Abstract
Metastasis is the major cause of death in patients suffering from malignant melanoma, one of the most aggressive types of cancer. Local recurrence is rare in melanoma, but regional and distant metastasis, particularly in the brain, bone, lung and liver, may arise even many years after primary tumor resection, probably due to reactivation of dormant melanoma cells. Dormancy of dispersed melanoma cells is regulated by tumor cell intrinsic as well as extrinsic factors, including angiogenesis, immunosurveillance, and other stroma-dependent processes. Melanoma metastasis correlates with local invasion and the vertical growth phase at the primary site. During this phase, cancer cells invade deep into the dermis and interact with various stromal cells to gain access to blood and lymphatic vessels. Subsequently, melanoma cells migrate along the local lymphatic vasculature, sometimes resulting in locoregional lesions such as in-transit metastases, before reaching the draining lymph node and spreading systemically. Both lymphatic and blood vessels play a critical role in the dispersion of melanomas. Besides providing a simple transport route for cancer cells, endothelial cells are emerging as important and active players in melanoma metastasis. Conditioned by factors derived from the tumor microenvironment, the vasculature undergoes morphological and functional changes, which facilitate the metastatic process in multiple ways. Consequently, therapeutic manipulation of lymphatic and blood vessels may represent a new way to combat melanoma metastasis.
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
Alitalo A, Detmar M (2012) Interaction of tumor cells and lymphatic vessels in cancer progression. Oncogene 31(42):4499–4508. https://doi.org/10.1038/onc.2011.602
Balch CM (2009) Microscopic satellites around a primary melanoma: another piece of the puzzle in melanoma staging. Ann Surg Oncol 16(5):1092–1094. https://doi.org/10.1245/s10434-009-0353-4
Balch CM, Soong SJ, Atkins MB, Buzaid AC, Cascinelli N, Coit DG, Fleming ID, Gershenwald JE, Houghton A Jr, Kirkwood JM, McMasters KM, Mihm MF, Morton DL, Reintgen DS, Ross MI, Sober A, Thompson JA, Thompson JF (2004) An evidence-based staging system for cutaneous melanoma. CA Cancer J Clin 54(3):131–149. https://doi.org/10.3322/canjclin.54.3.131
Blum KS, Proulx ST, Luciani P, Leroux JC, Detmar M (2013) Dynamics of lymphatic regeneration and flow patterns after lymph node dissection. Breast Cancer Res Treat 139(1):81–86. https://doi.org/10.1007/s10549-013-2537-7
Boyle ST, Ingman WV, Poltavets V, Faulkner JW, Whitfield RJ, McColl SR, Kochetkova M (2016) The chemokine receptor CCR7 promotes mammary tumorigenesis through amplification of stem-like cells. Oncogene 35(1):105–115. https://doi.org/10.1038/onc.2015.66
Cao ZF, Bao MM, Miele L, Sarkar FH, Wang ZW, Zhou QS (2013) Tumour vasculogenic mimicry is associated with poor prognosis of human cancer patients: a systemic review and meta-analysis. Eur J Cancer 49(18):3914–3923. https://doi.org/10.1016/j.ejca.2013.07.148
Dadras SS, Paul T, Bertoncini J, Brown LF, Muzikansky A, Jackson DG, Ellwanger U, Garbe C, Mihm MC, Detmar M (2003) Tumor lymphangiogenesis – a novel prognostic indicator for cutaneous melanoma metastasis and survival. Am J Pathol 162(6): 1951–1960. https://doi.org/10.1016/S0002-9440(10)64328-3
