Skip to main content

Advertisement

Log in

Hepatic metastatic niche: from normal to pre-metastatic and metastatic niche

  • Review
  • Published:
Tumor Biology

Abstract

Liver is the organ responsible for hematopoiesis during fetal life, which is also a target organ of metastasis for several cancers. In order to recognize the hepatic metastatic changes, obtain a better grasp of cancer prevention, treatment, and inhibition mode of hepatic metastasis progression, we investigate the changes and transformation of normal hepatic niche cells to metastatic niche ones in this review. On the other hand, since metastatic diseases alter the liver function, the changes in a number of cancers that metastasize to the liver have also been reviewed. Relevant English-language literature was searched and retrieved from PubMed (1994–2014) using the following keywords: hepatic stem cell niche, hepatic metastatic niche, chemokine, and microRNAs (miRNAs). Also, over 86 published studies were investigated, and bioinformatics analysis of differentially expressed miRNAs in hepatic cancer and metastasis was performed. Metastasis is developed in several stages with specific changes and mechanisms in each stage. Recognition of these changes would lead to detection of new biomarkers and clinical targets involved in specific stages of liver metastasis. Investigation of the hepatic stem cell niche, development of metastasis in liver tissue, as well as changes in chemokines and miRNAs in metastatic hepatic niche can significantly contribute to faster detection of liver metastasis progression.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Zhang Y, Davis C, Ryan J, Janney C, Peña MMO. Development and characterization of a reliable mouse model of colorectal cancer metastasis to the liver. Clin Exp Metastasis. 2013;30(7):903–18.

    Article  PubMed  Google Scholar 

  2. Greenbaum LE, Wells RG. The role of stem cells in liver repair and fibrosis. Int J Biochem Cell Biol. 2011;43(2):222–9.

    Article  CAS  PubMed  Google Scholar 

  3. Xia M, Hu M. The role of microRNA in tumor invasion and metastasis. J Cancer Mol. 2010;5(2):33–9.

    CAS  Google Scholar 

  4. Nicoloso MS, Spizzo R, Shimizu M, Rossi S, Calin GA. MicroRNAs—the micro steering wheel of tumour metastases. Nat Rev Cancer. 2009;9(4):293–302.

    Article  CAS  PubMed  Google Scholar 

  5. Katoonizadeh A, Poustchi H. Adult hepatic progenitor cell niche: how it affects the progenitor cell fate. Middle East J Digestive Dis. 2014;6(2):57–64.

    Google Scholar 

  6. Clark AM, Wheeler SE, Taylor DP, Pillai VC, Young CL, Prantil-Baun R, et al. A microphysiological system model of therapy for liver micrometastases. Exp Biol Med. 2014;239(9):1170–9.

    Article  Google Scholar 

  7. Payushina OV. Hematopoietic microenvironment in the fetal liver: roles of different cell populations. ISRN Cell Biology. 2012;2012:1–7.

    Article  Google Scholar 

  8. Oertel M, Shafritz DA. Stem cells, cell transplantation and liver repopulation. Biochim Biophys Acta (BBA) - Mol Basis Dis. 2008;1782(2):61–74.

    Article  CAS  Google Scholar 

  9. Kuwahara R, Kofman AV, Landis CS, Swenson ES, Barendswaard E, Theise ND. The hepatic stem cell niche: identification by label-retaining cell assay. Hepatology. 2008;47(6):1994–2002.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Petersen B, Shupe T. Location is everything: the liver stem cell niche. Hepatology. 2008;47(6):1810–2.

    Article  PubMed  Google Scholar 

  11. Kamiya A, Kakinuma S, Yamazaki Y, Nakauchi H. Enrichment and clonal culture of progenitor cells during mouse postnatal liver development in mice. Gastroenterology. 2009;137(3):1114–26.

