Skip to main content
SpringerLink
Log in

The Biology of Colorectal Liver Metastases

  • Chapter
  • First Online:
Book cover Colorectal Cancer Liver Metastases

  • 1003 Accesses

Abstract

Despite advances in the detection, surgical care, and systemic treatment of colorectal cancer, many patients develop metastatic disease. Metastasis is the major cause of cancer-related mortality and continues to be a major challenge for clinicians and scientists. Developing earlier detection methods and more effective therapies requires understanding the complex mechanisms that drive colorectal cancer liver metastasis biology. However, due to the limitations of current experimental models and enormous biologic complexity associated with metastatic progression, our understanding of the genetic, epigenetic, transcriptional, and cellular interactions in the native and host microenvironments is in its initial stages. In this chapter, the stages of colorectal cancer liver metastasis are presented and highlighted by our current mechanistic understanding of metastasis biology.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 99.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 129.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 179.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394–424.

    Article  PubMed  Google Scholar 

  2. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65:87–108.

    Article  PubMed  Google Scholar 

  3. Tzeng C-WD, Aloia TA. Colorectal Liver Metastases. J Gastrointest Surg. 2013;17:195–202.

    Article  PubMed  Google Scholar 

  4. Choti MA, Sitzmann JV, Tiburi MF, et al. Trends in long-term survival following liver resection for hepatic colorectal metastases. Ann Surg. 2002;235:759–66.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Brouquet A, Abdalla EK, Kopetz S, et al. High survival rate after two-stage resection of advanced colorectal liver metastases: response-based selection and complete resection define outcome. J Clin Oncol. 2011;29:1083–90.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Brouquet A, Mortenson MM, Vauthey JN, et al. Surgical strategies for synchronous colorectal liver metastases in 156 consecutive patients: classic, combined or reverse strategy? J Am Coll Surg. 2010;210:934–41.

    Article  PubMed  Google Scholar 

  7. Fidler IJ. The pathogenesis of cancer metastasis: the ‘seed and soil’ hypothesis revisited. Nat Rev Cancer. 2003;3:453–8.

    Article  PubMed  CAS  Google Scholar 

  8. Chaffer CL, Weinberg RA. A perspective on cancer cell metastasis. Science. 2011;331:1559–64.

    Article  PubMed  CAS  Google Scholar 

  9. Jones S, Chen WD, Parmigiani G, et al. Comparative lesion sequencing provides insights into tumor evolution. Proc Natl Acad Sci U S A. 2008;105:4283–8.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Barker N, Ridgway RA, van Es JH, et al. Crypt stem cells as the cells-of-origin of intestinal cancer. Nature. 2009;457:608–11.

    Article  PubMed  CAS  Google Scholar 

  11. Barker N, van Es JH, Kuipers J, et al. Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature. 2007;449:1003–7.

    Article  PubMed  CAS  Google Scholar 

  12. Reya T, Clevers H. Wnt signalling in stem cells and cancer. Nature. 2005;434:843–50.

    Article  PubMed  CAS  Google Scholar 

  13. Vogelstein B, Fearon ER, Hamilton SR, et al. Genetic alterations during colorectal-tumor development. N Engl J Med. 1988;319:525–32.

    Article  PubMed  CAS  Google Scholar 

  14. Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell. 1990;61:759–67.

    Article  PubMed  CAS  Google Scholar 

  15. Seshagiri S, Stawiski EW, Durinck S, et al. Recurrent R-spondin fusions in colon cancer. Nature. 2012;488:660–4.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Cancer Genome Atlas Network. Comprehensive molecular characterization of human colon and rectal cancer. Nature. 2012;487:330–7.

    Article  CAS  Google Scholar 

  17. Vermeulen L, De Sousa EMF, van der Heijden M, et al. Wnt activity defines colon cancer stem cells and is regulated by the microenvironment. Nat Cell Biol. 2010;12:468–76.

    Article  PubMed  CAS  Google Scholar 

  18. Li HJ, Reinhardt F, Herschman HR, Weinberg RA. Cancer-stimulated mesenchymal stem cells create a carcinoma stem cell niche via prostaglandin E2 signaling. Cancer Discov. 2012;2:840–55.