Dadras SS, Lange-Asschenfeldt B, Velasco P, Nguyen L, Vora A, Muzikansky A, Jahnke K, Hauschild A, Hirakawa S, Mihm MC, Detmar M (2005) Tumor lymphangiogenesis predicts melanoma metastasis to sentinel lymph nodes. Mod Pathol 18(9):1232–1242. https://doi.org/10.1038/Modpathol.3800410
Damsky WE, Rosenbaum LE, Bosenberg M (2011) Decoding melanoma metastasis. Cancers (Basel) 3(1): 126–163. https://doi.org/10.3390/cancers3010126
Damsky WE, Theodosakis N, Bosenberg M (2014) Melanoma metastasis: new concepts and evolving paradigms. Oncogene 33(19):2413–2422. https://doi.org/10.1038/onc.2013.194
Detmar M (2000) The role of VEGF and thrombospondins in skin angiogenesis. J Dermatol Sci 24(Suppl 1):S78–S84
Dieterich LC, Detmar M (2016) Tumor lymphangiogenesis and new drug development. Adv Drug Deliv Rev 99(Pt B):148–160. https://doi.org/10.1016/j.addr.2015.12.011
Doeden K, Ma ZH, Narasimhan B, Swetter SM, Detmar M, Dadras SS (2009) Lymphatic invasion in cutaneous melanoma is associated with sentinel lymph node metastasis. J Cutan Pathol 36(7):772–780. https://doi.org/10.1111/J.1600-0560.2008.01166.X
Elder DE (2016) Melanoma progression. Pathology 48(2):147–154. https://doi.org/10.1016/j.pathol.2015.12.002
Gaggioli C, Sahai E (2007) Melanoma invasion – current knowledge and future directions. Pigment Cell Res 20(3):161–172. https://doi.org/10.1111/j.1600-0749.2007.00378.x
Gundem G, Van Loo P, Kremeyer B, Alexandrov LB, Tubio JM, Papaemmanuil E, Brewer DS, Kallio HM, Hognas G, Annala M, Kivinummi K, Goody V, Latimer C, O’Meara S, Dawson KJ, Isaacs W, Emmert-Buck MR, Nykter M, Foster C, Kote-Jarai Z, Easton D, Whitaker HC, Group IPU, Neal DE, Cooper CS, Eeles RA, Visakorpi T, Campbell PJ, McDermott U, Wedge DC, Bova GS (2015) The evolutionary history of lethal metastatic prostate cancer. Nature 520(7547):353–357. https://doi.org/10.1038/nature14347
Helfrich I, Edler L, Sucker A, Thomas M, Christian S, Schadendorf D, Augustin HG (2009) Angiopoietin-2 levels are associated with disease progression in metastatic malignant melanoma. Clin Cancer Res 15(4): 1384–1392. https://doi.org/10.1158/1078-0432.CCR-08-1615
Hendrix MJC, Seftor EA, Seftor REB, Chao JT, Chien DS, Chu YW (2016) Tumor cell vascular mimicry: novel targeting opportunity in melanoma. Pharmacol Ther 159:83–92. https://doi.org/10.1016/j.pharmthera.2016.01.006
Hirakawa S, Kodama S, Kunstfeld R, Kajiya K, Brown LF, Detmar M (2005) VEGF-A induces tumor and sentinel lymph node lymphangiogenesis and promotes lymphatic metastasis. J Exp Med 201(7):1089–1099. https://doi.org/10.1084/jem.20041896
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):1010–1017. https://doi.org/10.1182/Blood-2006-05-021758
Hood JL, San RS, Wickline SA (2011) Exosomes released by melanoma cells prepare sentinel lymph nodes for tumor metastasis. Cancer Res 71(11):3792–3801. https://doi.org/10.1158/0008-5472.CAN-10-4455
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):820–827. https://doi.org/10.1038/nature04186
Karaman S, Detmar M (2014) Mechanisms of lymphatic metastasis. J Clin Invest 124(3):922–928. https://doi.org/10.1172/J071606
Kerjaschki D, Bago-Horvath Z, Rudas M, Sexl V, Schneckenleithner C, Wolbank S, Bartel G, Krieger S, Kalt R, Hantusch B, Keller T, Nagy-Bojarszky K, Huttary N, Raab I, Lackner K, Krautgasser K, Schachner H, Kaserer K, Rezar S, Madlener S, Vonach C, Davidovits A, Nosaka H, Hammerle M, Viola K, Dolznig H, Schreiber M, Nader A, Mikulits W, Gnant M, Hirakawa S, Detmar M, Alitalo K, Nijman S, Offner F, Maier TJ, Steinhilber D, Krupitza G (2011) Lipoxygenase mediates invasion of intrametastatic lymphatic vessels and propagates lymph node metastasis of human mammary carcinoma xenografts in mouse. J Clin Invest 121(5): 2000–2012. https://doi.org/10.1172/Jci44751
