Clinical & Experimental Metastasis

, Volume 29, Issue 7, pp 729–736

Lymphatics, lymph nodes and the immune system: barriers and gateways for cancer spread

  • Robert L. Ferris
  • Michael T. Lotze
  • Stanley P. L. Leong
  • David S. B. Hoon
  • Donald L. Morton
Research Paper

Abstract

Metastasis to the regional lymph node is the most important prognostic indicator for the outcomes of patients with sold cancer. In general, it is well recognized that cancer development is genetically determined with progression from the microenvironment of the primary tumor site, oftentimes via the SLN gateway, to the distant sites. In about 20 % of the time, the cancer cells may spread directly through the blood vascular system to the distant sites. Thus, in general, cancer progression is consistent with Hellman’s spectrum theory in that development of nodal and systemic metastasis from a localized cancer growth is a progressive process. Cancer proliferation within the tumor microenvironment may give rise to increased tumor heterogeneity, which is further complicated by its continuous change through its evolution within the host in a Darwinian sense. It is crucial to understand the molecular process of lymphangiogenesis and hemangiogenesis in the tumor microenvironment with respect to the initial steps of cancer cells entering into the lymphatic and vascular systems so that rational therapy can be developed to curb the process of specific routes of metastasis. This chapter elucidates the role of lymphatics, nodal metastasis and antitumor immunity. We present novel immune targets in nodal metastases, the importance of the lymph node as a pre-metastatic niche, and immune-related proteins as biomarkers of metastasis.