    Article  PubMed  CAS  Google Scholar 

  19. Drost J, van Jaarsveld RH, Ponsioen B, et al. Sequential cancer mutations in cultured human intestinal stem cells. Nature. 2015;521:43–7.

    Article  PubMed  CAS  Google Scholar 

  20. Fujii M, Shimokawa M, Date S, et al. A colorectal tumor organoid library demonstrates progressive loss of niche factor requirements during tumorigenesis. Cell Stem Cell. 2016;18:827–38.

    Article  PubMed  CAS  Google Scholar 

  21. Matano M, Date S, Shimokawa M, et al. Modeling colorectal cancer using CRISPR-Cas9-mediated engineering of human intestinal organoids. Nat Med. 2015;21:256–62.

    Article  PubMed  CAS  Google Scholar 

  22. Ricci-Vitiani L, Lombardi DG, Pilozzi E, et al. Identification and expansion of human colon-cancer-initiating cells. Nature. 2007;445:111–5.

    Article  PubMed  CAS  Google Scholar 

  23. 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.

    Article  PubMed  CAS  Google Scholar 

  24. Dalerba P, Dylla SJ, Park IK, et al. Phenotypic characterization of human colorectal cancer stem cells. Proc Natl Acad Sci U S A. 2007;104:10158–63.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Budinska E, Popovici V, Tejpar S, et al. Gene expression patterns unveil a new level of molecular heterogeneity in colorectal cancer. J Pathol. 2013;231:63–76.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Schlicker A, Beran G, Chresta CM, et al. Subtypes of primary colorectal tumors correlate with response to targeted treatment in colorectal cell lines. BMC Med Genet. 2012;5:66.

    CAS  Google Scholar 

  27. Roepman P, Schlicker A, Tabernero J, et al. Colorectal cancer intrinsic subtypes predict chemotherapy benefit, deficient mismatch repair and epithelial-to-mesenchymal transition. Int J Cancer. 2014;134:552–62.

    Article  PubMed  CAS  Google Scholar 

  28. Sadanandam A, Lyssiotis CA, Homicsko K, et al. A colorectal cancer classification system that associates cellular phenotype and responses to therapy. Nat Med. 2013;19:619–25.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. De Sousa EMF, Wang X, Jansen M, et al. Poor-prognosis colon cancer is defined by a molecularly distinct subtype and develops from serrated precursor lesions. Nat Med. 2013;19:614–8.

    Article  CAS  Google Scholar 

  30. Marisa L, de Reynies A, Duval A, et al. Gene expression classification of colon cancer into molecular subtypes: characterization, validation, and prognostic value. PLoS Med. 2013;10:e1001453.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Guinney J, Dienstmann R, Wang X, et al. The consensus molecular subtypes of colorectal cancer. Nat Med. 2015;21:1350–6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Calon A, Lonardo E, Berenguer-Llergo A, et al. Stromal gene expression defines poor-prognosis subtypes in colorectal cancer. Nat Genet. 2015;47:320–9.

    Article  PubMed  CAS  Google Scholar 

  33. Isella C, Terrasi A, Bellomo SE, et al. Stromal contribution to the colorectal cancer transcriptome. Nat Genet. 2015;47:312–9.

    Article  PubMed  CAS  Google Scholar 

  34. Bao S, Ouyang G, Bai X, et al. Periostin potently promotes metastatic growth of colon cancer by augmenting cell survival via the Akt/PKB pathway. Cancer Cell. 2004;5:329–39.

    Article  PubMed  CAS  Google Scholar 

  35. Keklikoglou I, Kadioglu E, Bissinger S, et al. Periostin limits tumor response to VEGFA inhibition. Cell Rep. 2018;22:2530–40.

    Article  PubMed  CAS  Google Scholar 

  36. Calon A, Espinet E, Palomo-Ponce S, et al. Dependency of colorectal cancer on a TGF-beta-driven program in stromal cells for metastasis initiation. Cancer Cell. 2012;22:571–84.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Putoczki TL, Thiem S, Loving A, et al. Interleukin-11 is the dominant IL-6 family cytokine during gastrointestinal tumorigenesis and can be targeted therapeutically. Cancer Cell. 2013;24:257–71.