    Article  CAS  PubMed  Google Scholar 

  12. Vestentoft PS. Development and molecular composition of the hepatic progenitor cell niche. Danish Med J. 2013;60(5):B4640-B.

    Google Scholar 

  13. Villeneuve J, Pelluard-Nehme F, Combe C, Carles D, Chaponnier C, Ripoche J, et al. Immunohistochemical study of the phenotypic change of the mesenchymal cells during portal tract maturation in normal and fibrous (ductal plate malformation) fetal liver. Comp Hepatol. 2009;8(5):1–12.

    Google Scholar 

  14. Kiassov AP, Van Eyken P, van Pelt JF, Depla E, Fevery J, Desmet VJ, et al. Desmin expressing nonhematopoietic liver cells during rat liver development: an immunohistochemical and morphometric study. Differentiation. 1995;59(4):253–8.

    Article  CAS  PubMed  Google Scholar 

  15. Fujio K, Evarts RP, Hu Z, Marsden ER, Thorgeirsson SS. Expression of stem cell factor and its receptor, c-kit, during liver regeneration from putative stem cells in adult rat. Laboratory Investig J Tech Methods Pathol. 1994;70(4):511–6.

    CAS  Google Scholar 

  16. Kordes C, Sawitza I, Götze S, Häussinger D. Hepatic stellate cells support hematopoiesis and are liver-resident mesenchymal stem cells. Cell Physiol Biochem. 2013;31(2–3):290–304.

    Article  CAS  PubMed  Google Scholar 

  17. Li D, Wang G-Y, Liu Z-F, Shi Y-X, Zhang H, Bai Z-L. Macrophage-associated erythropoiesis and lymphocytopoiesis in mouse fetal liver: ultrastructural and ISH analysis. Cell Biol Int. 2004;28(6):457–61.

    Article  CAS  PubMed  Google Scholar 

  18. Van den Eynden GG, Majeed AW, Illemann M, Vermeulen PB, Bird NC, Høyer-Hansen G, et al. The multifaceted role of the microenvironment in liver metastasis: biology and clinical implications. Cancer Res. 2013;73(7):2031–43.

    Article  PubMed  Google Scholar 

  19. Isern J, Fraser ST, He Z, Baron MH. The fetal liver is a niche for maturation of primitive erythroid cells. Proc Natl Acad Sci. 2008;105(18):6662–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Lee WB, Erm SK, Kim KY, Becker RP. Emperipolesis of erythroblasts within kupffer cells during hepatic hemopoiesis in human fetus. Anat Rec. 1999;256(2):158–64.

    Article  CAS  PubMed  Google Scholar 

  21. Kodama Y, Hijikata M, Kageyama R, Shimotohno K, Chiba T. The role of notch signaling in the development of intrahepatic bile ducts. Gastroenterology. 2004;127(6):1775–86.

    Article  CAS  PubMed  Google Scholar 

  22. Morell CM, Strazzabosco M. Notch signaling and new therapeutic options in liver disease. J Hepatol. 2014;60(4):885–90.

    Article  CAS  PubMed  Google Scholar 

  23. Zong Y, Panikkar A, Xu J, Antoniou A, Raynaud P, Lemaigre F, et al. Notch signaling controls liver development by regulating biliary differentiation. Development. 2009;136(10):1727–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Vidal-Vanaclocha F. The Tumor microenvironment at different stages of hepatic metastasis. In: Brodt P, editor . 1st ed. Liver metastasis: biology and clinical management; 2011.

  25. Seubert B, Grünwald B, Kobuch J, Cui H, Schelter F, Schaten S, et al. Tissue inhibitor of metalloproteinases (TIMP)-1 creates a premetastatic niche in the liver through SDF-1/CXCR4-dependent neutrophil recruitment in mice. Hepatology. 2015;61(1):238–48.

