Decoding Melanoma Metastasis

Cancers - Tập 3 Số 1 - Trang 126-163
William Damsky1,2, Lara E. Rosenbaum1, Marcus Bosenberg1
1Department of Dermatology, Yale School of Medicine, New Haven, Connecticut, USA
2Department of Pathology, University of Vermont College of Medicine, Burlington, Vermont, USA

Tóm tắt

Metastasis accounts for the vast majority of morbidity and mortality associated with melanoma. Evidence suggests melanoma has a predilection for metastasis to particular organs. Experimental analyses have begun to shed light on the mechanisms regulating melanoma metastasis and organ specificity, but these analyses are complicated by observations of metastatic dormancy and dissemination of melanocytes that are not yet fully malignant. Additionally, tumor extrinsic factors in the microenvironment, both at the site of the primary tumor and the site of metastasis, play important roles in mediating the metastatic process. As metastasis research moves forward, paradigms explaining melanoma metastasis as a step-wise process must also reflect the temporal complexity and heterogeneity in progression of this disease. Genetic drivers of melanoma as well as extrinsic regulators of disease spread, particularly those that mediate metastasis to specific organs, must also be incorporated into newer models of melanoma metastasis.

Từ khóa


Tài liệu tham khảo

Rigel, 2000, Malignant melanoma: Prevention, early detection, and treatment in the 21st century, CA Cancer J. Clin., 50, 215, 10.3322/canjclin.50.4.215

Bedrosian, 2000, Incidence of sentinel node metastasis in patients with thin primary melanoma (< or = 1 mm) with vertical growth phase, Ann. Surg. Oncol., 7, 262, 10.1007/s10434-000-0262-z

Balch, 2001, Prognostic factors analysis of 17,600 melanoma patients: Validation of the American Joint Committee on Cancer melanoma staging system, J. Clin. Oncol., 19, 3622, 10.1200/JCO.2001.19.16.3622

Ko, 2011, A new era: Melanoma genetics and therapeutics, J. Pathol., 223, 241, 10.1002/path.2804

Ernfors, 2010, Cellular origin and developmental mechanisms during the formation of skin melanocytes, Exp. Cell. Res., 316, 1397, 10.1016/j.yexcr.2010.02.042

Weston, 1995, Soluble and cell-bound forms of steel factor activity play distinct roles in melanocyte precursor dispersal and survival on the lateral neural crest migration pathway, Development, 121, 731, 10.1242/dev.121.3.731

Ikeya, 1997, Wnt signaling required for expansion of neural crest and CNS progenitors, Nature, 389, 966, 10.1038/40146

Hari, 2002, Lineage-specific requirements of beta-catenin in neural crest development, J. Cell. Biol., 159, 867, 10.1083/jcb.200209039

Rimm, 1999, Frequent nuclear/cytoplasmic localization of beta-catenin without exon 3 mutations in malignant melanoma, Am. J. Pathol., 154, 325, 10.1016/S0002-9440(10)65278-9

Garraway, 2005, Integrative genomic analyses identify Mitf as a lineage survival oncogene amplified in malignant melanoma, Nature, 436, 117, 10.1038/nature03664

Larue, 2006, The Wnt/beta-catenin pathway in melanoma, Front. Biosci., 11, 733, 10.2741/1831

Gupta, 2005, The melanocyte differentiation program predisposes to metastasis after neoplastic transformation, Nat. Genet., 37, 1047, 10.1038/ng1634

Hearing, V.J., and Leong, S.P. (2006). From Melanocytes to Melanoma the Progression of Malignancy, Humana Press.