    Article  PubMed  CAS  Google Scholar 

  38. Liu C, Billadeau DD, Abdelhakim H, et al. IQGAP1 suppresses TbetaRII-mediated myofibroblastic activation and metastatic growth in liver. J Clin Invest. 2013;123:1138–56.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Kitamura T, Kometani K, Hashida H, et al. SMAD4-deficient intestinal tumors recruit CCR1+ myeloid cells that promote invasion. Nat Genet. 2007;39:467–75.

    Article  PubMed  CAS  Google Scholar 

  40. Itatani Y, Kawada K, Fujishita T, et al. Loss of SMAD4 from colorectal cancer cells promotes CCL15 expression to recruit CCR1+ myeloid cells and facilitate liver metastasis. Gastroenterology. 2013;145:1064–75. e11

    Article  PubMed  CAS  Google Scholar 

  41. Dudley AC. Tumor endothelial cells. Cold Spring Harb Perspect Med. 2012;2:a006536.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Yonenaga Y, Mori A, Onodera H, et al. Absence of smooth muscle actin-positive pericyte coverage of tumor vessels correlates with hematogenous metastasis and prognosis of colorectal cancer patients. Oncology. 2005;69:159–66.

    Article  PubMed  Google Scholar 

  43. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350:2335–42.

    Article  PubMed  CAS  Google Scholar 

  44. Zhang Y, Davis C, Shah S, et al. IL-33 promotes growth and liver metastasis of colorectal cancer in mice by remodeling the tumor microenvironment and inducing angiogenesis. Mol Carcinog. 2017;56:272–87.

    Article  PubMed  CAS  Google Scholar 

  45. Maywald RL, Doerner SK, Pastorelli L, et al. IL-33 activates tumor stroma to promote intestinal polyposis. Proc Natl Acad Sci U S A. 2015;112:E2487–96.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Lu J, Ye X, Fan F, et al. Endothelial cells promote the colorectal cancer stem cell phenotype through a soluble form of Jagged-1. Cancer Cell. 2013;23:171–85.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Wieland E, Rodriguez-Vita J, Liebler SS, et al. Endothelial Notch1 activity facilitates metastasis. Cancer Cell. 2017;31:355–67.

    Article  PubMed  CAS  Google Scholar 

  48. Sonoshita M, Aoki M, Fuwa H, et al. Suppression of colon cancer metastasis by Aes through inhibition of Notch signaling. Cancer Cell. 2011;19:125–37.

    Article  PubMed  CAS  Google Scholar 

  49. 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.

    Article  PubMed  CAS  Google Scholar 

  50. Ueno H, Price AB, Wilkinson KH, Jass JR, Mochizuki H, Talbot IC. A new prognostic staging system for rectal cancer. Ann Surg. 2004;240:832–9.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Ueno H, Murphy J, Jass JR, Mochizuki H, Talbot IC. Tumour ‘budding’ as an index to estimate the potential of aggressiveness in rectal cancer. Histopathology. 2002;40:127–32.

    Article  PubMed  CAS  Google Scholar 

  52. Jung A, Schrauder M, Oswald U, et al. The invasion front of human colorectal adenocarcinomas shows co-localization of nuclear beta-catenin, cyclin D1, and p16INK4A and is a region of low proliferation. Am J Pathol. 2001;159:1613–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Todaro M, Gaggianesi M, Catalano V, et al. CD44v6 is a marker of constitutive and reprogrammed cancer stem cells driving colon cancer metastasis. Cell Stem Cell. 2014;14:342–56.

    Article  PubMed  CAS  Google Scholar 

  54. Engell HC. Cancer cells in the circulating blood; a clinical study on the occurrence of cancer cells in the peripheral blood and in venous blood draining the tumour area at operation. Ugeskr Laeger. 1955;117:822–3.

    PubMed  CAS  Google Scholar 

  55. Peach G, Kim C, Zacharakis E, Purkayastha S, Ziprin P. Prognostic significance of circulating tumour cells following surgical resection of colorectal cancers: a systematic review. Br J Cancer. 2010;102:1327–34.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Iinuma H, Okinaga K, Egami H, et al. Usefulness and clinical significance of quantitative real-time RT-PCR to detect isolated tumor cells in the peripheral blood and tumor drainage blood of patients with colorectal cancer. Int J Oncol. 2006;28:297–306.

