Clinical & Experimental Metastasis

, Volume 29, Issue 7, pp 737–746 | Cite as

The connectivity of lymphogenous and hematogenous tumor cell dissemination: biological insights and clinical implications

Research Paper

Abstract

Although tumor cells are found in the blood early after tumorigenesis, dissemination through the lymphatic system and in particular the formation of lymph node metastases has long been considered to be a driving force behind the formation of secondary tumors in distant vital organs. Contemporary experimental observations and clinical trial results suggest that this may not be the case. In this review we survey the evidence for both points of view, and examine the hypothesis that the prognostic relevance of lymph node metastases may lie in their ability to indicate that primary tumors are producing soluble factors that have the potential to promote metastasis at these distant sites, for example by releasing tumor cells from dormancy. Furthermore, the interconnectivity between the lymphatic and blood circulatory systems underscores the relevance of the analysis of the properties of circulating and disseminated tumor cells for prognostic evaluation, patient stratification and understanding the biology of metastasis. We therefore give an overview of the current state of the art in this field.

Keywords

Metastasis Circulating tumor cell Lymph node Stromal progression 

References

  1. 1.
    Sleeman JP, Nazarenko I, Thiele W (2011) Do all roads lead to Rome? Routes to metastasis development. Int J Cancer 128(11):2511–2526. doi:10.1002/ijc.26027 PubMedCrossRefGoogle Scholar
  2. 2.
    Cady B (2007) Regional lymph node metastases; a singular manifestation of the process of clinical metastases in cancer: contemporary animal research and clinical reports suggest unifying concepts. Ann Surg Oncol 14(6):1790–1800PubMedCrossRefGoogle Scholar
  3. 3.
    Fisher B, Fisher ER (1966) Transmigration of lymph nodes by tumor cells. Science 152(727):1397–1398PubMedCrossRefGoogle Scholar
  4. 4.
    Fisher B, Fisher ER (1966) The interrelationship of hematogenous and lymphatic tumor cell dissemination. Surg Gynecol Obstet 122(4):791–798PubMedGoogle Scholar
  5. 5.
    Fisher B, Fisher ER (1970) Significance of the interrelationship of the lymph and blood vascular systems in tumor cell dissemination. Prog Clin Cancer 4:84–96PubMedGoogle Scholar
  6. 6.
    Fisher B, Fisher ER (1967) The organ distribution of disseminated 51 Cr-labeled tumor cells. Cancer Res 27(2):412–420PubMedGoogle Scholar
  7. 7.
    Sleeman J, Schmid A, Thiele W (2009) Tumor lymphatics. Semin Cancer Biol 19(5):285PubMedCrossRefGoogle Scholar
  8. 8.
    Cochran AJ, Huang RR, Lee J, Itakura E, Leong SP, Essner R (2006) Tumour-induced immune modulation of sentinel lymph nodes. Nat Rev Immunol 6(9):659–670. doi:10.1038/nri1919 PubMedCrossRefGoogle Scholar
  9. 9.
    Madden RE, Gyure L (1968) Translymphnodal passage of tumor cells. Oncology 22(4):281–289PubMedCrossRefGoogle Scholar
  10. 10.
    Kurokawa Y (1970) Experiments on lymph node metastasis by intralymphatic inoculation of rat ascites tumor cells, with special reference to lodgement, passage, and growth of tumor cells in lymph nodes. Gann 61(5):461–471PubMedGoogle Scholar
  11. 11.
    Hewitt HB, Blake E (1975) Quantitative studies of translymphnodal passage of tumour cells naturally disseminated from a non immunogenic murine squamous carcinoma. Br J Cancer 31(1):25–35PubMedCrossRefGoogle Scholar
  12. 12.
    Carr J, Carr I, Dreher B, Betts K (1980) Lymphatic metastasis: invasion of lymphatic vessels and efflux of tumour cells in the afferent popliteal lymph as seen in the Walker rat carcinoma. J Pathol 132(4):287–305. doi:10.1002/path.1711320402 PubMedCrossRefGoogle Scholar
  13. 13.
    Grundmann E, Vollmer E (1985) Early local reaction and lymph node permeation of rat carcinoma HH9-cl 14 cells. An immunohistological approach. Pathol Res Pract 179(3):304–309PubMedCrossRefGoogle Scholar
  14. 14.
    Leijte JA, van der Ploeg IM, Valdes Olmos RA, Nieweg OE, Horenblas S (2009) Visualization of tumor blockage and rerouting of lymphatic drainage in penile cancer patients by use of SPECT/CT. J Nucl Med 50(3):364–367. doi:10.2967/jnumed.108.059733 PubMedCrossRefGoogle Scholar
  15. 15.
    Kim MY, Oskarsson T, Acharyya S, Nguyen DX, Zhang XH, Norton L, Massague J (2009) Tumor self-seeding by circulating cancer cells. Cell 139(7):1315–1326. doi:10.1016/j.cell.2009.11.025 PubMedCrossRefGoogle Scholar
  16. 16.
    Crile G Jr, Isbister W, Deodhar SD (1971) Demonstration that large metastases in lymph nodes disseminate cancer cells to blood and lungs. Cancer 28(3):657PubMedCrossRefGoogle Scholar
  17. 17.
    Ward PM, Weiss L (1989) Metachronous seeding of lymph node metastases in rats bearing the MT-100-TC mammary carcinoma: the effect of elective lymph node dissection. Breast Cancer Res Treat 14(3):315–320PubMedCrossRefGoogle Scholar
  18. 18.
    Sleeman JP (2000) The lymph node as a bridgehead in the metastatic dissemination of tumors. Recent Results Cancer Res 157:55–81PubMedCrossRefGoogle Scholar
  19. 19.
    Wiley HE, Gonzalez EB, Maki W, Wu MT, Hwang ST (2001) Expression of CC chemokine receptor-7 and regional lymph node metastasis of B16 murine melanoma. J Natl Cancer Inst 93(21):1638–1643PubMedCrossRefGoogle Scholar
  20. 20.
    Shields JD, Emmett MS, Dunn DB, Joory KD, Sage LM, Rigby H, Mortimer PS, Orlando A, Levick JR, Bates DO (2007) Chemokine-mediated migration of melanoma cells towards lymphatics—a mechanism contributing to metastasis. Oncogene 26(21):2997–3005PubMedCrossRefGoogle Scholar
  21. 21.
    Shields JD, Fleury ME, Yong C, Tomei AA, Randolph GJ, Swartz MA (2007) Autologous chemotaxis as a mechanism of tumor cell homing to lymphatics via interstitial flow and autocrine CCR7 signaling. Cancer Cell 11(6):526–538PubMedCrossRefGoogle Scholar
  22. 22.
    Paget S (1889) The distribution of secondary growths in cancer of the breast. Lancet I:571–573CrossRefGoogle Scholar
  23. 23.
    Koch F (1939) Zur Frage der Metastasenbildung bei Impftumoren. Z Krebsforsch 48:495–507CrossRefGoogle Scholar
  24. 24.
    Nicolson GL (1988) Organ specificity of tumor metastasis: role of preferential adhesion, invasion and growth of malignant cells at specific secondary sites. Cancer Metastasis Rev 7(2):143–188PubMedCrossRefGoogle Scholar
  25. 25.
    Muller A, Homey B, Soto H, Ge N, Catron D, Buchanan ME, McClanahan T, Murphy E, Yuan W, Wagner SN, Barrera JL, Mohar A, Verastegui E, Zlotnik A (2001) Involvement of chemokine receptors in breast cancer metastasis. Nature 410(6824):50–56PubMedCrossRefGoogle Scholar
  26. 26.
    Arya M, Patel HR, McGurk C, Tatoud R, Klocker H, Masters J, Williamson M (2004) The importance of the CXCL12-CXCR4 chemokine ligand–receptor interaction in prostate cancer metastasis. J Exp Ther Oncol 4(4):291–303PubMedGoogle Scholar
  27. 27.
    Darash-Yahana M, Pikarsky E, Abramovitch R, Zeira E, Pal B, Karplus R, Beider K, Avniel S, Kasem S, Galun E, Peled A (2004) Role of high expression levels of CXCR4 in tumor growth, vascularization, and metastasis. Faseb J 18(11):1240–1242. doi:10.1096/fj.03-0935fje PubMedGoogle Scholar
  28. 28.
    Gervasoni JE Jr, Taneja C, Chung MA, Cady B (2000) Biologic and clinical significance of lymphadenectomy. Surg Clin N Am 80(6):1631–1673PubMedCrossRefGoogle Scholar
  29. 29.
    Veronesi U, Marubini E, Mariani L, Valagussa P, Zucali R (1999) The dissection of internal mammary nodes does not improve the survival of breast cancer patients. 30-year results of a randomised trial. Eur J Cancer 35(9):1320–1325PubMedCrossRefGoogle Scholar
  30. 30.
    Terrone C, Cracco C, Porpiglia F, Bollito E, Scoffone C, Poggio M, Berruti A, Ragni F, Cossu M, Scarpa RM, Rossetti SR (2006) Reassessing the current TNM lymph node staging for renal cell carcinoma. Eur Urol 49(2):324–331. doi:10.1016/j.eururo.2005.11.014 PubMedCrossRefGoogle Scholar
  31. 31.
    Blazer DG 3rd, Sabel MS, Sondak VK (2003) Is there a role for sentinel lymph node biopsy in the management of sarcoma? Surg Oncol 12(3):201–206PubMedCrossRefGoogle Scholar
  32. 32.
    Klein CA, Holzel D (2006) Systemic cancer progression and tumor dormancy: mathematical models meet single cell genomics. Cell Cycle 5(16):1788–1798PubMedCrossRefGoogle Scholar
  33. 33.
    Klein CA (2009) Parallel progression of primary tumours and metastases. Nat Rev Cancer 9(4):302–312PubMedCrossRefGoogle Scholar
  34. 34.
    Kienast Y, von Baumgarten L, Fuhrmann M, Klinkert WE, Goldbrunner R, Herms J, Winkler F (2010) Real-time imaging reveals the single steps of brain metastasis formation. Nat Med 16(1):116–122PubMedCrossRefGoogle Scholar
  35. 35.
    Sleeman JP, Christofori G, Fodde R, Collard JG, Berx G, Decraene C, Ruegg C (2012) Concepts of metastasis in flux: the stromal progression model. Semin Cancer Biol. doi:10.1016/j.semcancer.2012.02.007 Google Scholar
  36. 36.
    Uhr JW, Pantel K (2011) Controversies in clinical cancer dormancy. Proc Natl Acad Sci USA 108(30):12396–12400PubMedCrossRefGoogle Scholar
  37. 37.
    Kauffman HM, McBride MA, Delmonico FL (2000) First report of the united network for organ sharing transplant tumor registry: donors with a history of cancer. Transplantation 70(12):1747–1751PubMedCrossRefGoogle Scholar
  38. 38.
    Buell JF, Trofe J, Hanaway MJ, Lo A, Rosengard B, Rilo H, Alloway R, Beebe T, First MR, Woodle ES (2001) Transmission of donor cancer into cardiothoracic transplant recipients. Surgery 130 (4):660–666 (discussion 666–668). doi:10.1067/msy.2001.117102 Google Scholar
  39. 39.
    Naumov GN, MacDonald IC, Weinmeister PM, Kerkvliet N, Nadkarni KV, Wilson SM, Morris VL, Groom AC, Chambers AF (2002) Persistence of solitary mammary carcinoma cells in a secondary site: a possible contributor to dormancy. Cancer Res 62(7):2162–2168PubMedGoogle Scholar
  40. 40.
    MacKie RM, Reid R, Junor B (2003) Fatal melanoma transferred in a donated kidney 16 years after melanoma surgery. N Engl J Med 348(6):567–568. doi:10.1056/NEJM200302063480620 PubMedCrossRefGoogle Scholar
  41. 41.
    Meng S, Tripathy D, Frenkel EP, Shete S, Naftalis EZ, Huth JF, Beitsch PD, Leitch M, Hoover S, Euhus D, Haley B, Morrison L, Fleming TP, Herlyn D, Terstappen LW, Fehm T, Tucker TF, Lane N, Wang J, Uhr JW (2004) Circulating tumor cells in patients with breast cancer dormancy. Clin Cancer Res 10(24):8152–8162PubMedCrossRefGoogle Scholar
  42. 42.
    Becker R, Lenter MC, Vollkommer T, Boos AM, Pfaff D, Augustin HG, Christian S (2008) Tumor stroma marker endosialin (Tem1) is a binding partner of metastasis-related protein Mac-2 BP/90 K. Faseb J 22(8):3059–3067PubMedCrossRefGoogle Scholar
  43. 43.
    Kaplan RN, Riba RD, Zacharoulis S, Bramley AH, Vincent L, Costa C, MacDonald DD, Jin DK, Shido K, Kerns SA, Zhu Z, Hicklin D, Wu Y, Port JL, Altorki N, Port ER, Ruggero D, Shmelkov SV, Jensen KK, Rafii S, Lyden D (2005) VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 438(7069):820–827PubMedCrossRefGoogle Scholar
  44. 44.
    Hiratsuka S, Watanabe A, Aburatani H, Maru Y (2006) Tumour-mediated upregulation of chemoattractants and recruitment of myeloid cells predetermines lung metastasis. Nat Cell Biol 8(12):1369–1375PubMedCrossRefGoogle Scholar
  45. 45.
    Hiratsuka S, Watanabe A, Sakurai Y, Akashi-Takamura S, Ishibashi S, Miyake K, Shibuya M, Akira S, Aburatani H, Maru Y (2008) The S100A8-serum amyloid A3-TLR4 paracrine cascade establishes a pre-metastatic phase. Nat Cell Biol 10(11):1349–1355PubMedCrossRefGoogle Scholar
  46. 46.
    Hirakawa S, Brown LF, Kodama S, Paavonen K, Alitalo K, Detmar M (2007) VEGF-C-induced lymphangiogenesis in sentinel lymph nodes promotes tumor metastasis to distant sites. Blood 109(3):1010–1017PubMedCrossRefGoogle Scholar
  47. 47.
    Jakob C, Aust DE, Liebscher B, Baretton GB, Datta K, Muders MH (2011) Lymphangiogenesis in regional lymph nodes is an independent prognostic marker in rectal cancer patients after neoadjuvant treatment. PLoS ONE 6(11):e27402. doi:10.1371/journal.pone.0027402 PubMedCrossRefGoogle Scholar
  48. 48.
    Pitchford SC, Furze RC, Jones CP, Wengner AM, Rankin SM (2009) Differential mobilization of subsets of progenitor cells from the bone marrow. Cell Stem Cell 4(1):62–72PubMedCrossRefGoogle Scholar
  49. 49.
    Cristofanilli M, Braun S (2010) Circulating tumor cells revisited. JAMA 303(11):1092–1093PubMedCrossRefGoogle Scholar
  50. 50.
    Pantel K, Brakenhoff RH (2004) Dissecting the metastatic cascade. Nat Rev Cancer 4(6):448–456PubMedCrossRefGoogle Scholar
  51. 51.
    Pantel K, Brakenhoff RH, Brandt B (2008) Detection, clinical relevance and specific biological properties of disseminating tumour cells. Nat Rev Cancer 8:329–340PubMedCrossRefGoogle Scholar
  52. 52.
    Pantel K, Schlimok G, Kutter D, Schaller G, Genz T, Wiebecke B, Backmann R, Funke I, Riethmuller G (1991) Frequent down-regulation of major histocompatibility class I antigen expression on individual micrometastatic carcinoma cells. Cancer Res 51(17):4712–4715PubMedGoogle Scholar
  53. 53.
    Braun S, Pantel K, Muller P, Janni W, Hepp F, Kentenich CR, Gastroph S, Wischnik A, Dimpfl T, Kindermann G, Riethmuller G, Schlimok G (2000) Cytokeratin-positive cells in the bone marrow and survival of patients with stage I, II, or III breast cancer. N Engl J Med 342(8):525–533PubMedCrossRefGoogle Scholar
  54. 54.
    Kollermann J, Weikert S, Schostak M, Kempkensteffen C, Kleinschmidt K, Rau T, Pantel K (2008) Prognostic significance of disseminated tumor cells in the bone marrow of prostate cancer patients treated with neoadjuvant hormone treatment. J Clin Oncol 26(30):4928–4933PubMedCrossRefGoogle Scholar
  55. 55.
    Braun S, Vogl FD, Naume B, Janni W, Osborne MP, Coombes RC, Schlimok G, Diel IJ, Gerber B, Gebauer G, Pierga JY, Marth C, Oruzio D, Wiedswang G, Solomayer EF, Kundt G, Strobl B, Fehm T, Wong GY, Bliss J, Vincent-Salomon A, Pantel K (2005) A pooled analysis of bone marrow micrometastasis in breast cancer. N Engl J Med 353(8):793–802PubMedCrossRefGoogle Scholar
  56. 56.
    Alix-Panabieres C, Schwarzenbach H, Pantel K (2012) Circulating tumor cells and circulating tumor DNA. Annu Rev Med 63:199–215PubMedCrossRefGoogle Scholar
  57. 57.
    Xenidis N, Ignatiadis M, Apostolaki S, Perraki M, Kalbakis K, Agelaki S, Stathopoulos EN, Chlouverakis G, Lianidou E, Kakolyris S, Georgoulias V, Mavroudis D (2009) Cytokeratin-19 mRNA-positive circulating tumor cells after adjuvant chemotherapy in patients with early breast cancer. J Clin Oncol 27(13):2177–2184PubMedCrossRefGoogle Scholar
  58. 58.
    Riethdorf S, Fritsche H, Muller V, Rau T, Schindlbeck C, Rack B, Janni W, Coith C, Beck K, Janicke F, Jackson S, Gornet T, Cristofanilli M, Pantel K (2007) Detection of circulating tumor cells in peripheral blood of patients with metastatic breast cancer: a validation study of the cell search system. Clin Cancer Res 13(3):920–928PubMedCrossRefGoogle Scholar
  59. 59.
    Bednarz N, Eltze E, Semjonow A, Rink M, Andreas A, Mulder L, Hannemann J, Fisch M, Pantel K, Weier HU, Bielawski KP, Brandt B (2010) BRCA1 loss preexisting in small subpopulations of prostate cancer is associated with advanced disease and metastatic spread to lymph nodes and peripheral blood. Clin Cancer Res 16(13):3340–3348PubMedCrossRefGoogle Scholar
  60. 60.
    Joosse SA, Hannemann J, Spotter J, Bauche A, Andreas A, Muller V, Pantel K (2012) Changes in keratin expression during metastatic progression of breast cancer: impact on the detection of circulating tumor cells. Clin Cancer Res 18(4):993–1003PubMedCrossRefGoogle Scholar
  61. 61.
    Cristofanilli M, Budd GT, Ellis MJ, Stopeck A, Matera J, Miller MC, Reuben JM, Doyle GV, Allard WJ, Terstappen LW, Hayes DF (2004) Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med 351(8):781–791PubMedCrossRefGoogle Scholar
  62. 62.
    Cohen SJ, Punt CJ, Iannotti N, Saidman BH, Sabbath KD, Gabrail NY, Picus J, Morse M, Mitchell E, Miller MC, Doyle GV, Tissing H, Terstappen LW, Meropol NJ (2008) Relationship of circulating tumor cells to tumor response, progression-free survival, and overall survival in patients with metastatic colorectal cancer. J Clin Oncol 26(19):3213–3221PubMedCrossRefGoogle Scholar
  63. 63.
    de Bono JS, Scher HI, Montgomery RB, Parker C, Miller MC, Tissing H, Doyle GV, Terstappen LW, Pienta KJ, Raghavan D (2008) Circulating tumor cells predict survival benefit from treatment in metastatic castration-resistant prostate cancer. Clin Cancer Res 14(19):6302–6309PubMedCrossRefGoogle Scholar
  64. 64.
    Krebs MG, Sloane R, Priest L, Lancashire L, Hou JM, Greystoke A, Ward TH, Ferraldeschi R, Hughes A, Clack G, Ranson M, Dive C, Blackhall FH (2011) Evaluation and prognostic significance of circulating tumor cells in patients with non-small-cell lung cancer. J Clin Oncol 29(12):1556–1563PubMedCrossRefGoogle Scholar
  65. 65.
    Pantel K, Deneve E, Nocca D, Coffy A, Vendrell JP, Maudelonde T, Riethdorf S, Alix-Panabieres C (2012) Circulating epithelial cells in patients with benign colon diseases. Clin Chem. doi: 10.1373/clinchem.2011.175570
  66. 66.
    Riethdorf S, Muller V, Zhang L, Rau T, Loibl S, Komor M, Roller M, Huober J, Fehm T, Schrader I, Hilfrich J, Holms F, Tesch H, Eidtmann H, Untch M, von Minckwitz G, Pantel K (2010) Detection and HER2 expression of circulating tumor cells: prospective monitoring in breast cancer patients treated in the neoadjuvant GeparQuattro trial. Clin Cancer Res 16(9):2634–2645PubMedCrossRefGoogle Scholar
  67. 67.
    Smirnov DA, Zweitzig DR, Foulk BW, Miller MC, Doyle GV, Pienta KJ, Meropol NJ, Weiner LM, Cohen SJ, Moreno JG, Connelly MC, Terstappen LW, O’Hara SM (2005) Global gene expression profiling of circulating tumor cells. Cancer Res 65(12):4993–4997PubMedCrossRefGoogle Scholar
  68. 68.
    Watson MA, Ylagan LR, Trinkaus KM, Gillanders WE, Naughton MJ, Weilbaecher KN, Fleming TP, Aft RL (2007) Isolation and molecular profiling of bone marrow micrometastases identifies TWIST1 as a marker of early tumor relapse in breast cancer patients. Clin Cancer Res 13(17):5001–5009PubMedCrossRefGoogle Scholar
  69. 69.
    Sieuwerts AM, Kraan J, de Bolt Vries J, van der Spoel P, Mostert B, Martens JW, Gratama JW, Sleijfer S, Foekens JA (2009) Molecular characterization of circulating tumor cells in large quantities of contaminating leukocytes by a multiplex real-time PCR. Breast Cancer Res Treat 118(3):455–468PubMedCrossRefGoogle Scholar
  70. 70.
    Markou A, Strati A, Malamos N, Georgoulias V, Lianidou ES (2011) Molecular characterization of circulating tumor cells in breast cancer by a liquid bead array hybridization assay. Clin Chem 57(3):421–430PubMedCrossRefGoogle Scholar
  71. 71.
    Alix-Panabieres C, Vendrell JP, Pelle O, Rebillard X, Riethdorf S, Muller V, Fabbro M, Pantel K (2007) Detection and characterization of putative metastatic precursor cells in cancer patients. Clin Chem 53(3):537–539PubMedCrossRefGoogle Scholar
  72. 72.
    Alix-Panabieres C, Vendrell JP, Slijper M, Pelle O, Barbotte E, Mercier G, Jacot W, Fabbro M, Pantel K (2009) Full length cytokeratin-19 is released by human tumor cells: a potential role in metastatic progression of breast cancer. Breast Cancer Res 11(3):R39PubMedCrossRefGoogle Scholar
  73. 73.
    Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF (2003) Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA 100(7):3983–3988PubMedCrossRefGoogle Scholar
  74. 74.
    Bartkowiak K, Effenberger KE, Harder S, Andreas A, Buck F, Peter-Katalinic J, Pantel K, Brandt BH (2010) Discovery of a novel unfolded protein response phenotype of cancer stem/progenitor cells from the bone marrow of breast cancer patients. J Proteome Res 9(6):3158–3168PubMedCrossRefGoogle Scholar
  75. 75.
    Shiozawa Y, Pedersen EA, Havens AM, Jung Y, Mishra A, Joseph J, Kim JK, Patel LR, Ying C, Ziegler AM, Pienta MJ, Song J, Wang J, Loberg RD, Krebsbach PH, Pienta KJ, Taichman RS (2011) Human prostate cancer metastases target the hematopoietic stem cell niche to establish footholds in mouse bone marrow. J Clin Invest 121(4):1298–1312PubMedCrossRefGoogle Scholar
  76. 76.
    Balic M, Lin H, Young L, Hawes D, Giuliano A, McNamara G, Datar RH, Cote RJ (2006) Most early disseminated cancer cells detected in bone marrow of breast cancer patients have a putative breast cancer stem cell phenotype. Clin Cancer Res 12(19):5615–5621PubMedCrossRefGoogle Scholar
  77. 77.
    Thiery JP, Sleeman JP (2006) Complex networks orchestrate epithelial–mesenchymal transitions. Nat Rev Mol Cell Biol 7(2):131–142PubMedCrossRefGoogle Scholar
  78. 78.
    Aktas B, Tewes M, Fehm T, Hauch S, Kimmig R, Kasimir-Bauer S (2009) Stem cell and epithelial–mesenchymal transition markers are frequently overexpressed in circulating tumor cells of metastatic breast cancer patients. Breast Cancer Res 11(4):R46PubMedCrossRefGoogle Scholar
  79. 79.
    Baehner FL, Li R, Jenkins T, Hwang J, Kashani-Sabet M, Allen RE, Leong SPL (2012) The impact of primary melanoma thickness and microscopic tumor burden in sentinel lymph nodes on melanoma patient survival. Ann Surg Oncol 19:1034–1042PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2012

Authors and Affiliations

  • Jonathan P. Sleeman
    • 1
    • 2
  • Blake Cady
    • 3
  • Klaus Pantel
    • 4
  1. 1.Centre for Biomedicine and Medical Technology Mannheim (CBTM)Universitätsmedizin Mannheim, University of HeidelbergMannheimGermany
  2. 2.KIT Karlsruhe Campus NordEggenstein-LeopoldshafenGermany
  3. 3.Comprehensive Breast Clinic, Cambridge HospitalCambridgeUSA
  4. 4.Department of Tumor BiologyUniversity Medical Center Hamburg-EppendorfHamburgGermany

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