Tang, 1994, E-cadherin is the major mediator of human melanocyte adhesion to keratinocytes in vitro, J. Cell Sci., 107(Pt 4), 983, 10.1242/jcs.107.4.983

Clark, 1984, A study of tumor progression: The precursor lesions of superficial spreading and nodular melanoma, Hum. Pathol., 15, 1147, 10.1016/S0046-8177(84)80310-X

Gruber, 1989, Nevomelanocytic proliferations in association with cutaneous malignant melanoma: A multivariate analysis, J. Am. Acad. Dermatol., 21, 773, 10.1016/S0190-9622(89)70253-X

Marks, 1990, Do all melanomas come from “Moles”? A study of the histological association between melanocytic naevi and melanoma, Australas J. Dermatol., 31, 77, 10.1111/j.1440-0960.1990.tb00656.x

Bevona, 2003, Cutaneous melanomas associated with nevi, Arch. Dermatol., 139, 1620, 10.1001/archderm.139.12.1620

Miller, 2006, Melanoma, N. Engl. J. Med., 355, 51, 10.1056/NEJMra052166

Pollock, 2003, High frequency of Braf mutations in nevi, Nat. Genet., 33, 19, 10.1038/ng1054

Poynter, 2006, Braf and Nras mutations in melanoma and melanocytic nevi, Melanoma Res., 16, 267, 10.1097/01.cmr.0000222600.73179.f3

Chandeck, 2010, Oncogene-induced cellular senescence, Adv. Anat. Pathol., 17, 42, 10.1097/PAP.0b013e3181c66f4e

Tsao, 2003, The transformation rate of moles (melanocytic nevi) into cutaneous melanoma: A population-based estimate, Arch. Dermatol., 139, 282, 10.1001/archderm.139.3.282

Bennett, 2008, How to make a melanoma: What do we know of the primary clonal events?, Pigment Cell Melanoma Res., 21, 27, 10.1111/j.1755-148X.2007.00433.x

Charames, 2003, Genomic instability and cancer, Curr Mol Med, 3, 589, 10.2174/1566524033479456

Ossowski, 2010, Dormancy of metastatic melanoma, Pigment Cell Melanoma Res., 23, 41, 10.1111/j.1755-148X.2009.00647.x

Talmadge, 1982, Evidence for the clonal origin of spontaneous metastases, Science, 217, 361, 10.1126/science.6953592

Fidler, 1986, Evidence that intravenously derived murine pulmonary melanoma metastases can originate from the expansion of a single tumor cell, Cancer Res., 46, 5167

Tait, 2004, Do metastases metastasize?, J. Pathol., 203, 515, 10.1002/path.1544

Fidler, 1973, Selection of successive tumour lines for metastasis, Nat. New Biol., 242, 148, 10.1038/newbio242148a0

Fidler, 1977, Metastasis results from preexisting variant cells within a malignant tumor, Science, 197, 893, 10.1126/science.887927

Kozlowski, 1984, A human melanoma line heterogeneous with respect to metastatic capacity in athymic nude mice, J. Natl. Cancer. Inst., 72, 913

Wong, 2006, Lymphatic or hematogenous dissemination: How does a metastatic tumor cell decide?, Cell Cycle, 5, 812, 10.4161/cc.5.8.2646

Hanahan, 2000, The hallmarks of cancer, Cell, 100, 57, 10.1016/S0092-8674(00)81683-9

Fidler, 1970, Metastasis: Guantitative analysis of distribution and fate of tumor emboli labeled with 125 i-5-iodo-2'-deoxyuridine, J. Natl. Cancer Inst., 45, 773

Butler, 1975, Quantitation of cell shedding into efferent blood of mammary adenocarcinoma, Cancer Res., 35, 512

Virchow, 1989, Cellular pathologie, 1858, Nutr. Rev., 47, 23, 10.1111/j.1753-4887.1989.tb02747.x

Ewing, J. (1928). Neoplastic diseases: A treatise on tumors, WB Saunders. [3rd ed.].

Paget, 1889, The distribution of secondary growths in cancer of the breast, Lancet, 133, 571, 10.1016/S0140-6736(00)49915-0

Hart, 1980, Role of organ selectivity in the determination of metastatic patterns of B16 melanoma, Cancer Res., 40, 2281

Hess, 2006, Metastatic patterns in adenocarcinoma, Cancer, 106, 1624, 10.1002/cncr.21778

Edlund, 2004, Modulation of prostate cancer growth in bone microenvironments, J. Cell Biochem., 91, 686, 10.1002/jcb.10702

Bakalian, 2008, Molecular pathways mediating liver metastasis in patients with uveal melanoma, Clin. Cancer Res., 14, 951, 10.1158/1078-0432.CCR-06-2630

Logan, 2008, Single-cell tumor dormancy model of uveal melanoma, Clin. Exp. Metastasis, 25, 509, 10.1007/s10585-008-9158-2

Pidhorecky, 2001, Risk factors for nodal recurrence after lymphadenectomy for melanoma, Ann. Surg. Oncol., 8, 109, 10.1007/s10434-001-0109-2

Balch, 1993, Efficacy of 2-cm surgical margins for intermediate-thickness melanomas (1 to 4 mm). Results of a multi-institutional randomized surgical trial, Ann. Surg., 218, 262, 10.1097/00000658-199309000-00005

Balch, 2009, Final version of 2009 AJCC melanoma staging and classification, J. Clin. Oncol., 27, 6199, 10.1200/JCO.2009.23.4799

Balch, C.M., Houghton, A.N., Sober, A.J., and Soong, S. (2003). Cutaneous Melanoma, Quality Medical Publishing. [4th edition].

McCarthy, 1988, Time and frequency of recurrence of cutaneous stage I malignant melanoma with guidelines for follow-up study, Surg. Gynecol. Obstet., 166, 497

Schultz, 1990, Time to recurrence varies inversely with thickness in clinical stage 1 cutaneous melanoma, Surg. Gynecol. Obstet., 171, 393

Nathanson, 2003, Insights into the mechanisms of lymph node metastasis, Cancer, 98, 413, 10.1002/cncr.11464

Wong, 2006, Melanoma patients with positive sentinel nodes who did not undergo completion lymphadenectomy: A multi-institutional study, Ann. Surg. Oncol., 13, 809, 10.1245/ASO.2006.03.058

Kingham, 2010, Outcome of patients with a positive sentinel lymph node who do not undergo completion lymphadenectomy, Ann. Surg. Oncol., 17, 514, 10.1245/s10434-009-0836-3

Gimotty, 2004, Thin primary cutaneous malignant melanoma: A prognostic tree for 10-year metastasis is more accurate than American Joint Committee on Cancer staging, J. Clin. Oncol., 22, 3668, 10.1200/JCO.2004.12.015

Wolf, 2004, Locoregional cutaneous metastases of malignant melanoma and their management, Dermatol. Surg., 30, 244

Patel, 1978, Metastatic pattern of malignant melanoma. A study of 216 autopsy cases, Am. J. Surg., 135, 807, 10.1016/0002-9610(78)90171-X

Crowley, 1990, Late recurrence of malignant melanoma. Analysis of 168 patients, Ann. Surg., 212, 173, 10.1097/00000658-199008000-00010

Slingluff, 1992, The annual risk of melanoma progression. Implications for the concept of cure, Cancer, 70, 1917, 10.1002/1097-0142(19921001)70:7<1917::AID-CNCR2820700719>3.0.CO;2-5

Shen, 2000, Can elective lymph node dissection decrease the frequency and mortality rate of late melanoma recurrences?, Ann. Surg. Oncol., 7, 114, 10.1007/s10434-000-0114-x

Tsao, 1997, Ultra-late recurrence (15 years or longer) of cutaneous melanoma, Cancer, 79, 2361, 10.1002/(SICI)1097-0142(19970615)79:12<2361::AID-CNCR10>3.0.CO;2-P

Nguyen, 2009, Metastasis: From dissemination to organ-specific colonization, Nat. Rev. Cancer, 9, 274, 10.1038/nrc2622

Fisher, 1959, Experimental evidence in support of the dormant tumor cell, Science, 130, 918, 10.1126/science.130.3380.918

Demicheli, 2001, Tumour dormancy: Findings and hypotheses from clinical research on breast cancer, Semin. Cancer Biol., 11, 297, 10.1006/scbi.2001.0385

Hendrix, 2007, Reprogramming metastatic tumour cells with embryonic microenvironments, Nat. Rev. Cancer, 7, 246, 10.1038/nrc2108

Parlakian, 2010, Skeletal muscle phenotypically converts and selectively inhibits metastatic cells in mice, PLoS One, 5, e9299, 10.1371/journal.pone.0009299

Hill, 1998, Fas and Fas ligand interactions suppress melanoma lung metastasis, J. Exp. Med., 188, 1717, 10.1084/jem.188.9.1717