    Article  CAS  PubMed  Google Scholar 

  26. Kopitz C, Gerg M, Bandapalli OR, Ister D, Pennington CJ, Hauser S, et al. Tissue inhibitor of metalloproteinases-1 promotes liver metastasis by induction of hepatocyte growth factor signaling. Cancer Res. 2007;67(18):8615–23.

    Article  CAS  PubMed  Google Scholar 

  27. Tanaka M, Itoh T, Tanimizu N, Miyajima A. Liver stem/progenitor cells: their characteristics and regulatory mechanisms. J Biochem. 2011;149(3):231–9.

    Article  CAS  PubMed  Google Scholar 

  28. Chirco R, Liu X-W, Jung K-K, Kim H-RC. Novel functions of TIMPs in cell signaling. Cancer Metastasis Rev. 2006;25(1):99–113.

    Article  CAS  PubMed  Google Scholar 

  29. Psaila B, Lyden D. The metastatic niche: adapting the foreign soil. Nat Rev Cancer. 2009;9(4):285–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Dachs G, Tozer G. Hypoxia modulated gene expression: angiogenesis, metastasis and therapeutic exploitation. Eur J Cancer. 2000;36(13):1649–60.

    Article  CAS  PubMed  Google Scholar 

  31. Benvenuti S, Comoglio PM. The MET receptor tyrosine kinase in invasion and metastasis. J Cell Physiol. 2007;213(2):316–25.

    Article  CAS  PubMed  Google Scholar 

  32. Pennacchietti S, Michieli P, Galluzzo M, Mazzone M, Giordano S, Comoglio PM. Hypoxia promotes invasive growth by transcriptional activation of the met protooncogene. Cancer Cell. 2003;3(4):347–61.

    Article  PubMed  Google Scholar 

  33. Schelter F, Halbgewachs B, Bäumler P, Neu C, Görlach A, Schrötzlmair F, et al. Tissue inhibitor of metalloproteinases-1-induced scattered liver metastasis is mediated by hypoxia-inducible factor-1α. Clin Exp Metastasis. 2011;28(2):91–9.

    Article  CAS  PubMed  Google Scholar 

  34. Lee TK, Poon RT, Yuen AP, Ling MT, Kwok WK, Wang XH, et al. Twist overexpression correlates with hepatocellular carcinoma metastasis through induction of epithelial-mesenchymal transition. Clin Cancer Res. 2006;12(18):5369–76.

    Article  CAS  PubMed  Google Scholar 

  35. 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(7069):820–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Ma S, Chan KW, Hu L, Lee TKW, Wo JYH, Ng IOL, et al. Identification and characterization of tumorigenic liver cancer stem/progenitor cells. Gastroenterology. 2007;132(7):2542–56.

    Article  CAS  PubMed  Google Scholar 

  37. Gassmann P, Hemping-Bovenkerk A, Mees ST, Haier J. Metastatic tumor cell arrest in the liver–lumen occlusion and specific adhesion are not exclusive. Int J Color Dis. 2009;24(7):851–8.

    Article  Google Scholar 

  38. Singh S, Sadanandam A, Singh RK. Chemokines in tumor angiogenesis and metastasis. Cancer Metastasis Rev. 2007;26(3–4):453–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Khatib A-M, Auguste P, Fallavollita L, Wang N, Samani A, Kontogiannea M, et al. Characterization of the host proinflammatory response to tumor cells during the initial stages of liver metastasis. Am J Pathol. 2005;167(3):749–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Auguste P, Fallavollita L, Wang N, Burnier J, Bikfalvi A, Brodt P. The host inflammatory response promotes liver metastasis by increasing tumor cell arrest and extravasation. Am J Pathol. 2007;170(5):1781–92.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Khatib A-M, Kontogiannea M, Fallavollita L, Jamison B, Meterissian S, Brodt P. Rapid induction of cytokine and E-selectin expression in the liver in response to metastatic tumor cells. Cancer Res. 1999;59(6):1356–61.