Kim M, Koh YJ, Kim KE, Koh BI, Nam DH, Alitalo K, Kim I, Koh GY (2010) CXCR4 signaling regulates metastasis of chemoresistant melanoma cells by a lymphatic metastatic niche. Cancer Res 70(24): 10411–10421. https://doi.org/10.1158/0008-5472.CAN-10-2591
Krock BL, Skuli N, Simon MC (2011) Hypoxia-induced angiogenesis: good and evil. Genes Cancer 2(12): 1117–1133. https://doi.org/10.1177/1947601911423654
Landsberg J, Kohlmeyer J, Renn M, Bald T, Rogava M, Cron M, Fatho M, Lennerz V, Wolfel T, Holzel M, Tuting T (2012) Melanomas resist T-cell therapy through inflammation-induced reversible dedifferentiation. Nature 490(7420):412–416. https://doi.org/10.1038/nature11538
Landsberg J, Tuting T, Barnhill RL, Lugassy C (2016) The role of neutrophilic inflammation, angiotropism, and pericytic mimicry in melanoma progression and metastasis. J Invest Dermatol 136(2):372–377. https://doi.org/10.1016/j.jid.2015.11.013
Lanitis E, Irving M, Coukos G (2015) Targeting the tumor vasculature to enhance T cell activity. Curr Opin Immunol 33:55–63. https://doi.org/10.1016/j.coi.2015.01.011
Leong SP, Mihm MC Jr, Murphy GF, Hoon DS, Kashani-Sabet M, Agarwala SS, Zager JS, Hauschild A, Sondak VK, Guild V, Kirkwood JM (2012) Progression of cutaneous melanoma: implications for treatment. Clin Exp Metastasis 29(7):775–796. https://doi.org/10.1007/s10585-012-9521-1
Lugassy C, Zadran S, Bentolila LA, Wadehra M, Prakash R, Carmichael ST, Kleinman HK, Peault B, Larue L, Barnhill RL (2014) Angiotropism, pericytic mimicry and extravascular migratory metastasis in melanoma: an alternative to intravascular cancer dissemination. Cancer Microenviron 7(3):139–152. https://doi.org/10.1007/s12307-014-0156-4
Lund AW, Wagner M, Fankhauser M, Steinskog ES, Broggi MA, Spranger S, Gajewski TF, Alitalo K, Eikesdal HP, Wiig H, Swartz MA (2016) Lymphatic vessels regulate immune microenvironments in human and murine melanoma. J Clin Invest. https://doi.org/10.1172/JCI79434
Maniotis AJ, Folberg R, Hess A, Seftor EA, Gardner LM, Pe'er J, Trent JM, Meltzer PS, Hendrix MJ (1999) Vascular channel formation by human melanoma cells in vivo and in vitro: vasculogenic mimicry. Am J Pathol 155(3):739–752. https://doi.org/10.1016/S0002-9440(10)65173-5
Ossowski L, Aguirre-Ghiso JA (2010) Dormancy of metastatic melanoma. Pigment Cell Melanoma Res 23(1):41–56. https://doi.org/10.1111/j.1755-148X.2009.00647.x
Peinado H, Aleckovic M, Lavotshkin S, Matei I, Costa-Silva B, Moreno-Bueno G, Hergueta-Redondo M, Williams C, Garcia-Santos G, Ghajar CM, Nitadori-Hoshino A, Hoffman C, Badal K, Garcia BA, Callahan MK, Yuan JD, Martins VR, Skog J, Kaplan RN, Brady MS, Wolchok JD, Chapman PB, Kang YB, Bromberg J, Lyden D (2012) Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. Nat Med 18(6):883–891. https://doi.org/10.1038/nm.2753
Proulx ST, Luciani P, Christiansen A, Karaman S, Blum KS, Rinderknecht M, Leroux JC, Detmar M (2013) Use of a PEG-conjugated bright near-infrared dye for functional imaging of rerouting of tumor lymphatic drainage after sentinel lymph node metastasis. Biomaterials 34(21):5128–5137. https://doi.org/10.1016/j.biomaterials.2013.03.034
Read RL, Haydu L, Saw RPM, Quinn MJ, Shannon K, Spillane AJ, Stretch JR, Scolyer RA, Thompson JF (2015) In-transit melanoma metastases: incidence, prognosis, and the role of lymphadenectomy. Ann Surg Oncol 22(2):475–481. https://doi.org/10.1245/s10434-014-4100-0
Rinderknecht M, Detmar M (2008) Tumor lymphangiogenesis and melanoma metastasis. J Cell Physiol 216(2):347–354. https://doi.org/10.1002/jcp.21494
Rouhani SJ, Eccles JD, Tewalt EF, Engelhard VH (2014) Regulation of T-cell tolerance by lymphatic endothelial cells. J Clin Cell Immunol 5. https://doi.org/10.4172/2155-9899.1000242
Schietroma C, Cianfarani F, Lacal PM, Odorisio T, Orecchia A, Kanitakis J, D’Atri S, Failla CM, Zambruno G (2003) Vascular endothelial growth factor-C expression correlates with lymph node localization of human melanoma metastases. Cancer 98(4):789–797. https://doi.org/10.1002/cncr.11583
Senft D, Ronai ZA (2016) Immunogenic, cellular, and angiogenic drivers of tumor dormancy-a melanoma view. Pigment Cell Melanoma Res 29(1):27–42. https://doi.org/10.1111/pcmr.12432
Shaikh L, Sagebiel RW, Ferreira MQMM, Nosrati M, Miller JR, Kashani-Sabet M (2005) The role of microsatellites as a prognostic factor in primary malignant melanoma. Arch Dermatol 141(6):739–742. https://doi.org/10.1001/Archderm.141.6.739
Simons M, Gordon E, Claesson-Welsh L (2016) Mechanisms and regulation of endothelial VEGF receptor signalling. Nat Rev Mol Cell Biol 17(10):611–625. https://doi.org/10.1038/nrm.2016.87
Skobe M, Detmar M (2000) Structure, function, and molecular control of the skin lymphatic system. J Investig Dermatol Symp Proc 5(1):14–19. https://doi.org/10.1046/J.1087-0024.2000.00001.X
Stacker SA, Williams SP, Karnezis T, Shayan R, Fox SB, Achen MG (2014) Lymphangiogenesis and lymphatic vessel remodelling in cancer. Nat Rev Cancer 14(3): 159–172. https://doi.org/10.1038/Nrc3677
Streit M, Detmar M (2003) Angiogenesis, lymphangiogenesis, and melanoma metastasis. Oncogene 22(20): 3172–3179. https://doi.org/10.1038/sj.onc.1206457
Svedman FC, Pillas D, Taylor A, Kaur M, Linder R, Hansson J (2016) Stage-specific survival and recurrence in patients with cutaneous malignant melanoma in Europe – a systematic review of the literature. Clin Epidemiol 8:109–122. https://doi.org/10.2147/CLEP.S99021
Vesely MD, Schreiber RD (2013) Cancer immunoediting: antigens, mechanisms, and implications to cancer immunotherapy. Ann N Y Acad Sci 1284:1–5. https://doi.org/10.1111/nyas.12105
Whiteside TL (2016) Tumor-derived exosomes and their role in cancer progression. Adv Clin Chem 74(74):103–141. https://doi.org/10.1016/bs.acc.2015.12.005
Zgraggen S, Ochsenbein AM, Detmar M (2013) An important role of blood and lymphatic vessels in inflammation and allergy. J Allergy (Cairo) 2013:672381. https://doi.org/10.1155/2013/672381
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Section Editor information
Rights and permissions
Copyright information
© 2019 Springer Science+Business Media, LLC, part of Springer Nature
About this entry
Cite this entry
Ma, Q., Dieterich, L.C., Detmar, M. (2019). Biology of Melanoma Metastasis. In: Fisher, D., Bastian, B. (eds) Melanoma. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-7147-9_27
Download citation
DOI: https://doi.org/10.1007/978-1-4614-7147-9_27
Published:
Publisher Name: Springer, New York, NY
Print ISBN: 978-1-4614-7148-6
Online ISBN: 978-1-4614-7147-9
eBook Packages: MedicineReference Module Medicine