    PubMed  CAS  Google Scholar 

  57. Iinuma H, Watanabe T, Mimori K, et al. Clinical significance of circulating tumor cells, including cancer stem-like cells, in peripheral blood for recurrence and prognosis in patients with Dukes’ stage B and C colorectal cancer. J Clin Oncol. 2011;29:1547–55.

    Article  PubMed  Google Scholar 

  58. Cristofanilli M, Budd GT, Ellis MJ, et al. Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med. 2004;351:781–91.

    Article  PubMed  CAS  Google Scholar 

  59. Cohen SJ, Punt CJ, Iannotti N, et al. Relationship of circulating tumor cells to tumor response, progression-free survival, and overall survival in patients with metastatic colorectal cancer. J Clin Oncol. 2008;26:3213–21.

    Article  PubMed  Google Scholar 

  60. Rahbari NN, Aigner M, Thorlund K, et al. Meta-analysis shows that detection of circulating tumor cells indicates poor prognosis in patients with colorectal cancer. Gastroenterology. 2010;138:1714–26.

    Article  PubMed  Google Scholar 

  61. Aktas B, Tewes M, Fehm T, Hauch S, Kimmig R, Kasimir-Bauer S. Stem cell and epithelial-mesenchymal transition markers are frequently overexpressed in circulating tumor cells of metastatic breast cancer patients. Breast Cancer Res. 2009;11:R46.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  62. Hermann PC, Huber SL, Herrler T, et al. Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer. Cell Stem Cell. 2007;1:313–23.

    Article  PubMed  CAS  Google Scholar 

  63. Pang R, Law WL, Chu AC, et al. A subpopulation of CD26+ cancer stem cells with metastatic capacity in human colorectal cancer. Cell Stem Cell. 2010;6:603–15.

    Article  PubMed  CAS  Google Scholar 

  64. Dieter SM, Ball CR, Hoffmann CM, et al. Distinct types of tumor-initiating cells form human colon cancer tumors and metastases. Cell Stem Cell. 2011;9:357–65.

    Article  PubMed  CAS  Google Scholar 

  65. Chambers AF, Groom AC, MacDonald IC. Dissemination and growth of cancer cells in metastatic sites. Nat Rev Cancer. 2002;2:563–72.

    Article  PubMed  CAS  Google Scholar 

  66. Luzzi KJ, MacDonald IC, Schmidt EE, et al. Multistep nature of metastatic inefficiency: dormancy of solitary cells after successful extravasation and limited survival of early micrometastases. Am J Pathol. 1998;153:865–73.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  67. Al-Mehdi AB, Tozawa K, Fisher AB, Shientag L, Lee A, Muschel RJ. Intravascular origin of metastasis from the proliferation of endothelium-attached tumor cells: a new model for metastasis. Nat Med. 2000;6:100–2.

    Article  PubMed  CAS  Google Scholar 

  68. Nguyen DX, Bos PD, Massague J. Metastasis: from dissemination to organ-specific colonization. Nat Rev Cancer. 2009;9:274–84.

    Article  PubMed  CAS  Google Scholar 

  69. Urosevic J, Garcia-Albeniz X, Planet E, et al. Colon cancer cells colonize the lung from established liver metastases through p38 MAPK signalling and PTHLH. Nat Cell Biol. 2014;16:685–94.

    Article  PubMed  CAS  Google Scholar 

  70. Sosa MS, Bragado P, Aguirre-Ghiso JA. Mechanisms of disseminated cancer cell dormancy: an awakening field. Nat Rev Cancer. 2014;14:611–22.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  71. Aguirre-Ghiso JA. Models, mechanisms and clinical evidence for cancer dormancy. Nat Rev Cancer. 2007;7:834–46.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  72. Folkman J. Role of angiogenesis in tumor growth and metastasis. Semin Oncol. 2002;29:15–8.