Keywords

Lymphatic metastasis Premetastatic niche Antitumor immunity Immune biomarker 

References

  1. 1.
    Morton DL, Thompson JF, Cochran AJ, Mozzillo N, Elashoff R, Essner R et al (2006) Sentinel-node biopsy or nodal observation in melanoma. N Engl J Med 355(13):1307–1317PubMedCrossRefGoogle Scholar
  2. 2.
    Cox CE, Kiluk JV, Riker AI, Cox JM, Allred N, Ramos DC et al (2008) Significance of sentinel lymph node micrometastases in human breast cancer. J Am Coll Surg 206(2):261–268PubMedCrossRefGoogle Scholar
  3. 3.
    Leong SP, Zuber M, Ferris RL, Kitagawa Y, Cabanas R, Levenback C et al (2011) Impact of nodal status and tumor burden in sentinel lymph nodes on the clinical outcomes of cancer patients. J Surg Oncol 103(6):518–530PubMedCrossRefGoogle Scholar
  4. 4.
    Paget S (1889) The distribution of secondary growths in cancer of the breast. The Lancet 133(3421):571–573CrossRefGoogle Scholar
  5. 5.
    Karnofsky HS (1994) Memorial lecture. Natural history of small breast cancers. J Clin Oncol 12(10):2229–2234Google Scholar
  6. 6.
    Hellman S (1997) Darwin’s clinical relevance. Cancer 79(12):2275–2281PubMedCrossRefGoogle Scholar
  7. 7.
    Holopainen T, Bry M, Alitalo K, Saaristo A (2011) Perspectives on lymphangiogenesis and angiogenesis in cancer. J Surg Oncol 103(6):484–488PubMedCrossRefGoogle Scholar
  8. 8.
    Tobler NE, Detmar M (2006) Tumor and lymph node lymphangiogenesis—impact on cancer metastasis. J Leukoc Biol 80(4):691–696PubMedCrossRefGoogle Scholar
  9. 9.
    Rinderknecht M, Detmar M (2008) Tumor lymphangiogenesis and melanoma metastasis. J Cell Physiol 216(2):347–354PubMedCrossRefGoogle Scholar
  10. 10.
    Pantel K, Brakenhoff RH (2004) Dissecting the metastatic cascade. Nat Rev Cancer 4(6):448–456PubMedCrossRefGoogle Scholar
  11. 11.
    Witte MH, Dellinger MT, McDonald DM, Nathanson SD, Boccardo FM, Campisi CC et al (2011) Lymphangiogenesis and hemangiogenesis: potential targets for therapy. J Surg Oncol 103(6):489–500PubMedCrossRefGoogle Scholar
  12. 12.
    Leong S (2006) Proceedings of the 1st international symposium on cancer metastasis and lymphovascular system: basis for rational therapy. Cancer Metastasis Rev 25:157–294CrossRefGoogle Scholar
  13. 13.
    Leong S (2007) Cancer metastasis and the lymphovascular system: basis for rational therapy. Cancer Treatment and Research. New York: SpringerGoogle Scholar
  14. 14.
    Leong SP (2009) Cancer metastasis: from local proliferation to distant sites. Humana Press, New YorkGoogle Scholar
  15. 15.
    Thompson JF, Soong SJ, Balch CM, Gershenwald JE, Ding S, Coit DG et al (2011) Prognostic significance of mitotic rate in localized primary cutaneous melanoma: an analysis of patients in the multi-institutional American Joint Committee on Cancer melanoma staging database. J Clin Oncol 29(16):2199–2205PubMedCrossRefGoogle Scholar
  16. 16.
    Gershenwald JE, Soong SJ, Balch CM, American Joint Committee on Cancer Melanoma Staging C (2010) TNM staging system for cutaneous melanoma…and beyond. Ann Surg Oncol 17(6):1475–1477PubMedCrossRefGoogle Scholar
  17. 17.
    Singletary SE, Greene FL, Sobin LH (2003) Classification of isolated tumor cells: clarification of the 6th edition of the American Joint Committee on Cancer Staging Manual. Cancer 98(12):2740–2741PubMedCrossRefGoogle Scholar
  18. 18.
    Scheri RP, Essner R, Turner RR, Ye X, Morton DL (2007) Isolated tumor cells in the sentinel node affect long-term prognosis of patients with melanoma. Ann Surg Oncol 14(10):2861–2866PubMedCrossRefGoogle Scholar
  19. 19.
    Baehner FL, Li R, Jenkins T, Hwang J, Kashani-Sabet M, Allen RE et al (2012) The impact of primary melanoma thickness and microscopic tumor burden in sentinel lymph nodes on melanoma patient survival. Ann Surg Oncol 19(3):1034–1042PubMedCrossRefGoogle Scholar
  20. 20.
    Dillman RO, Aaron K, Heinemann FS, McClure SE (2009) Identification of 12 or more lymph nodes in resected colon cancer specimens as an indicator of quality performance. Cancer 115(9):1840–1848PubMedCrossRefGoogle Scholar
  21. 21.
    Smith DD, Schwarz RR, Schwarz RE (2005) Impact of total lymph node count on staging and survival after gastrectomy for gastric cancer: data from a large US-population database. J Clin Oncol 23(28):7114–7124PubMedCrossRefGoogle Scholar
  22. 22.
    Argiris A, Karamouzis MV, Raben D, Ferris RL (2008) Head and neck cancer. Lancet 371(9625):1695–1709PubMedCrossRefGoogle Scholar
  23. 23.
    Duvvuri U, Simental AA Jr, D’Angelo G, Johnson JT, Ferris RL, Gooding W et al (2004) Elective neck dissection and survival in patients with squamous cell carcinoma of the oral cavity and oropharynx. Laryngoscope 114(12):2228–2234PubMedCrossRefGoogle Scholar
  24. 24.
    Morton DL, Wen DR, Wong JH, Economou JS, Cagle LA, Storm FK et al (1992) Technical details of intraoperative lymphatic mapping for early stage melanoma. Arch Surg 127(4):392–399PubMedCrossRefGoogle Scholar
  25. 25.
    Alex JC, Sasaki CT, Krag DN, Wenig B, Pyle PB (2000) Sentinel lymph node radiolocalization in head and neck squamous cell carcinoma. Laryngoscope 110(2 Pt 1):198–203PubMedCrossRefGoogle Scholar
  26. 26.
    Chepeha DB, Taylor RJ, Chepeha JC, Teknos TN, Bradford CR, Sharma PK et al (2002) Functional assessment using constant’s shoulder scale after modified radical and selective neck dissection. Head Neck 24(5):432–436PubMedCrossRefGoogle Scholar
  27. 27.
    Tassone F, Hagerman RJ, Taylor AK, Gane LW, Godfrey TE, Hagerman PJ (2000) Elevated levels of FMR1 mRNA in carrier males: a new mechanism of involvement in the fragile-X syndrome. Am J Hum Genet 66(1):6–15PubMedCrossRefGoogle Scholar
  28. 28.
    Hughes SJ, Xi L, Gooding WE, Cole DJ, Mitas M, Metcalf J et al (2009) A quantitative reverse transcription-PCR assay for rapid, automated analysis of breast cancer sentinel lymph nodes. J Mol Diagn 11(6):576–582PubMedCrossRefGoogle Scholar
  29. 29.
    Hughes SJ, Xi L, Raja S, Gooding W, Cole DJ, Gillanders WE et al (2006) A rapid, fully automated, molecular-based assay accurately analyzes sentinel lymph nodes for the presence of metastatic breast cancer. Ann Surg 243(3):389–398PubMedCrossRefGoogle Scholar
  30. 30.
    Ferris RL, Xi L, Raja S, Hunt JL, Wang J, Gooding WE et al (2005) Molecular staging of cervical lymph nodes in squamous cell carcinoma of the head and neck. Cancer Res 65(6):2147–2156PubMedCrossRefGoogle Scholar
  31. 31.
    Ferris RL, Xi L, Seethala RR, Chan J, Desai S, Hoch B et al (2011) Intraoperative qRT-PCR for detection of lymph node metastasis in head and neck cancer. Clin Cancer Res 17(7):1858–1866PubMedCrossRefGoogle Scholar
  32. 32.
    Filho PA, Lopez-Albaitero A, Xi L, Gooding W, Godfrey T, Ferris RL (2009) Quantitative expression and immunogenicity of MAGE-3 and -6 in upper aerodigestive tract cancer. Int J Cancer 125(8):1912–1920PubMedCrossRefGoogle Scholar
  33. 33.
    Andrade Filho PA, Ito D, Deleo AB, Ferris RL (2010) CD8+ T cell recognition of polymorphic wild-type sequence p53(65–73) peptides in squamous cell carcinoma of the head and neck. Cancer Immunol Immunother 59(10):1561–1568Google Scholar
  34. 34.
    Andrade Filho PA, Lopez-Albaitero A, Gooding W, Ferris RL (2010) Novel immunogenic HLA-A*0201-restricted epidermal growth factor receptor-specific T-cell epitope in head and neck cancer patients. J Immunother 33(1):83–91Google Scholar
  35. 35.
    Chapoval AI, Ni J, Lau JS, Wilcox RA, Flies DB, Liu D et al (2001) B7-H3: a costimulatory molecule for T cell activation and IFN-gamma production. Nat Immunol 2(3):269–274PubMedCrossRefGoogle Scholar
  36. 36.
    Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB et al (2002) Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med 8(8):793–800PubMedGoogle Scholar
  37. 37.
    Flies DB, Chen L (2007) The new B7s: playing a pivotal role in tumor immunity. J Immunother 30(3):251–260PubMedCrossRefGoogle Scholar
  38. 38.
    Zang X, Allison JP (2007) The B7 family and cancer therapy: costimulation and coinhibition. Clin Cancer Res 13(18 Pt 1):5271–5279PubMedCrossRefGoogle Scholar
  39. 39.
    Greenwald RJ, Freeman GJ, Sharpe AH (2005) The B7 family revisited. Annu Rev Immunol 23:515–548PubMedCrossRefGoogle Scholar
  40. 40.
    Freeman GJ, Gribben JG, Boussiotis VA, Ng JW, Restivo VA Jr, Lombard LA et al (1993) Cloning of B7-2: a CTLA-4 counter-receptor that costimulates human T cell proliferation. Science 262(5135):909–911PubMedCrossRefGoogle Scholar
  41. 41.
    Cao Y, Zhang L, Ritprajak P, Tsushima F, Youngnak-Piboonratanakit P, Kamimura Y et al (2011) Immunoregulatory molecule B7-H1 (CD274) contributes to skin carcinogenesis. Cancer Res 71(14):4737–4741PubMedCrossRefGoogle Scholar
  42. 42.
    Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB et al (2010) Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363(8):711–723PubMedCrossRefGoogle Scholar
  43. 43.
    Castriconi R, Dondero A, Augugliaro R, Cantoni C, Carnemolla B, Sementa AR et al (2004) Identification of 4Ig-B7-H3 as a neuroblastoma-associated molecule that exerts a protective role from an NK cell-mediated lysis. Proc Natl Acad Sci USA 101(34):12640–12645PubMedCrossRefGoogle Scholar
  44. 44.
    Roth TJ, Sheinin Y, Lohse CM, Kuntz SM, Frigola X, Inman BA et al (2007) B7-H3 ligand expression by prostate cancer: a novel marker of prognosis and potential target for therapy. Cancer Res 67(16):7893–7900PubMedCrossRefGoogle Scholar
  45. 45.
    Sun Y, Wang Y, Zhao J, Gu M, Giscombe R, Lefvert AK et al (2006) B7-H3 and B7-H4 expression in non-small-cell lung cancer. Lung Cancer 53(2):143–151PubMedCrossRefGoogle Scholar
  46. 46.
    Tekle C, Nygren MK, Chen YW, Dybsjord I, Nesland JM, Maelandsmo GM et al (2012) B7 = H3 contributes to the metastatic capacity of melanoma cells by modulation of known metastasis-associated genes. Int J Cancer 130(10):2282–2290PubMedCrossRefGoogle Scholar
  47. 47.
    Arigami T, Narita N, Mizuno R, Nguyen L, Ye X, Chung A et al (2010) B7-h3 ligand expression by primary breast cancer and associated with regional nodal metastasis. Ann Surg 252(6):1044–1051PubMedCrossRefGoogle Scholar
  48. 48.
    Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100(1):57–70PubMedCrossRefGoogle Scholar
  49. 49.
    Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646–674PubMedCrossRefGoogle Scholar
  50. 50.
    Tang D, Kang R, Livesey KM, Kroemer G, Billiar TR, Van Houten B et al (2011) High-mobility group box 1 is essential for mitochondrial quality control. Cell Metab 13(6):701–711PubMedCrossRefGoogle Scholar
  51. 51.
    Rhim AD, Mirek ET, Aiello NM, Maitra A, Bailey JM, McAllister F et al (2012) EMT and dissemination precede pancreatic tumor formation. Cell 148(1–2):349–361PubMedCrossRefGoogle Scholar
  52. 52.
    Weiner LM, Lotze MT (2012) Tumor-cell death, autophagy, and immunity. N Engl J Med 366(12):1156–1158PubMedCrossRefGoogle Scholar
  53. 53.
    Fox BA, Schendel DJ, Butterfield LH, Aamdal S, Allison JP, Ascierto PA et al (2011) Defining the critical hurdles in cancer immunotherapy. J Transl Med 9(1):214PubMedCrossRefGoogle Scholar
  54. 54.
    Peinado H, Lavotshkin S, Lyden D (2011) The secreted factors responsible for pre-metastatic niche formation: old sayings and new thoughts. Semin Cancer Biol 21(2):139–146PubMedCrossRefGoogle Scholar
  55. 55.
    Tang D, Kang R, Livesey KM, Zeh HJ 3rd, Lotze MT (2011) High mobility group box 1 (HMGB1) activates an autophagic response to oxidative stress. Antioxid Redox Signal 15(8):2185–2195PubMedCrossRefGoogle Scholar
  56. 56.
    Livesey K, Kang R, Vernon P, Buchser W, Loughran P, Watkins SC et al (2012) p53/HMGB1 complexes regulate autophagy and apoptosis. Cancer Res 72:1996–2005PubMedCrossRefGoogle Scholar
  57. 57.
    Hoppo T, Komori J, Manohar R, Stolz DB, Lagasse E (2011) Rescue of lethal hepatic failure by hepatized lymph nodes in mice. Gastroenterology 140(2):656–666 e2Google Scholar
  58. 58.
    Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pages C et al (2006) Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 313(5795):1960–1964PubMedCrossRefGoogle Scholar
  59. 59.
    Vakkila J, Jaffe R, Michelow M, Lotze MT (2006) Pediatric cancers are infiltrated predominantly by macrophages and contain a paucity of dendritic cells: a major nosologic difference with adult tumors. Clin Cancer Res 12(7 Pt 1):2049–2054PubMedCrossRefGoogle Scholar
  60. 60.
    Zhang Q, Raoof M, Chen Y, Sumi Y, Sursal T, Junger W et al (2010) Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature 464(7285):104–107PubMedCrossRefGoogle Scholar
  61. 61.
    Tang D, Lotze MT, Kang R, Zeh HJ (2011) Apoptosis promotes early tumorigenesis. Oncogene 30(16):1851–1854PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2012

Authors and Affiliations

  • Robert L. Ferris
    • 4
  • Michael T. Lotze
    • 6
    • 7
  • Stanley P. L. Leong
    • 1
    • 2
    • 3
  • David S. B. Hoon
    • 5
  • Donald L. Morton
    • 5
  1. 1.Melanoma Program Center for Melanoma Research and TreatmentSan FranciscoUSA
  2. 2.California Pacific Medical Center Research instituteSan FranciscoUSA
  3. 3.University of CaliforniaSan FranciscoUSA
  4. 4.Hillman Cancer Center ResearchPittsburghUSA
  5. 5.John Wayne Cancer InstituteSanta MonicaUSA
  6. 6.University of Pittsburgh School of MedicinePittsburghUSA
  7. 7.Translational Research Molecular Medicine InstitutePittsburghUSA

Personalised recommendations