Abstract
Hematogenous and lymph node metastasis of melanoma cells is a major cause of death in the United States and Canada. Melanoma cells have a propensity for spreading to lymph nodes via the lymphatics. However, little is known about regional growth patterns of draining lymph node metastases arising from dermal melanomas. In a mouse model, by 10–14 days following intradermal injection, melanoma cells were replicating as discrete, evenly spaced lymph node metastases. When the injection site was excised at 4 days post intradermal injection, neither primary dermal tumors nor lymph node metastases were observed, indicating that metastasizing cells did not come directly from the initial injection and that the primary dermal tumor was required for lymph node metastases. While 23.1% of melanoma cells were proliferating in the lymph node, only 0.9% of these cells were undergoing apoptosis. We never observed metastasizing cancer cells replicating in blood or lymphatic vessels. When melanoma cells undergo hematogenous metastasis after portal vein injection, they are initially arrested in the liver by size constraints. However, they extravasate as an active process involving pseudopodial projections; during this process the vasculature remains intact. The metastasizing cells can then migrate to preferred sites for replication. In the lung, after intravenous injection, melanoma cells become arrested by size constraint at sites directly proportional to the available lung volume. By 10 days post injection, cancer cell replication preferentially occurs at the lung surface with 80% coverage. The vast majority of single, extravasated melanoma cells in the lung and liver are dormant. However, metastatic efficiency and dormancy of melanoma cells can vary widely with the melanoma cell line injected and/or the organ involved. The percentage of inoculated cells that remain as single, dormant cells at 2 weeks post inoculation is tenfold higher for B16F1 cells in liver compared with B16F10 cells in the lung. In contrast, metastatic efficiency of B16 F10 cells in lung is >500-fold higher than for B16F1 cells in liver.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Botella-Estrada R, Dasi F, Ramos D, Nagore E, Herrero M, Gimenez J, Fuster C, Sanmartin O, Guillen C, Alino S (2005) Cytokine expression and dendritic cell density in melanoma sentinal nodes. Melanoma Res 15:99–106
Brody J, Costantino C, Berger A, Sato T, Lisanti M, Yeo C, Emmons R, Witkiewicz A (2009) Expression of indoleamine 2,3-dioxygenase in metastatic malignant melanoma recruits regulatory T cells to avoid immune detection and affects survival. Cell Cycle 8:1930–1934
Cameron M, Schmidt E, Kerkvliet N, Nadkarni K, Morris V, Groom A, Chambers A, MacDonald I (2000) Temporal progression of metastasis in lung: cell survival, dormancy, and location dependence of metastatic inefficiency. Cancer Res 60:2541–2546
Connolly K, Bogdanffy M (1993) Evaluation of proliferating cell nuclear antigen (PCNA) as an endogenous marker of cell proliferation in rat liver: a dual-stain comparison with 5-bromo-2′-deoxyuridine. J Histochem Cytochem 41:1–6
Crivellato E, Vacca A, Ribatti D (2004) Setting the stage: an anatomist’s view of the immune system. Trends Immunol 25:210–217
Dadras S, Paul T, Bertoncini J, Brown L, Muzikansky A, Jackson D, Ellwanger U, Garbe C, Mihn M, Detmar M (2003) Tumor lymphangiogenesis: a novel prognostic indicator for cutaneous melanoma metastasis and survival. Am J Pathol 162:1951–1960
Diepgen T, Mahler V (2002) The epidemiology of skin cancer. Br J Dermatol 146(Suppl61):1–6
Duff M, Stapleton P, Mestre J, Maddali S, Smyth G, Yan Z, Freeman T, Daly J (2003) Cyclooxygenase-2 inhibition improves macrophage function in melanoma and increases the antineoplastic activity of interferon. Ann Surg Oncol 10:305–313
Fallarino F, Grohmann U, Vacca C, Blanchi R, Orabona C, Spreca A, Floretti M, Puccetti P (2002) T cell apoptosis by tryptophan catabolism. Cell Death Differ 9:1069–1077
Foley J, Dietrich D, Swenberg J, Maronpot R (1991) Detection and evaluation of proliferating cell nuclear antigen (PCNA) in rat tissue by an improved immunohistochemical procedure. J Histotechnol 14:237–241
Hangan D, Morris V, Boeters L, Von Ballestrem C, Uniyal S, Chan B (1997) An epitope on VLA-6 (alpha 6 beta1) integrin involved in migration but not adhesion is required for extravasation of murine melanoma B16F1 cells in liver. Cancer Res 57:3812–3817
Hedley B, Vaidya K, Phadke P, MacKenzie L, Dales D, Postenka C, MacDonald I, Chambers A (2008) BRMS1 Suppresses breast cancer metastasis in multiple experimental models of metastasis by reducing solitary cell survival and inhibiting growth initiation. Clin Exp Metastasis 25:727–740
Kim A, Lim J-S (2007) Methyselenol generated from selenomethionine and methioninase induces apoptosis and blocks metastasis of melanoma. Women Health 3:17–21
Kirstein J, Graham K, MacKenzie L, Johnston D, Martin L, Tuck A, MacDonald I, Chambers A (2009) Effect of anti-fibrinolytic therapy on experimental melanoma metastasis. Clin Exp Metastasis 26:121–131
Kobayashi M, Kobayashi H, Pollard R, Suzuki F (1998) A pathogenic role of Th2 cells and their cytokine products on pulmonary metastasis of murine B16 melanoma. J Immunol 160:5869–5873
Kurumbail R, Stevens A, Gierse J, McDonald J, Stegeman R, Pak J, Gildehaus D, Miyashiro J, Penning T, Seibert K, Isakson P, Stallings W (1996) Structural basis for selective inhibition of cyclooxygenase-2 by anti-inflammatory agents. Nature 384:644–648
Lebedis C, Chen K, Fallavollita L, Boutros T, Brodt P (2002) Peripheral lymph node stromal cells can promote growth and tumorigenicity of breast carcinoma cells through the release of IGF-1 and EGF. Int J Cancer 100:2–8
Lee J, Torisu-Itakara H, Cochran A, Kadison A, Huynh Y, Morton D, Essner R (2005) Quantitative analysis of melanoma-induced cytokine-mediated immunosuppression in melanoma sentinal nodes. Clin Cancer Res 11:107–112
Luzzi K, MacDonald I, Schmidt E, Kerkvliet N, Morris V, Chambers A, Groom A (1998) Multistep nature of metastatic inefficiency: dormancy of solitary cells after successful extravasation and limited survival of early micrometastases. Am J Pathol 153:865–873
MacDonald I, Groom A, Chambers A (2002) Cancer spread and micrometastasis development: quantitative approaches for in vivo models. Bioessays 24:885–893
Malaponte G, Zacchia A, Bevelacqua Y, Marconi A, Perrotta R, Mazzarino M, Cardile V, Stivala F (2010) Co-regulated expression of matrix metalloproteinase-2 and transforming growth factor-beta in melanoma development and progression. Oncol Rep 24:81–87
Morris V, Schmidt E, MacDonald I, Groom A, Chambers A (1997) Sequential steps in hematogenous metastasis of cancer cells studied by in vivo videomicroscopy. Invasion Metastasis 17:281–296
Munn D, Sharma M, Hou D, Baban B, Lee J, Antonia S, Messina J, Chandler P, Koni P, Mellor A (2004) Expression of indoleamine 2,3-dioxygenase by plasmacytoid dendritic cells in tumor-draining lymph nodes. J Clin Invest 114:280–290
Munn D, Sharma M, Baban B, Harding H, Zhang Y, Ron D, Mellor A (2005) GCN2 kinase in T cells mediates proliferative arrest and anergy induction in response to indoleamine 2,3-dioxygenase. Immunity 22:633–642
Naumov G, Townson J, MacDonald I, Wilson S, Bramwell V, Groom A, Chambers A (2003) Ineffectiveness of doxorubicin treatment on solitary dormant mammary carcinoma cells or late-developing metastases. Breast Cancer Res Treat 82:199–206
Nip J, Shibata H, Loskutoff D, Cheresh D, Brodt P (1992) Human melanoma cells derived from lymphatic metastases use integrin alpha v beta 3 to adhere to lymph node vitronectin. J Clin Invest 90:1406–1413
Polak M, Borthwick N, Gabriel F, Johnson P, Higgins B, Hurren J, McCormick D, Jager M, Cree I (2007) Mechanisms of local immunosuppression in cutaneous melanoma. Br J Cancer 96:1879–1887
Prendergast G (2008) Immune escape as a fundamental trait of cancer: focus on IDO. Oncogene 27:3889–3900
Ratheesh A, Ingle A, Gude R (2007) Pentoxifylline modulates cell surface integrin expression and integrin mediated adhesion of B16F10 cells to extracellular matrix components. Cancer Biol Ther 6:1743–1752
Reilly J, Nash J, Mackie M, McVerry B (1985) Distribution of fibronectin and laminin in normal and pathological lymphoid tissue. J Clin Pathol 38:849–854
Schietroma C, Clanfarani F, Lacal P, Odorisio T, Orecchia A, Kanitakis J, D’Atri S, Failla C, Zambruno G (2003) Vascular endothelial growth factor-C expression correlates with lymph node localization of human melanoma metastases. Cancer 98:789–797
Smith W, Dewitt D (1996) Prostaglandin endoperoxide H synthases-1 and -2. Adv Immunol 62:167–215
Trites J, Yoo J, Taylor M, Schmidt E, Morris V, MacDonald I, Chambers A, Groom A (2000) Lymph node metastasis in malignant melanoma: an in vivo animal model. J Otolaryngol 29:233–238
Willard-Mack C (2006) Normal structure, function, and histology of lymph nodes. Toxicol Pathol 34:409–424
Wiman K (2010) Pharmacological reactivation of mutant p53: from protein structure to the cancer patient. Oncogene 29:4245–4252
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2013 Springer Science+Business Media Dordrecht
About this chapter
Cite this chapter
Morris, V.L., Percy, D.B., Lizardo, M.M., Chambers, A.F., MacDonald, I.C. (2013). Dormancy and Metastasis of Melanoma Cells to Lymph Nodes, Lung and Liver. In: Hayat, M. (eds) Tumor Dormancy, Quiescence, and Senescence, Volume 1. Tumor Dormancy and Cellular Quiescence and Senescence, vol 1. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-5958-9_6
Download citation
DOI: https://doi.org/10.1007/978-94-007-5958-9_6
Published:
Publisher Name: Springer, Dordrecht
Print ISBN: 978-94-007-5957-2
Online ISBN: 978-94-007-5958-9
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)