    Article  PubMed  CAS  Google Scholar 

  73. Demicheli R, Retsky MW, Hrushesky WJ, Baum M, Gukas ID. The effects of surgery on tumor growth: a century of investigations. Ann Oncol. 2008;19:1821–8.

    Article  PubMed  CAS  Google Scholar 

  74. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74.

    Article  PubMed  CAS  Google Scholar 

  75. Gulubova MV, Ananiev JR, Vlaykova TI, Yovchev Y, Tsoneva V, Manolova IM. Role of dendritic cells in progression and clinical outcome of colon cancer. Int J Color Dis. 2012;27:159–69.

    Article  Google Scholar 

  76. Solito S, Falisi E, Diaz-Montero CM, et al. A human promyelocytic-like population is responsible for the immune suppression mediated by myeloid-derived suppressor cells. Blood. 2011;118:2254–65.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  77. Sun HL, Zhou X, Xue YF, et al. Increased frequency and clinical significance of myeloid-derived suppressor cells in human colorectal carcinoma. World J Gastroenterol. 2012;18:3303–9.

    PubMed  PubMed Central  Google Scholar 

  78. Baier PK, Wimmenauer S, Hirsch T, et al. Analysis of the T cell receptor variability of tumor-infiltrating lymphocytes in colorectal carcinomas. Tumour Biol. 1998;19:205–12.

    Article  PubMed  CAS  Google Scholar 

  79. Naito Y, Saito K, Shiiba K, et al. CD8+ T cells infiltrated within cancer cell nests as a prognostic factor in human colorectal cancer. Cancer Res. 1998;58:3491–4.

    PubMed  CAS  Google Scholar 

  80. Diederichsen AC, Hjelmborg J, Christensen PB, Zeuthen J, Fenger C. Prognostic value of the CD4+/CD8+ ratio of tumour infiltrating lymphocytes in colorectal cancer and HLA-DR expression on tumour cells. Cancer Immunol Immunother. 2003;52:423–8.

    Article  PubMed  CAS  Google Scholar 

  81. Angelova M, Mlecnik B, Vasaturo A, et al. Evolution of metastases in space and time under immune selection. Cell. 2018;175:751–65 e16.

    Article  PubMed  CAS  Google Scholar 

  82. Pages F, Berger A, Camus M, et al. Effector memory T cells, early metastasis, and survival in colorectal cancer. N Engl J Med. 2005;353:2654–66.

    Article  PubMed  CAS  Google Scholar 

  83. Galon J, Costes A, Sanchez-Cabo F, et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science. 2006;313:1960–4.

    Article  PubMed  CAS  Google Scholar 

  84. Rooney MS, Shukla SA, Wu CJ, Getz G, Hacohen N. Molecular and genetic properties of tumors associated with local immune cytolytic activity. Cell. 2015;160:48–61.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  85. Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372:2509–20.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Surgical Oncology, Harold C. Simmons Cancer Center, Dallas, TX, USA

    Mathew M. Augustine

  2. Department of Surgery, UT Southwestern Medical Center, Dallas, TX, USA

    Mathew M. Augustine

Authors
  1. Mathew M. Augustine
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mathew M. Augustine .

Editor information

Editors and Affiliations

  1. National Cancer Institute, Rio de Janeiro, Brazil

    Mauro Monteiro Correia

  2. Banner MD Anderson Cancer Center, Phoenix, AZ, USA

    Michael A. Choti

  3. Virginia Mason Medical Center, Seattle, WA, USA

    Flavio G. Rocha

  4. Center for Advanced Treatment of HBP Diseases, Ageo Central General Hospital, Ageo Shi, Saitama, Japan

    Go Wakabayashi

Rights and permissions

Reprints and permissions

Copyright information

© 2020 This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Augustine, M.M. (2020). The Biology of Colorectal Liver Metastases. In: Correia, M., Choti, M., Rocha, F., Wakabayashi, G. (eds) Colorectal Cancer Liver Metastases. Springer, Cham. https://doi.org/10.1007/978-3-030-25486-5_2

Download citation

  • DOI: https://doi.org/10.1007/978-3-030-25486-5_2

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-030-25485-8

  • Online ISBN: 978-3-030-25486-5

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation