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Molecular mechanisms of liver metastasis

  • Kenji KawadaEmail author
  • Suguru Hasegawa
  • Teppei Murakami
  • Yoshiro Itatani
  • Hisahiro Hosogi
  • Masahiro Sonoshita
  • Takanori Kitamura
  • Teruaki Fujishita
  • Masayoshi Iwamoto
  • Takuya Matsumoto
  • Ryo Matsusue
  • Koya Hida
  • Gaku Akiyama
  • Kae Okoshi
  • Masahiro Yamada
  • Junichiro Kawamura
  • Makoto Mark Taketo
  • Yoshiharu Sakai
Review Article

Abstract

Colorectal cancer is the second most common cancer, and is the third leading cause of cancer-related death in Japan. The majority of these deaths is attributable to liver metastasis. Recent studies have provided increasing evidence that the chemokine–chemokine receptor system is a potential mechanism of tumor metastasis via multiple complementary actions: (a) by promoting cancer cell migration, invasion, survival and angiogenesis; and (b) by recruiting distal stromal cells (i.e., myeloid bone marrow-derived cells) to indirectly facilitate tumor invasion and metastasis. Here, we discuss recent preclinical and clinical data supporting the view that chemokine pathways are potential therapeutic targets for liver metastasis of colorectal cancer.

Keywords

Liver metastasis Colorectal cancer Chemokine 

Notes

Acknowledgment

The author would like to thank Hideyo Hirai for discussions and encouragements.

Conflict of interest

No potential conflicts of interest were disclosed.

References

  1. 1.
    Matsuda T, Marugame T, Kamo K et al (2008) Cancer incidence and incidence rates in Japan in 2002: based on data from 11 population-based cancer registries. Jpn J Clin Oncol 38:641–648PubMedCrossRefGoogle Scholar
  2. 2.
    Weinberg RA (2007) Multi-step tumorigenesis. Biol Cancer (Garland Science) 11:399–462Google Scholar
  3. 3.
    Millikan KW, Staren ED, Doolas A (1997) Invasive therapy of metastatic colorectal cancer to the liver. Surg Clin North Am 77:27–28PubMedCrossRefGoogle Scholar
  4. 4.
    Jemal A, Murray T, Ward E et al (2005) Cancer statistics, 2005. CA Cancer J Clin 55:10–30PubMedCrossRefGoogle Scholar
  5. 5.
    Rees M, Tekkis PP, Welsh FK et al (2008) Evaluation of long-term survival after hepatic resection for metastatic colorectal cancer: a multifactorial model of 929 patients. Ann Surg 247:125–135PubMedCrossRefGoogle Scholar
  6. 6.
    Nordlinger B, Guiguet M, Vaillant J-C et al (1996) Surgical resection of colorectal carcinoma metastases to the liver. A prognostic scoring system to improve case selection, based on 1568 patients. Cancer 77:1254–1262PubMedCrossRefGoogle Scholar
  7. 7.
    Chambers AF, Groom AC, MacDonald IC (2002) Dissemination and growth of cancer cells in metastatic sites. Nat Rev Cancer 2:563–572PubMedCrossRefGoogle Scholar
  8. 8.
    Wang JM, Deng X, Gong W et al (1998) Chemokines and their role in tumor growth and metastasis. J Immunol Methods 220:1–17PubMedCrossRefGoogle Scholar
  9. 9.
    Müller A, Homey B, Soto H et al (2001) Involvement of chemokine receptors in breast cancer metastasis. Nature 410:50–56PubMedCrossRefGoogle Scholar
  10. 10.
    Kang Y, Siegel PM, Shu W et al (2003) A multigenic program mediating breast cancer metastasis to bone. Cancer Cell 3:537–549PubMedCrossRefGoogle Scholar
  11. 11.
    Nagasawa T, Hirota S, Tachibana K et al (1996) Defects of B-cell lymphopoiesis and bone-marrow myelopoiesis in mice lacking the CXC chemokine PBSF/SDF-1. Nature 382:635–638PubMedCrossRefGoogle Scholar
  12. 12.
    Tachibana K, Hirota S, Iizasa H et al (1998) The chemokine receptor CXCR4 is essential for vascularization of the gastrointestinal tract. Nature 393:591–594PubMedCrossRefGoogle Scholar
  13. 13.
    Zeelenberg IS, Ruuls-Van Stalle L, Roos E (2003) The chemokine receptor CXCR4 is required for outgrowth of colon carcinoma micrometastasis. Cancer Res 62:3833–3839Google Scholar
  14. 14.
    Kim J, Takeuchi H, Lam ST et al (2005) Chemokine receptor CXCR4 expression in colorectal cancer patients increases the risk for recurrence and for poor survival. J Clin Oncol 23:2744–2753PubMedCrossRefGoogle Scholar
  15. 15.
    Gassmann P, Haier J, Schlüter K et al (2009) CXCR4 regulates the early extravasation of metastatic tumor cells in vivo. Neoplasia 11:651–661PubMedGoogle Scholar
  16. 16.
    Matsusue R, Kubo H, Hisamori S et al (2009) Hepatic stellate cells promote liver metastasis of colon cancer cells by the action of SDF-1/CXCR4 axis. Ann Surg Oncol 16:2645–2653PubMedCrossRefGoogle Scholar
  17. 17.
    Xu L, Duda DG, di Tomaso E et al (2009) Direct evidence that bevacizumab, an anti-VEGF antibody, up-regulates SDF1α, CXCR4, CXCL6, and Neuropilin 1 in tumors from patients with rectal cancer. Cancer Res 69:7905–7910PubMedCrossRefGoogle Scholar
  18. 18.
    Willett CG, Duda DG, di Tomaso E et al (2009) Efficacy, safety and biomarkers of neoadjuvant bevacizumab, radiation therapy, and fluorouracil in rectal cancer: a multidisciplinary phase II study. J Clin Oncol 27:3020–3026PubMedCrossRefGoogle Scholar
  19. 19.
    Cella M, Jarrossay D, Facchetti F et al (1999) Plasmacytoid monocytes migrate to inflamed lymph nodes and produce large amounts of type I interferon. Nat Med 5:919–923PubMedCrossRefGoogle Scholar
  20. 20.
    Janatpour MJ, Hudak S, Sathe M et al (2001) Tumor necrosis factor-dependent segmental control of MIG expression by high endothelial venules in inflamed lymph nodes regulates monocyte recruitment. J Exp Med 193:1375–1384CrossRefGoogle Scholar
  21. 21.
    Martin-Fontecha A, Thomsen LL, Brett S et al (2004) Induced recruitment of NK cells to lymph nodes provides IFN-γ for TH1 priming. Nat Immunol 5:1260–1265PubMedCrossRefGoogle Scholar
  22. 22.
    Yoneyama H, Narumi S, Zhang Y et al (2002) Pivotal role of dendritic cell-derived CXCL10 in the retention of T helper cell lymphocytes in secondary lymph nodes. J Exp Med 195:1257–1266PubMedCrossRefGoogle Scholar
  23. 23.
    Kawada K, Sonoshita M, Sakashita H et al (2004) Pivotal role of CXCR3 in melanoma cell metastasis to lymph nodes. Cancer Res 64:4010–4017PubMedCrossRefGoogle Scholar
  24. 24.
    Kawada K, Hosogi H, Sonoshita M et al (2007) Chemokine receptor CXCR3 promotes colon cancer metastasis to lymph nodes. Ongocene 26:4679–4688Google Scholar
  25. 25.
    Kawada K, Taketo MM (2011) Significance and mechanism of lymph node metastasis in cancer progression. Cancer Res 71:1214–1218PubMedCrossRefGoogle Scholar
  26. 26.
    Zipin-Roitman A, Meshel T, Sagi-Assif O et al (2007) CXCL10 promotes invasion-related properties in human colorectal carcinoma cells. Cancer Res 67:3396–3405PubMedCrossRefGoogle Scholar
  27. 27.
    Rubie C, Kollmar O, Frick VO et al (2008) Differential CXC receptor expression in colorectal carcinomas. Scand J Immunol 68:635–644PubMedGoogle Scholar
  28. 28.
    Cambien B, Karimdjee BF, Richard-Fiardo P et al (2009) Organ-specific inhibition of metastatic colon carcinoma by CXCR3 antagonism. Br J Cancer 100:1755–1764PubMedCrossRefGoogle Scholar
  29. 29.
    Walser TC, Rifat S, Ma X et al (2006) Antagonism of CXCR3 inhibits lung metastasis in a murine model of metastatic breast cancer. Cancer Res 66:7701–7707PubMedCrossRefGoogle Scholar
  30. 30.
    Ma X, Norsworthy K, Kundu N et al (2009) CXCR3 expression is associated with poor survival in breast cancer and promotes metastasis in a murine model. Mol Cancer Ther 8:490–498PubMedCrossRefGoogle Scholar
  31. 31.
    Shimizu Y, Murata H, Kashii Y et al (2001) CC-chemokine receptor 6 and its ligand macrophage inflammatory protein 3alpha might be involved in the amplification of local necroinflammatory response in the liver. Hepatology 34:311–319PubMedCrossRefGoogle Scholar
  32. 32.
    Dwinell MB, Eckmann L, Leopard JD et al (1999) Chemokine receptor expression by human intestinal epithelial cells. Gastroenterology 117:359–367PubMedCrossRefGoogle Scholar
  33. 33.
    Ghadjar P, Coupland SE, Na I-K et al (2006) Chemokine receptor CCR6 expression level and liver metastases in colorectal cancer. J Clin Oncol 24:1910–1916PubMedCrossRefGoogle Scholar
  34. 34.
    Rubie C, Oliveira V, Kempf K et al (2006) Involvement of chemokine receptor CCR6 in colorectal cancer metastasis. Tumor Biol 27:166–174CrossRefGoogle Scholar
  35. 35.
    Kagaya T, Nakamoto Y, Sakai Y et al (2006) Monocyte chemoattractant protein-1 gene delivery enhances antitumor effects of herpes simplex virus thymidine kinase/ganciclovir system in a model of colon cancer. Cancer Gene Ther 13:357–366PubMedCrossRefGoogle Scholar
  36. 36.
    Bailey C, Negus R, Morris A et al (2007) Chemokine expression is associated with the accumulation of tumour associated macrophages (TAMs) and progression in human colorectal cancer. Clin Exp Metastasis 24:121–130PubMedCrossRefGoogle Scholar
  37. 37.
    Hu H, Sun L, Guo C et al (2009) Tumor cell-microenvironment interaction models coupled with clinical validation reveal CCL2 and SNCG as two predictors of colorectal cancer hepatic metastasis. Clin Cancer Res 15:5485–5493PubMedCrossRefGoogle Scholar
  38. 38.
    Folkman J (2002) Role of angiogenesis in tumor growth and metastasis. Semin Oncol 29:15–18PubMedGoogle Scholar
  39. 39.
    Strieter RM, Kunkel SL, Elner VM et al (1992) Interleukin-8, a corneal factor that induces neovascularization. Am J Pathol 141:1279–1284PubMedGoogle Scholar
  40. 40.
    Brew R, Southern SA, Flanagan BF et al (1996) Detection of interleukin-8 mRNA and protein in human colorectal carcinoma cells. Eur J Cancer 32A:2142–2147PubMedCrossRefGoogle Scholar
  41. 41.
    Yang S-K, Eckmann L, Panja A et al (1997) Differential and regulated expression of C-X-C. C–C, and C-chemokines by human colon epithelial cells. Gastroenterology 113:1214–1223PubMedCrossRefGoogle Scholar
  42. 42.
    Brew R, Southern SA, Flanagan BF et al (2000) Interleukin-8 as an autocrine growth factor for human colon carcinoma cells in vitro. Cytokine 12:78–85PubMedCrossRefGoogle Scholar
  43. 43.
    Li A, Varney ML, Singh RK (2001) Expression of interleukin 8 and its receptors in human colon carcinoma cells with different metastatic potentials. Clin Cancer Res 7:3298–3304PubMedGoogle Scholar
  44. 44.
    Mizukami Y, Jo W-S, Duerr E-M et al (2005) Induction of interleukin-8 preserves the angiogenic response in HIF-1-α-deficient colon cancer cells. Nat Med 11:992–997PubMedGoogle Scholar
  45. 45.
    Ning Y, Manegold PC, Hong YK et al (2010) Interleukin-8 is associated with proliferation, migration, angiogenesis and chemosensitivity in vitro and in vivo in colon cancer cell line models. Int J Cancer 128:2038–2049CrossRefGoogle Scholar
  46. 46.
    Varney ML, Singh S, Li A et al (2011) Small molecule antagonists for CXCR2 and CXCR1 inhibit human colon cancer liver metastases. Cancer Lett 300:180–188PubMedCrossRefGoogle Scholar
  47. 47.
    Ueda T, Shimada E, Urakawa T et al (1994) Serum levels of cytokines in patients with colorectal cancer: possible involvement of interleukin-6 and interleukin-8 in hematogenous metastasis. J Gastroenterol 29:423–429PubMedCrossRefGoogle Scholar
  48. 48.
    Richmond A, Thomas HG (1988) Melanoma growth stimulatory activity: isolation from human melanoma tumors and characterization of tissue distribution. J Cell Biochem 36:185–198PubMedCrossRefGoogle Scholar
  49. 49.
    Li A, Varney ML, Singh RK (2004) Constitutive expression of growth regulated oncogene (gro) in human colon carcinoma cells with different metastatic potential and its role in regulating their metastatic phenotype. Clin Exp Metast 21:571–579CrossRefGoogle Scholar
  50. 50.
    Wen Y, Giardina SF, Hamming D et al (2006) GROα is highly expressed in adenocarcinoma of the colon and down-regulates Fibulin-1. Clin Cancer Res 12:5951–5959PubMedCrossRefGoogle Scholar
  51. 51.
    Minn AJ, Gupta GP, Siegel PM et al (2005) Genes that mediate breast cancer metastasis to lung. Nature 436:518–524PubMedCrossRefGoogle Scholar
  52. 52.
    Doll D, Keller L, Maak M et al (2010) Differential expression of the chemokines GRO-2, GRO-3 and interleukin-8 in colon cancer and their impact on metastatic disease and survival. Ing J Colorectal Dis 25:573–581CrossRefGoogle Scholar
  53. 53.
    Rubie C, Frick VO, Pfeil S et al (2007) Correlation of IL-8 with induction, progression and metastatic potential of colorectal cancer. World J Gastroenterol 11:125–131Google Scholar
  54. 54.
    Smith SC, Theodorescu D (2009) Learning therapeutic lessons from metastasis suppressor proteins. Nat Rev Cancer 9:253–264PubMedCrossRefGoogle Scholar
  55. 55.
    Kalluri R, Zeisberg M (2006) Fibroblasts in cancer. Nat Rev Cancer 6:392–401PubMedCrossRefGoogle Scholar
  56. 56.
    Coussens LM, Tinkle CL, Hanahan D et al (2000) MMP-9 supplied by bone marrow-derived cells contributes to skin carcinogenesis. Cell 103:481–490PubMedCrossRefGoogle Scholar
  57. 57.
    Orimo A, Gupta PB, Sgroi DC et al (2005) Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell 121:335–348PubMedCrossRefGoogle Scholar
  58. 58.
    Lin EY, Nguyen AV, Russel RG et al (2001) Colony-stimulating factor 1 promotes progression of mammary tumors to malignancy. J Exp Med 193:727–739PubMedCrossRefGoogle Scholar
  59. 59.
    Karnoub AE, Dash AB, Vo AP et al (2007) Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature 446:557–563CrossRefGoogle Scholar
  60. 60.
    Joyce JA, Pollard JW (2009) Microenvironmental regulation of metastasis. Nat Rev Cancer 9:239–252PubMedCrossRefGoogle Scholar
  61. 61.
    Kaplan RN, Riba RD, Zacharoulis S et al (2005) VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 438:820–827PubMedCrossRefGoogle Scholar
  62. 62.
    Hiratsuka S, Watanabe A, Aburatani H et al (2006) Tumour-mediated upregulation of chemoattractants and recruitment of myeloid cells predetermines lung metastasis. Nat Cell Biol 8:1369–1375PubMedCrossRefGoogle Scholar
  63. 63.
    Erler JT, Bennewith KL, Cox TR et al (2009) Hypoxia-induced lysyl oxidase is a critical mediator of bone marrow cell recruitment to form the premetastatic niche. Cancer Cell 15:35–44PubMedCrossRefGoogle Scholar
  64. 64.
    Murdoch C, Muthana M, Coffelt SB et al (2008) The role of myeloid cells in the promotion of tumour angiogenesis. Nat Rev Cancer 8:618–631PubMedCrossRefGoogle Scholar
  65. 65.
    Hiratsuka S, Duda DG, Huang Y et al (2011) C-X-C receptor type 4 promotes metastasis by activating p38 mitogen-activated protein kinase in myeloid differentiation antigen (Gr-1)-positive cells. Proc Natl Acad Sci USA 108:302–307PubMedCrossRefGoogle Scholar
  66. 66.
    Yamamoto M, Kikuchi H, Ohta M et al (2008) TSU68 prevents liver metastasis of colon cancer xenografts by modulating the premetastatic niche. Cancer Res 68:9754–9762PubMedCrossRefGoogle Scholar
  67. 67.
    Taketo MM, Edelmann W (2009) Mouse models of colon cancer. Gastroenterology 136:780–798PubMedCrossRefGoogle Scholar
  68. 68.
    Takaku K, Oshima M, Miyoshi H et al (1998) Intestinal tumorigenesis in compound mutant mice of both Dpc4 (Smad4) and Apc genes. Cell 92:645–656PubMedCrossRefGoogle Scholar
  69. 69.
    Kitamura T, Kometani K, Hashida H et al (2007) SMAD4-deficient intestinal tumors recruit CCR1 + myeloid cells that promote invasion. Nat Genet 39:467–475PubMedCrossRefGoogle Scholar
  70. 70.
    Kitamura T, Taketo MM (2007) Keeping out the bad guys: gateway to cellular target therapy. Cancer Res 67:10099–10102PubMedCrossRefGoogle Scholar
  71. 71.
    Yang L, Huang J, Ren X et al (2008) Abrogation of TGF beta signaling in mammary carcinomas recruits Gr-1 + CD11b + myeloid cells that promote metastasis. Cancer Cell 13:23–35PubMedCrossRefGoogle Scholar
  72. 72.
    Kitamura T, Fujishita T, Loetscher P et al (2010) Inactivation of chemokine (C–C motif) receptor 1 (CCR1) suppresses colon cancer liver metastasis by blocking accumulation of immature myeloid cells in a mouse model. Proc Natl Acad Sci USA 107:13063–13068PubMedCrossRefGoogle Scholar
  73. 73.
    Kusmartsev S, Gabrilovich DI (2006) Role of immature myeloid cells in mechanisms of immune evasion in cancer. Cancer Immunol Immunother 55:237–245PubMedCrossRefGoogle Scholar
  74. 74.
    Yang L, Debusk LM, Fukuda K et al (2004) Expansion of myeloid immune suppressor Gr+ CD11b+ cells in tumor-bearing host directly promotes tumor angiogenesis. Cancer Cell 6:409–421PubMedCrossRefGoogle Scholar
  75. 75.
    Wells TN, Power CA, Shaw JP et al (2006) Chemokine blockers–therapeutics in the making? Trends Pharmacol Sci 27:41–47PubMedCrossRefGoogle Scholar
  76. 76.
    Pradelli E, Karimdjee-Soilihi B, Michiels JF et al (2009) Antagonism of chemokine receptor CXCR3 inhibits osteosarcoma metastasis to lungs. Int J Cancer 125:2586–2594PubMedCrossRefGoogle Scholar
  77. 77.
    Wijtmans M, Verzijl D, Leurs R et al (2008) Towards small-molecule CXCR3 ligands with clinical potential. Chem Med Chem. 3:861–872PubMedGoogle Scholar
  78. 78.
    McGuinness BF, Carroll CD, Zawacki LG et al (2009) Novel CXCR3 antagonists with a piperazinyl-piperidine core. Bioorg Med Chem Lett 19:5205–5208PubMedCrossRefGoogle Scholar
  79. 79.
    Crosignani S, Missotten M, Cleva C et al (2010) Discovery of a novel series of CXCR3 antagonists. Bioorg Med Chem Lett 20:3614–3617PubMedCrossRefGoogle Scholar
  80. 80.
    Wijtmans M, Verzijl D, Bergmans S et al (2011) CXCR3 antagonists: quaternary ammonium salts equipped with biphenyl- and polycycloaliphatic-anchors. Bioorg Med Chem 19:3384–3393PubMedCrossRefGoogle Scholar
  81. 81.
    Gladue RP, Brown MF, Zwillich SH (2010) CCR1 antagonists: what have we learned from clinical trials. Curr Top Med Chem 10:1268–1277PubMedCrossRefGoogle Scholar
  82. 82.
    Sonoshita M, Aoki M, Fuwa H et al (2011) Suppression of colon cancer metastasis by Aes through inhibition of Notch signaling. Cancer Cell 19:125–137PubMedCrossRefGoogle Scholar
  83. 83.
    Taketo MM (2011) Reflections on the spread of metastasis to cancer prevention. Cancer Prev Res 4:324–328CrossRefGoogle Scholar
  84. 84.
    Garber K (2009) First results for agents targeting cancer-related inflammation. J Natl Cancer Inst 101:1110–1112PubMedCrossRefGoogle Scholar
  85. 85.
    Sun X, Cheng G, Hao M et al (2010) CXCL12/CXCR4/CXCR7 chemokine axis and cancer progression. Cancer Metastasis Rev 29:709–722PubMedCrossRefGoogle Scholar
  86. 86.
    Burger JA, Stewart DJ (2009) CXCR4 chemokine receptor antagonists: perspectives in SCLC. Expert Opin Investig Drugs 18:481–490PubMedCrossRefGoogle Scholar

Copyright information

© Japan Society of Clinical Oncology 2011

Authors and Affiliations

  • Kenji Kawada
    • 1
    Email author
  • Suguru Hasegawa
    • 1
  • Teppei Murakami
    • 1
  • Yoshiro Itatani
    • 1
    • 2
  • Hisahiro Hosogi
    • 1
  • Masahiro Sonoshita
    • 2
  • Takanori Kitamura
    • 2
    • 3
  • Teruaki Fujishita
    • 2
  • Masayoshi Iwamoto
    • 1
  • Takuya Matsumoto
    • 1
  • Ryo Matsusue
    • 1
  • Koya Hida
    • 1
  • Gaku Akiyama
    • 1
  • Kae Okoshi
    • 1
  • Masahiro Yamada
    • 1
  • Junichiro Kawamura
    • 1
  • Makoto Mark Taketo
    • 2
  • Yoshiharu Sakai
    • 1
  1. 1.Department of Surgery, Graduate School of MedicineKyoto UniversityKyotoJapan
  2. 2.Department of PharmacologyKyoto University Graduate School of MedicineKyotoJapan
  3. 3.Department of Developmental and Molecular BiologyAlbert Einstein College of MedicineNew YorkUSA

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