEmail author


Despite improvements in diagnostic and therapeutic modalities, the prognosis of advanced cancer with extensive invasion and metastasis remains poor. The severity of a clinical prognosis depends on whether lymph node metastasis has occurred. For metastasis to occur, tumor cells must undergo a multistep process through a series of sequential and selective events. The metastatic process consists of detachment, local invasion, motility, lymphangiogenesis, lymphatic vessel invasion, survival in the circulation, adhesion to endothelial cells, extravasation, and regrowth in lymph nodes. Among them, the most important process is lymphangiogenesis, which is regulated by members of the vascular endothelial growth factor (VEGF) family and their receptors. In addition to lymphangiogenesis, it is well accepted that cancer stem cells play a significant role in metastasis. Although several types of metastasis-associated molecules have been identified, the expression of these molecules differs among esophageal, gastric, and colorectal cancer. This chapter will review the cellular and molecular mechanisms of lymph node metastasis including lymphangiogenesis and cancer stem cells in these human cancer types.


VEGF PDGF Migration Cancer stem cell 


  1. 1.
    Kumar R, Eue I, Dong Z, Killion JJ, Fidler IJ. Expression of inflammatory cytokines by murine macrophages activated with a new synthetic lipopeptide JT3002. Cancer Biother Radiopharm. 1997;12:333–40.PubMedCrossRefGoogle Scholar
  2. 2.
    Sundar SS, Ganesan TS. Role of lymphangiogenesis in cancer. J Clin Oncol. 2007;25:4298–307.PubMedCrossRefGoogle Scholar
  3. 3.
    Beasley NJ, Prevo R, Banerji S, Leek RD, Moore J, van Trappen P, et al. Intratumoral lymphangiogenesis and lymph node metastasis in head and neck cancer. Cancer Res. 2002;62:1315–20.PubMedGoogle Scholar
  4. 4.
    Nakayama Y, Matsumoto K, Nagato M, Inoue Y, Katsuki T, Minagawa N, et al. Significance of lymphangiogenesis as assessed by immunohistochemistry for podoplanin in patients with esophageal carcinoma. Anticancer Res. 2007;27:619–25.PubMedGoogle Scholar
  5. 5.
    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;5:1823–9.PubMedGoogle Scholar
  6. 6.
    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;38:1413–9.PubMedCrossRefGoogle Scholar
  7. 7.
    Parr C, Jiang WG. Quantitative analysis of lymphangiogenic markers in human colorectal cancer. Int J Oncol. 2003;23:533–9.PubMedGoogle Scholar
  8. 8.
    Kitadai Y. Angiogenesis and lymphangiogenesis of gastric cancer. J Oncol. 2010;2010:468725.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Stacker SA, Achen MG, Jussila L, Baldwin ME, Alitalo K. Lymphangiogenesis and cancer metastasis. Nat Rev Cancer. 2002;2:573–83.PubMedCrossRefGoogle Scholar
  10. 10.
    He Y, Rajantie I, Pajusola K, Jeltsch M, Holopainen T, Yla-Herttuala S, et al. Vascular endothelial cell growth factor receptor 3-mediated activation of lymphatic endothelium is crucial for tumor cell entry and spread via lymphatic vessels. Cancer Res. 2005;65:4739–46.PubMedCrossRefGoogle Scholar
  11. 11.
    Karkkainen MJ, Haiko P, Sainio K, Partanen J, Taipale J, Petrova TV, et al. Vascular endothelial growth factor C is required for sprouting of the first lymphatic vessels from embryonic veins. Nat Immunol. 2004;5:74–80.PubMedCrossRefGoogle Scholar
  12. 12.
    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;7:192–8.PubMedCrossRefGoogle Scholar
  13. 13.
    Kitadai Y, Amioka T, Haruma K, Tanaka S, Yoshihara M, Sumii K, et al. Clinicopathological significance of vascular endothelial growth factor (VEGF)-C in human esophageal squamous cell carcinomas. Int J Cancer. 2001;93:662–6.PubMedCrossRefGoogle Scholar
  14. 14.
    Matsumoto M, Natsugoe S, Okumura H, Arima H, Yanagita S, Uchikado Y, et al. Overexpression of vascular endothelial growth factor-C correlates with lymph node micrometastasis in submucosal esophageal cancer. J Gastrointest Surg. 2006;10:1016–22.PubMedCrossRefGoogle Scholar
  15. 15.
    Onogawa S, Kitadai Y, Tanaka S, Kuwai T, Kimura S, Chayama K. Expression of VEGF-C and VEGF-D at the invasive edge correlates with lymph node metastasis and prognosis of patients with colorectal carcinoma. Cancer Sci. 2004;95:32–9.PubMedCrossRefGoogle Scholar
  16. 16.
    Hachisuka T, Narikiyo M, Yamada Y, Ishikawa H, Ueno M, Uchida H, et al. High lymphatic vessel density correlates with overexpression of VEGF-C in gastric cancer. Oncol Rep. 2005;13:733–7.PubMedGoogle Scholar
  17. 17.
    Li X, Liu B, Xiao J, Yuan Y, Ma J, Zhang Y. Roles of VEGF-C and Smad4 in the lymphangiogenesis, lymphatic metastasis, and prognosis in colon cancer. J Gastrointest Surg. 2011;15:2001–10.PubMedCrossRefGoogle Scholar
  18. 18.
    Matsumura S, Oue N, Mitani Y, Kitadai Y, Yasui W. DNA demethylation of vascular endothelial growth factor-C is associated with gene expression and its possible involvement of lymphangiogenesis in gastric cancer. Int J Cancer. 2007;120:1689–95.PubMedCrossRefGoogle Scholar
  19. 19.
    Stacker SA, Caesar C, Baldwin ME, Thornton GE, Williams RA, Prevo R, et al. VEGF-D promotes the metastatic spread of tumor cells via the lymphatics. Nat Med. 2001;7:186–91.PubMedCrossRefGoogle Scholar
  20. 20.
    Baldwin ME, Catimel B, Nice EC, Roufail S, Hall NE, Stenvers KL, et al. The specificity of receptor binding by vascular endothelial growth factor-d is different in mouse and man. J Biol Chem. 2001;276:19166–71.PubMedCrossRefGoogle Scholar
  21. 21.
    Karnezis T, Shayan R, Caesar C, Roufail S, Harris NC, Ardipradja K, et al. VEGF-D promotes tumor metastasis by regulating prostaglandins produced by the collecting lymphatic endothelium. Cancer Cell. 2012;21:181–95.PubMedCrossRefGoogle Scholar
  22. 22.
    Kozlowski M, Naumnik W, Niklinski J, Milewski R, Dziegielewski P, Laudanski J. Vascular endothelial growth factor C and D expression correlates with lymph node metastasis and poor prognosis in patients with resected esophageal cancer. Neoplasma. 2011;58:311–9.PubMedCrossRefGoogle Scholar
  23. 23.
    Onogawa S, Kitadai Y, Amioka T, Kodama M, Cho S, Kuroda T, et al. Expression of vascular endothelial growth factor (VEGF)-C and VEGF-D in early gastric carcinoma: correlation with clinicopathological parameters. Cancer Lett. 2005;226:85–90.PubMedCrossRefGoogle Scholar
  24. 24.
    Arigami T, Natsugoe S, Uenosono Y, Yanagita S, Ehi K, Arima H, et al. Vascular endothelial growth factor-C and -D expression correlates with lymph node micrometastasis in pN0 early gastric cancer. J Surg Oncol. 2009;99:148–53.PubMedCrossRefGoogle Scholar
  25. 25.
    Wang XL, Fang JP, Tang RY, Chen XM. Different significance between intratumoral and peritumoral lymphatic vessel density in gastric cancer: a retrospective study of 123 cases. BMC Cancer. 2010;10:299.PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Su F, Li X, You K, Chen M, Xiao J, Zhang Y, et al. Expression of VEGF-D, SMAD4, and SMAD7 and their relationship with lymphangiogenesis and prognosis in colon cancer. J Gastrointest Surg. 2016;20:2074–82.PubMedCrossRefGoogle Scholar
  27. 27.
    Kaipainen A, Korhonen J, Mustonen T, van Hinsbergh VW, Fang GH, Dumont D, et al. Expression of the fms-like tyrosine kinase 4 gene becomes restricted to lymphatic endothelium during development. Proc Natl Acad Sci U S A. 1995;92:3566–70.PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Makinen T, Veikkola T, Mustjoki S, Karpanen T, Catimel B, Nice EC, et al. Isolated lymphatic endothelial cells transduce growth, survival and migratory signals via the VEGF-C/D receptor VEGFR-3. EMBO J. 2001;20:4762–73.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Valtola R, Salven P, Heikkila P, Taipale J, Joensuu H, Rehn M, et al. VEGFR-3 and its ligand VEGF-C are associated with angiogenesis in breast cancer. Am J Pathol. 1999;154:1381–90.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Su JL, Yang PC, Shih JY, Yang CY, Wei LH, Hsieh CY, et al. The VEGF-C/Flt-4 axis promotes invasion and metastasis of cancer cells. Cancer Cell. 2006;9:209–23.PubMedCrossRefGoogle Scholar
  31. 31.
    Kodama M, Kitadai Y, Tanaka M, Kuwai T, Tanaka S, Oue N, et al. Vascular endothelial growth factor C stimulates progression of human gastric cancer via both autocrine and paracrine mechanisms. Clin Cancer Res. 2008;14:7205–14.PubMedCrossRefGoogle Scholar
  32. 32.
    Tanaka M, Kitadai Y, Kodama M, Shinagawa K, Sumida T, Tanaka S, et al. Potential role for vascular endothelial growth factor-D as an autocrine factor for human gastric carcinoma cells. Cancer Sci. 2010;101:2121–7.PubMedCrossRefGoogle Scholar
  33. 33.
    Pietras K, Sjoblom T, Rubin K, Heldin CH, Ostman A. PDGF receptors as cancer drug targets. Cancer Cell. 2003;3:439–43.PubMedCrossRefGoogle Scholar
  34. 34.
    Heldin CH, Eriksson U, Ostman A. New members of the platelet-derived growth factor family of mitogens. Arch Biochem Biophys. 2002;398:284–90.PubMedCrossRefGoogle Scholar
  35. 35.
    Uehara H, Kim SJ, Karashima T, Shepherd DL, Fan D, Tsan R, et al. Effects of blocking platelet-derived growth factor-receptor signaling in a mouse model of experimental prostate cancer bone metastases. J Natl Cancer Inst. 2003;95:458–70.PubMedCrossRefGoogle Scholar
  36. 36.
    Cao R, Bjorndahl MA, Religa P, Clasper S, Garvin S, Galter D, et al. PDGF-BB induces intratumoral lymphangiogenesis and promotes lymphatic metastasis. Cancer Cell. 2004;6:333–45.PubMedCrossRefGoogle Scholar
  37. 37.
    Matsumoto S, Yamada Y, Narikiyo M, Ueno M, Tamaki H, Miki K, et al. Prognostic significance of platelet-derived growth factor-BB expression in human esophageal squamous cell carcinomas. Anticancer Res. 2007;27:2409–14.PubMedGoogle Scholar
  38. 38.
    Kodama M, Kitadai Y, Sumida T, Ohnishi M, Ohara E, Tanaka M, et al. Expression of platelet-derived growth factor (PDGF)-B and PDGF-receptor beta is associated with lymphatic metastasis in human gastric carcinoma. Cancer Sci. 2010;101:1984–9.PubMedCrossRefGoogle Scholar
  39. 39.
    Davis S, Aldrich TH, Jones PF, Acheson A, Compton DL, Jain V, et al. Isolation of angiopoietin-1, a ligand for the TIE2 receptor, by secretion-trap expression cloning. Cell. 1996;87:1161–9.PubMedCrossRefGoogle Scholar
  40. 40.
    Gale NW, Thurston G, Hackett SF, Renard R, Wang Q, McClain J, et al. Angiopoietin-2 is required for postnatal angiogenesis and lymphatic patterning, and only the latter role is rescued by Angiopoietin-1. Dev Cell. 2002;3:411–23.PubMedCrossRefGoogle Scholar
  41. 41.
    Jo MJ, Lee JH, Nam BH, Kook MC, Ryu KW, Choi IJ, et al. Preoperative serum angiopoietin-2 levels correlate with lymph node status in patients with early gastric cancer. Ann Surg Oncol. 2009;16:2052–7.PubMedCrossRefGoogle Scholar
  42. 42.
    Wang J, Wu K, Zhang D, Tang H, Xie H, Hong L, et al. Expressions and clinical significances of angiopoietin-1, -2 and Tie2 in human gastric cancer. Biochem Biophys Res Commun. 2005;337:386–93.PubMedCrossRefGoogle Scholar
  43. 43.
    Chen H, Chedotal A, He Z, Goodman CS, Tessier-Lavigne M. Neuropilin-2, a novel member of the neuropilin family, is a high affinity receptor for the semaphorins Sema E and Sema IV but not Sema III. Neuron. 1997;19:547–59.PubMedCrossRefGoogle Scholar
  44. 44.
    Favier B, Alam A, Barron P, Bonnin J, Laboudie P, Fons P, et al. Neuropilin-2 interacts with VEGFR-2 and VEGFR-3 and promotes human endothelial cell survival and migration. Blood. 2006;108:1243–50.PubMedCrossRefGoogle Scholar
  45. 45.
    Yuan L, Moyon D, Pardanaud L, Breant C, Karkkainen MJ, Alitalo K, et al. Abnormal lymphatic vessel development in neuropilin 2 mutant mice. Development. 2002;129:4797–806.PubMedGoogle Scholar
  46. 46.
    Caunt M, Mak J, Liang WC, Stawicki S, Pan Q, Tong RK, et al. Blocking neuropilin-2 function inhibits tumor cell metastasis. Cancer Cell. 2008;13:331–42.PubMedCrossRefGoogle Scholar
  47. 47.
    Fung TM, Ng KY, Tong M, Chen JN, Chai S, Chan KT, et al. Neuropilin-2 promotes tumourigenicity and metastasis in oesophageal squamous cell carcinoma through ERK-MAPK-ETV4-MMP-E-cadherin deregulation. J Pathol. 2016;239:309–19.PubMedCrossRefGoogle Scholar
  48. 48.
    Huntzinger E, Izaurralde E. Gene silencing by microRNAs: contributions of translational repression and mRNA decay. Nat Rev Genet. 2011;12:99–110.PubMedCrossRefGoogle Scholar
  49. 49.
    Yang B, Jing C, Wang J, Guo X, Chen Y, Xu R, et al. Identification of microRNAs associated with lymphangiogenesis in human gastric cancer. Clin Transl Oncol. 2014;16:374–9.PubMedCrossRefGoogle Scholar
  50. 50.
    Hu J, Cheng Y, Li Y, Jin Z, Pan Y, Liu G, et al. microRNA-128 plays a critical role in human non-small cell lung cancer tumourigenesis, angiogenesis and lymphangiogenesis by directly targeting vascular endothelial growth factor-C. Eur J Cancer. 2014;50:2336–50.PubMedCrossRefGoogle Scholar
  51. 51.
    Liu C, Li M, Hu Y, Shi N, Yu H, Liu H, et al. miR-486-5p attenuates tumor growth and lymphangiogenesis by targeting neuropilin-2 in colorectal carcinoma. Onco Targets Ther. 2016;9:2865–71.PubMedPubMedCentralGoogle Scholar
  52. 52.
    Chang LK, Garcia-Cardena G, Farnebo F, Fannon M, Chen EJ, Butterfield C, et al. Dose-dependent response of FGF-2 for lymphangiogenesis. Proc Natl Acad Sci U S A. 2004;101:11658–63.PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Mikami S, Ohashi K, Katsube K, Nemoto T, Nakajima M, Okada Y. Coexpression of heparanase, basic fibroblast growth factor and vascular endothelial growth factor in human esophageal carcinomas. Pathol Int. 2004;54:556–63.PubMedCrossRefGoogle Scholar
  54. 54.
    Ueki T, Koji T, Tamiya S, Nakane PK, Tsuneyoshi M. Expression of basic fibroblast growth factor and fibroblast growth factor receptor in advanced gastric carcinoma. J Pathol. 1995;177:353–61.PubMedCrossRefGoogle Scholar
  55. 55.
    Cao R, Bjorndahl MA, Gallego MI, Chen S, Religa P, Hansen AJ, et al. Hepatocyte growth factor is a lymphangiogenic factor with an indirect mechanism of action. Blood. 2006;107:3531–6.PubMedCrossRefGoogle Scholar
  56. 56.
    Kammula US, Kuntz EJ, Francone TD, Zeng Z, Shia J, Landmann RG, et al. Molecular co-expression of the c-Met oncogene and hepatocyte growth factor in primary colon cancer predicts tumor stage and clinical outcome. Cancer Lett. 2007;248:219–28.PubMedCrossRefGoogle Scholar
  57. 57.
    Sano M, Aoyagi K, Takahashi H, Kawamura T, Mabuchi T, Igaki H, et al. Forkhead box A1 transcriptional pathway in KRT7-expressing esophageal squamous cell carcinomas with extensive lymph node metastasis. Int J Oncol. 2010;36:321–30.PubMedGoogle Scholar
  58. 58.
    Jozwik KM, Carroll JS. Pioneer factors in hormone-dependent cancers. Nat Rev Cancer. 2012;12:381–5.PubMedCrossRefGoogle Scholar
  59. 59.
    Moll R, Divo M, Langbein L. The human keratins: biology and pathology. Histochem Cell Biol. 2008;129:705–33.PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Yamada A, Sasaki H, Aoyagi K, Sano M, Fujii S, Daiko H, et al. Expression of cytokeratin 7 predicts survival in stage I/IIA/IIB squamous cell carcinoma of the esophagus. Oncol Rep. 2008;20:1021–7.PubMedGoogle Scholar
  61. 61.
    Oue N, Noguchi T, Anami K, Kitano S, Sakamoto N, Sentani K, et al. Cytokeratin 7 is a predictive marker for survival in patients with esophageal squamous cell carcinoma. Ann Surg Oncol. 2012;19:1902–10.PubMedCrossRefGoogle Scholar
  62. 62.
    Payne SL, Hendrix MJ, Kirschmann DA. Paradoxical roles for lysyl oxidases in cancer--a prospect. J Cell Biochem. 2007;101:1338–54.PubMedCrossRefGoogle Scholar
  63. 63.
    Csiszar K. Lysyl oxidases: a novel multifunctional amine oxidase family. Prog Nucleic Acid Res Mol Biol. 2001;70:1–32.PubMedCrossRefGoogle Scholar
  64. 64.
    Barker HE, Chang J, Cox TR, Lang G, Bird D, Nicolau M, et al. LOXL2-mediated matrix remodeling in metastasis and mammary gland involution. Cancer Res. 2011;71:1561–72.PubMedCrossRefGoogle Scholar
  65. 65.
    Park JS, Lee JH, Lee YS, Kim JK, Dong SM, Yoon DS. Emerging role of LOXL2 in the promotion of pancreas cancer metastasis. Oncotarget. 2016;7:42539–52.PubMedPubMedCentralGoogle Scholar
  66. 66.
    Ren H, Zhang P, Tang Y, Wu M, Zhang W. Forkhead box protein A1 is a prognostic predictor and promotes tumor growth of gastric cancer. Onco Targets Ther. 2015;8:3029–39.PubMedPubMedCentralGoogle Scholar
  67. 67.
    Weeraratna AT, Jiang Y, Hostetter G, Rosenblatt K, Duray P, Bittner M, et al. Wnt5a signaling directly affects cell motility and invasion of metastatic melanoma. Cancer Cell. 2002;1:279–88.PubMedCrossRefGoogle Scholar
  68. 68.
    Kurayoshi M, Oue N, Yamamoto H, Kishida M, Inoue A, Asahara T, et al. Expression of Wnt-5a is correlated with aggressiveness of gastric cancer by stimulating cell migration and invasion. Cancer Res. 2006;66:10439–48.PubMedCrossRefGoogle Scholar
  69. 69.
    Yamamoto H, Kitadai Y, Yamamoto H, Oue N, Ohdan H, Yasui W, et al. Laminin gamma2 mediates Wnt5a-induced invasion of gastric cancer cells. Gastroenterology. 2009;137:242–52. 52 e1–6PubMedCrossRefGoogle Scholar
  70. 70.
    Li Q, Chen H. Silencing of Wnt5a during colon cancer metastasis involves histone modifications. Epigenetics. 2012;7:551–8.PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Dejmek J, Dejmek A, Safholm A, Sjolander A, Andersson T. Wnt-5a protein expression in primary dukes B colon cancers identifies a subgroup of patients with good prognosis. Cancer Res. 2005;65:9142–6.PubMedCrossRefGoogle Scholar
  72. 72.
    Fritzmann J, Morkel M, Besser D, Budczies J, Kosel F, Brembeck FH, et al. A colorectal cancer expression profile that includes transforming growth factor beta inhibitor BAMBI predicts metastatic potential. Gastroenterology. 2009;137:165–75.PubMedCrossRefGoogle Scholar
  73. 73.
    Onichtchouk D, Chen YG, Dosch R, Gawantka V, Delius H, Massague J, et al. Silencing of TGF-beta signalling by the pseudoreceptor BAMBI. Nature. 1999;401:480–5.PubMedCrossRefGoogle Scholar
  74. 74.
    Sekiya T, Adachi S, Kohu K, Yamada T, Higuchi O, Furukawa Y, et al. Identification of BMP and activin membrane-bound inhibitor (BAMBI), an inhibitor of transforming growth factor-beta signaling, as a target of the beta-catenin pathway in colorectal tumor cells. J Biol Chem. 2004;279:6840–6.PubMedCrossRefGoogle Scholar
  75. 75.
    Zhang Y, Yu Z, Xiao Q, Sun X, Zhu Z, Zhang J, et al. Expression of BAMBI and its combination with Smad7 correlates with tumor invasion and poor prognosis in gastric cancer. Tumour Biol. 2014;35:7047–56.PubMedCrossRefGoogle Scholar
  76. 76.
    Clarke MF, Fuller M. Stem cells and cancer: two faces of eve. Cell. 2006;124:1111–5.PubMedCrossRefGoogle Scholar
  77. 77.
    Visvader JE, Lindeman GJ. Cancer stem cells in solid tumours: accumulating evidence and unresolved questions. Nat Rev Cancer. 2008;8:755–68.PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Brabletz T, Jung A, Spaderna S, Hlubek F, Kirchner T. Opinion: migrating cancer stem cells – an integrated concept of malignant tumour progression. Nat Rev Cancer. 2005;5:744–9.PubMedCrossRefGoogle Scholar
  79. 79.
    O’Brien CA, Pollett A, Gallinger S, Dick JE. A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature. 2007;445:106–10.PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Li CY, Li BX, Liang Y, Peng RQ, Ding Y, Xu DZ, et al. Higher percentage of CD133+ cells is associated with poor prognosis in colon carcinoma patients with stage IIIB. J Transl Med. 2009;7:56.PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Li G, Liu C, Yuan J, Xiao X, Tang N, Hao J, et al. CD133(+) single cell-derived progenies of colorectal cancer cell line SW480 with different invasive and metastatic potential. Clin Exp Metastasis. 2010;27:517–27.PubMedCrossRefGoogle Scholar
  82. 82.
    Tang KH, Dai YD, Tong M, Chan YP, Kwan PS, Fu L, et al. A CD90(+) tumor-initiating cell population with an aggressive signature and metastatic capacity in esophageal cancer. Cancer Res. 2013;73:2322–32.PubMedCrossRefGoogle Scholar
  83. 83.
    Ginestier C, Hur MH, Charafe-Jauffret E, Monville F, Dutcher J, Brown M, et al. ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell. 2007;1:555–67.PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Wang Y, Zhe H, Gao P, Zhang N, Li G, Qin J. Cancer stem cell marker ALDH1 expression is associated with lymph node metastasis and poor survival in esophageal squamous cell carcinoma: a study from high incidence area of northern China. Dis Esophagus. 2012;25:560–5.PubMedCrossRefGoogle Scholar
  85. 85.
    Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007;131:861–72.PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Dalerba P, Dylla SJ, Park IK, Liu R, Wang X, Cho RW, et al. Phenotypic characterization of human colorectal cancer stem cells. Proc Natl Acad Sci U S A. 2007;104:10158–63.PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Takaishi S, Okumura T, Tu S, Wang SS, Shibata W, Vigneshwaran R, et al. Identification of gastric cancer stem cells using the cell surface marker CD44. Stem Cells. 2009;27:1006–20.PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Wakamatsu Y, Sakamoto N, Oo HZ, Naito Y, Uraoka N, Anami K, et al. Expression of cancer stem cell markers ALDH1, CD44 and CD133 in primary tumor and lymph node metastasis of gastric cancer. Pathol Int. 2012;62:112–9.PubMedCrossRefGoogle Scholar
  89. 89.
    Zhang J, Tam WL, Tong GQ, Wu Q, Chan HY, Soh BS, et al. Sall4 modulates embryonic stem cell pluripotency and early embryonic development by the transcriptional regulation of Pou5f1. Nat Cell Biol. 2006;8:1114–23.PubMedCrossRefGoogle Scholar
  90. 90.
    Zhang L, Xu Z, Xu X, Zhang B, Wu H, Wang M, et al. SALL4, a novel marker for human gastric carcinogenesis and metastasis. Oncogene. 2014;33:5491–500.PubMedCrossRefGoogle Scholar
  91. 91.
    Yamamoto Y, Sakamoto M, Fujii G, Tsuiji H, Kenetaka K, Asaka M, et al. Overexpression of orphan G-protein-coupled receptor, Gpr49, in human hepatocellular carcinomas with beta-catenin mutations. Hepatology. 2003;37:528–33.PubMedCrossRefGoogle Scholar
  92. 92.
    Barker N, van Es JH, Kuipers J, Kujala P, van den Born M, Cozijnsen M, et al. Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature. 2007;449:1003–7.PubMedCrossRefGoogle Scholar
  93. 93.
    Uchida H, Yamazaki K, Fukuma M, Yamada T, Hayashida T, Hasegawa H, et al. Overexpression of leucine-rich repeat-containing G protein-coupled receptor 5 in colorectal cancer. Cancer Sci. 2010;101:1731–7.PubMedCrossRefGoogle Scholar
  94. 94.
    Silinsky J, Grimes C, Driscoll T, Green H, Cordova J, Davis NK, et al. CD 133+ and CXCR4+ colon cancer cells as a marker for lymph node metastasis. J Surg Res. 2013;185:113–8.PubMedCrossRefGoogle Scholar
  95. 95.
    Langan RC, Mullinax JE, Ray S, Raiji MT, Schaub N, Xin HW, et al. A pilot study assessing the potential role of non-CD133 colorectal cancer stem cells as biomarkers. J Cancer. 2012;3:231–40.PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Tamoto E, Tada M, Murakawa K, Takada M, Shindo G, Teramoto K, et al. Gene-expression profile changes correlated with tumor progression and lymph node metastasis in esophageal cancer. Clin Cancer Res. 2004;10:3629–38.PubMedCrossRefGoogle Scholar
  97. 97.
    Kan T, Shimada Y, Sato F, Ito T, Kondo K, Watanabe G, et al. Prediction of lymph node metastasis with use of artificial neural networks based on gene expression profiles in esophageal squamous cell carcinoma. Ann Surg Oncol. 2004;11:1070–8.PubMedCrossRefGoogle Scholar
  98. 98.
    Yamabuki T, Daigo Y, Kato T, Hayama S, Tsunoda T, Miyamoto M, et al. Genome-wide gene expression profile analysis of esophageal squamous cell carcinomas. Int J Oncol. 2006;28:1375–84.PubMedGoogle Scholar
  99. 99.
    Uchikado Y, Inoue H, Haraguchi N, Mimori K, Natsugoe S, Okumura H, et al. Gene expression profiling of lymph node metastasis by oligomicroarray analysis using laser microdissection in esophageal squamous cell carcinoma. Int J Oncol. 2006;29:1337–47.PubMedGoogle Scholar
  100. 100.
    Hippo Y, Taniguchi H, Tsutsumi S, Machida N, Chong JM, Fukayama M, et al. Global gene expression analysis of gastric cancer by oligonucleotide microarrays. Cancer Res. 2002;62:233–40.PubMedGoogle Scholar
  101. 101.