    CAS  PubMed  Google Scholar 

  42. Yamamoto M, Kikuchi H, Ohta M, Kawabata T, Hiramatsu Y, Kondo K, et al. TSU68 prevents liver metastasis of colon cancer xenografts by modulating the premetastatic niche. Cancer Res. 2008;68(23):9754–62.

    Article  CAS  PubMed  Google Scholar 

  43. Spicer JD, McDonald B, Cools-Lartigue JJ, Chow SC, Giannias B, Kubes P, et al. Neutrophils promote liver metastasis via mac-1-mediated interactions with circulating tumor cells. Cancer Res. 2012;72(16):3919–27.

    Article  CAS  PubMed  Google Scholar 

  44. Fox-Robichaud A, Kubes P. Molecular mechanisms of tumor necrosis factor α-stimulated leukocyte recruitment into the murine hepatic circulation. Hepatology. 2000;31(5):1123–7.

    Article  CAS  PubMed  Google Scholar 

  45. Noël A, Jost M, Maquoi E. Matrix metalloproteinases at cancer tumor–host interface. Semin Cell Dev Biol. 2008;19(1):52–60.

    Article  PubMed  Google Scholar 

  46. Shi Y, Xu T, Li LP, Chen XP. Over-expression of VEGF and MMP-9 in residual tumor cells of hepatocellular carcinoma after embolization with lipidol. J Huazhong Univ Sci Technolog Med Sci. 2013;33:90–5.

    Article  PubMed  Google Scholar 

  47. Yamashita T, Wang XW. Cancer stem cells in the development of liver cancer. J Clin Invest. 2013;123(5):1911–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Janda E, Lehmann K, Killisch I, Jechlinger M, Herzig M, Downward J, et al. Ras and TGFβ cooperatively regulate epithelial cell plasticity and metastasis dissection of ras signaling pathways. J Cell Biol. 2002;156(2):299–314.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Burnier J, Wang N, Michel R, Hassanain M, Li S, Lu Y, et al. Type IV collagen-initiated signals provide survival and growth cues required for liver metastasis. Oncogene. 2011;30(35):3766–83.

    Article  CAS  PubMed  Google Scholar 

  50. 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(4):558–66.

    Article  CAS  PubMed  Google Scholar 

  51. Minn AJ, Gupta GP, Siegel PM, Bos PD, Shu W, Giri DD, et al. Genes that mediate breast cancer metastasis to lung. Nature. 2005;436(7050):518–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Irmisch A, Huelsken J. Metastasis: new insights into organ-specific extravasation and metastatic niches. Exp Cell Res. 2013;319(11):1604–10.

    Article  CAS  PubMed  Google Scholar 

  53. Oskarsson T, Acharyya S, Zhang XH, Vanharanta S, Tavazoie SF, Morris PG, et al. Breast cancer cells produce tenascin C as a metastatic niche component to colonize the lungs. Nat Med. 2011;17(7):867–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Ye C, Kiriyama K, Mistuoka C, Kannagi R, Ito K, Watanabe T, et al. Expression of E-selectin on endothelial cells of small veins in human colorectal cancer. Int J Cancer. 1995;61(4):455–60.

    Article  CAS  PubMed  Google Scholar 

  55. Sato T, Oshima T, Yoshihara K, Yamamoto N, Yamada R, Nagano Y, et al. Overexpression of the fibroblast growth factor receptor-1 gene correlates with liver metastasis in colorectal cancer. Oncol Rep. 2009;21(1):211–6.

    CAS  PubMed  Google Scholar 

  56. Li M, Lin Y-M, Hasegawa S, Shimokawa T, Murata K, Kameyama M, et al. Genes associated with liver metastasis of colon cancer, identified by genome-wide cDNA microarray. Int J Oncol. 2004;24(2):305–12.

    PubMed  Google Scholar 

  57. Osada T, Sakamoto M, Ino Y, Iwamatsu A, Matsuno Y, Muto T, et al. E‐cadherin is involved in the intrahepatic metastasis of hepatocellular carcinoma. Hepatology. 1996;24(6):1460–7.

    Article  CAS  PubMed  Google Scholar 

  58. Kinugasa T, Akagi Y, Ochi T, Tanaka N, Kawahara A, Ishibashi Y, et al. Increased claudin-1 protein expression in hepatic metastatic lesions of colorectal cancer. Anticancer Res. 2012;32(6):2309–14.

    PubMed  Google Scholar 

  59. Niedergethmann M, Alves F, Neff J, Heidrich B, Aramin N, Li L, et al. Gene expression profiling of liver metastases and tumour invasion in pancreatic cancer using an orthotopic SCID mouse model. Br J Cancer. 2007;97(10):1432–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Shi Q, Le X, Abbruzzese JL, Peng Z, Qian C-N, Tang H, et al. Constitutive Sp1 activity is essential for differential constitutive expression of vascular endothelial growth factor in human pancreatic adenocarcinoma. Cancer Res. 2001;61(10):4143–54.

    CAS  PubMed  Google Scholar 

  61. Wei D, Le X, Zheng L, Wang L, Frey JA, Gao AC, et al. Stat3 activation regulates the expression of vascular endothelial growth factor and human pancreatic cancer angiogenesis and metastasis. Oncogene. 2003;22(3):319–29.

    Article  CAS  PubMed  Google Scholar 

  62. Levy AP, Levy NS, Wegner S, Goldberg MA. Transcriptional regulation of the rat vascular endothelial growth factor gene by hypoxia. J Biol Chem. 1995;270(22):13333–40.

    Article  CAS  PubMed  Google Scholar 

  63. Zlotnik A. Chemokines in neoplastic progression. Semin Cancer Biol. 2004;14(3):181–5.

    Article  CAS  PubMed  Google Scholar 

  64. Saur D, Seidler B, Schneider G, Algül H, Beck R, Senekowitsch–Schmidtke R, et al. CXCR4 expression increases liver and lung metastasis in a mouse model of pancreatic cancer. Gastroenterology. 2005;129(4):1237–50.

    Article  CAS  PubMed  Google Scholar 

  65. Cho WC. OncomiRs: the discovery and progress of microRNAs in cancers. Mol Cancer. 2007;6(60):1–7.

    Article  PubMed  PubMed Central  Google Scholar 

  66. Davoodian N, Lotfi AS, Soleimani M, Mola SJ, Arjmand S. Let-7f microRNA negatively regulates hepatic differentiation of human adipose tissue-derived stem cells. J Physiol Biochem. 2014;70(3):781–9.

    Article  CAS  PubMed  Google Scholar 

  67. Qi W, Liang W, Jiang H, Waye MM. The function of miRNA in hepatic cancer stem cell. BioMed Res Int. 2013;2013:1–9.

    Article  Google Scholar 

  68. Chen H, Miao R, Fan J, Han Z, Wu J, Qiu G, et al. Decreased expression of miR-126 correlates with metastatic recurrence of hepatocellular carcinoma. Clin Exp Metastasis. 2013;30(5):651–8.

    Article  CAS  PubMed  Google Scholar 

  69. Crawford M, Brawner E, Batte K, Yu L, Hunter M, Otterson G, et al. MicroRNA-126 inhibits invasion in non-small cell lung carcinoma cell lines. Biochem Biophys Res Commun. 2008;373(4):607–12.

    Article  CAS  PubMed  Google Scholar 

  70. Wang H, Zhu Y, Zhao M, Wu C, Zhang P, Tang L, et al. miRNA-29c suppresses lung cancer cell adhesion to extracellular matrix and metastasis by targeting integrin beta1 and matrix metalloproteinase2 (MMP2). PloS one. PLoS One. 2013 6;8(8):e70192

  71. Ji D, Chen Z, Li M, Zhan T, Yao Y, Zhang Z, et al. MicroRNA-181a promotes tumor growth and liver metastasis in colorectal cancer by targeting the tumor suppressor WIF-1. Mol Cancer. 2014;13(1):86.

    Article  PubMed  PubMed Central  Google Scholar 

  72. Tsai WC, Hsu PWC, Lai TC, Chau GY, Lin CW, Chen CM, et al. MicroRNA-122, a tumor suppressor microRNA that regulates intrahepatic metastasis of hepatocellular carcinoma. Hepatology. 2009;49(5):1571–82.

    Article  CAS  PubMed  Google Scholar 

  73. Zhang X, Liu S, Hu T, Liu S, He Y, Sun S. Up-regulated microRNA-143 transcribed by nuclear factor kappa B enhances hepatocarcinoma metastasis by repressing fibronectin expression. Hepatology. 2009;50(2):490–9.

    Article  CAS  PubMed  Google Scholar 

  74. Yao J, Liang L, Huang S, Ding J, Tan N, Zhao Y, et al. MicroRNA-30d promotes tumor invasion and metastasis by targeting Galphai2 in hepatocellular carcinoma. Hepatology. 2010;51(3):846–56.

    CAS  PubMed  Google Scholar 

  75. Liang L, Wong CM, Ying Q, Fan DNY, Huang S, Ding J, et al. MicroRNA-125b suppressesed human liver cancer cell proliferation and metastasis by directly targeting oncogene LIN28B2. Hepatology. 2010;52(5):1731–40.

    Article  CAS  PubMed  Google Scholar 

  76. Kahlert C, Klupp F, Brand K, Lasitschka F, Diederichs S, Kirchberg J, et al. Invasion front-specific expression and prognostic significance of microRNA in colorectal liver metastases. Cancer Sci. 2011;102(10):1799–807.

    Article  CAS  PubMed  Google Scholar 

  77. Zhang Y, He X, Liu Y, Ye Y, Zhang H, He P, et al. MicroRNA-320a inhibits tumor invasion by targeting neuropilin 1 and is associated with liver metastasis in colorectal cancer. Oncol Rep. 2012;27(3):685–94.

    CAS  PubMed  Google Scholar 

  78. Kyutoku M, Taniyama Y, Katsuragi N, Shimizu H, Kunugiza Y, Iekushi K, et al. Role of periostin in cancer progression and metastasis: inhibition of breast cancer progression and metastasis by anti-periostin antibody in a murine model. Int J Mol Med. 2011;28(2):181–6.

    CAS  PubMed  Google Scholar 

  79. Wang J, Fallavollita L, Brodt P. Inhibition of experimental hepatic metastasis by a monoclonal antibody that blocks tumor-hepatocyte interaction. J Immunother. 1994;16(4):294–302.

    Article  CAS  Google Scholar 

Download references

Acknowledgments

We wish to thank all our colleagues in Shafa Hospital and Allied Health Sciences School, Ahvaz Jundishapur University of Medical Sciences.

Authors’ contributions

N.S. conceived the manuscript and revised it, Sh.A., A.A., M.Sh., and M.S. wrote the manuscript, prepared the figures and tables. F.R. performed the bioinformatic analysis.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Najmaldin Saki.

Ethics declarations

Conflicts of interest

None

Additional information

Highlights

Evaluation of the changes in hepatic pre-metastatic and metastatic niches

Factors involved in the formation of hepatic pre-metastatic and metastatic niches

Investigation of how cancer cells metastasize to the liver

Knowledge of tumor suppressor or oncogene function of miRNA molecules in hepatic metastatic niche

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Azizidoost, S., Ahmadzadeh, A., Rahim, F. et al. Hepatic metastatic niche: from normal to pre-metastatic and metastatic niche. Tumor Biol. 37, 1493–1503 (2016). https://doi.org/10.1007/s13277-015-4557-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-015-4557-x

Keywords

Navigation