    Inoue H, Matsuyama A, Mimori K, Ueo H, Mori M. Prognostic score of gastric cancer determined by cDNA microarray. Clin Cancer Res. 2002;8:3475–9.PubMedGoogle Scholar
  102. 102.
    Oue N, Hamai Y, Mitani Y, Matsumura S, Oshimo Y, Aung PP, et al. Gene expression profile of gastric carcinoma: identification of genes and tags potentially involved in invasion, metastasis, and carcinogenesis by serial analysis of gene expression. Cancer Res. 2004;64:2397–405.PubMedCrossRefGoogle Scholar
  103. 103.
    Marchet A, Mocellin S, Belluco C, Ambrosi A, DeMarchi F, Mammano E, et al. Gene expression profile of primary gastric cancer: towards the prediction of lymph node status. Ann Surg Oncol. 2007;14:1058–64.PubMedCrossRefGoogle Scholar
  104. 104.
    Mimori K, Fukagawa T, Kosaka Y, Ishikawa K, Iwatsuki M, Yokobori T, et al. A large-scale study of MT1-MMP as a marker for isolated tumor cells in peripheral blood and bone marrow in gastric cancer cases. Ann Surg Oncol. 2008;15:2934–42.PubMedCrossRefGoogle Scholar
  105. 105.
    Ueda T, Volinia S, Okumura H, Shimizu M, Taccioli C, Rossi S, et al. Relation between microRNA expression and progression and prognosis of gastric cancer: a microRNA expression analysis. Lancet Oncol. 2010;11:136–46.PubMedCrossRefGoogle Scholar
  106. 106.
    Yamashita K, Kuno A, Matsuda A, Ikehata Y, Katada N, Hirabayashi J, et al. Lectin microarray technology identifies specific lectins related to lymph node metastasis of advanced gastric cancer. Gastric Cancer. 2016;19:531–42.PubMedCrossRefGoogle Scholar
  107. 107.
    Parle-McDermott A, McWilliam P, Tighe O, Dunican D, Croke DT. Serial analysis of gene expression identifies putative metastasis-associated transcripts in colon tumour cell lines. Br J Cancer. 2000;83:725–8.PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    Bertucci F, Salas S, Eysteries S, Nasser V, Finetti P, Ginestier C, et al. Gene expression profiling of colon cancer by DNA microarrays and correlation with histoclinical parameters. Oncogene. 2004;23:1377–91.PubMedCrossRefGoogle Scholar
  109. 109.
    Kwon HC, Kim SH, Roh MS, Kim JS, Lee HS, Choi HJ, et al. Gene expression profiling in lymph node-positive and lymph node-negative colorectal cancer. Dis Colon Rectum. 2004;47:141–52.PubMedCrossRefGoogle Scholar
  110. 110.
    Watanabe T, Kobunai T, Tanaka T, Ishihara S, Matsuda K, Nagawa H. Gene expression signature and the prediction of lymph node metastasis in colorectal cancer by DNA microarray. Dis Colon Rectum. 2009;52:1941–8.PubMedCrossRefGoogle Scholar
  111. 111.
    Pytowski B, Goldman J, Persaud K, Wu Y, Witte L, Hicklin DJ, et al. Complete and specific inhibition of adult lymphatic regeneration by a novel VEGFR-3 neutralizing antibody. J Natl Cancer Inst. 2005;97:14–21.PubMedCrossRefGoogle Scholar
  112. 112.
    Takigawa H, Kitadai Y, Shinagawa K, Yuge R, Higashi Y, Tanaka S, et al. Multikinase inhibitor regorafenib inhibits the growth and metastasis of colon cancer with abundant stroma. Cancer Sci. 2016;107:601–8.PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Onoyama M, Kitadai Y, Tanaka Y, Yuge R, Shinagawa K, Tanaka S, et al. Combining molecular targeted drugs to inhibit both cancer cells and activated stromal cells in gastric cancer. Neoplasia. 2013;15:1391–9.PubMedPubMedCentralCrossRefGoogle Scholar

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© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  1. 1.Department of Molecular PathologyHiroshima University Institute of Biomedical and Health SciencesHiroshimaJapan

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