Pantel, 2004, Dissecting the metastatic cascade, Nat. Rev. Cancer, 4, 448, 10.1038/nrc1370

Wikman, 2008, Cancer micrometastasis and tumour dormancy, APMIS, 116, 754, 10.1111/j.1600-0463.2008.01033.x

Pantel, 2009, Cancer micrometastases, Nat. Rev. Clin. Oncol., 6, 339, 10.1038/nrclinonc.2009.44

Liu, 2002, EGFR is a transducer of the urokinase receptor initiated signal that is required for in vivo growth of a human carcinoma, Cancer Cell, 1, 445, 10.1016/S1535-6108(02)00072-7

Wall, 2007, The cyclin-dependent kinase inhibitors p15Ink4b and p21Cip1 are critical regulators of fibrillar collagen-induced tumor cell cycle arrest, J. Biol. Chem., 282, 24471, 10.1074/jbc.M702697200

Mahnke, 2005, Maintenance of long-term tumour-specific T-cell memory by residual dormant tumour cells, Immunology, 115, 325, 10.1111/j.1365-2567.2005.02163.x

Koebel, 2007, Adaptive immunity maintains occult cancer in an equilibrium state, Nature, 450, 903, 10.1038/nature06309

Kirkin, 1998, The immunogenic properties of melanoma-associated antigens recognized by cytotoxic T lymphocytes, Exp. Clin. Immunogenet., 15, 19, 10.1159/000019050

Umansky, 2008, Melanoma-specific memory T cells are functionally active in Ret transgenic mice without macroscopic tumors, Cancer Res., 68, 9451, 10.1158/0008-5472.CAN-08-1464

Lengagne, 2008, Distinct role for CD8 T cells toward cutaneous tumors and visceral metastases, J. Immunol., 180, 130, 10.4049/jimmunol.180.1.130

Eyles, 2010, Tumor cells disseminate early, but immunosurveillance limits metastatic outgrowth, in a mouse model of melanoma, J. Clin. Invest., 120, 2030, 10.1172/JCI42002

Hollenbeak, 2005, Increased incidence of melanoma in renal transplantation recipients, Cancer, 104, 1962, 10.1002/cncr.21404

Moloney, 2006, A population-based study of skin cancer incidence and prevalence in renal transplant recipients, Br. J. Dermatol., 154, 498, 10.1111/j.1365-2133.2005.07021.x

Strauss, 2010, Transmission of donor melanoma by organ transplantation, Lancet Oncol., 11, 790, 10.1016/S1470-2045(10)70024-3

Kauffman, 2007, Deceased donors with a past history of malignancy: An organ procurement and transplantation network/united network for organ sharing update, Transplantation, 84, 272, 10.1097/01.tp.0000267919.93425.fb

Folkman, 2002, Role of angiogenesis in tumor growth and metastasis, Semin. Oncol., 29, 15, 10.1053/sonc.2002.37263

Holmgren, 1995, Dormancy of micrometastases: Balanced proliferation and apoptosis in the presence of angiogenesis suppression, Nat. Med., 1, 149, 10.1038/nm0295-149

Naumov, 2006, Role of angiogenesis in human tumor dormancy: Animal models of the angiogenic switch, Cell Cycle, 5, 1779, 10.4161/cc.5.16.3018

Barnhill, 1998, Tumor vascularity, proliferation, and apoptosis in human melanoma micrometastases and macrometastases, Arch. Dermatol., 134, 991, 10.1001/archderm.134.8.991

Kienast, 2010, Real-time imaging reveals the single steps of brain metastasis formation, Nat. Med., 16, 116, 10.1038/nm.2072

Cameron, 2000, Temporal progression of metastasis in lung: Cell survival, dormancy, and location dependence of metastatic inefficiency, Cancer Res., 60, 2541

Sang, 2008, Control of the reversibility of cellular quiescence by the transcriptional repressor Hes1, Science, 321, 1095, 10.1126/science.1155998

Rocken, 2010, Early tumor dissemination, but late metastasis: Insights into tumor dormancy, J. Clin. Invest., 120, 1800, 10.1172/JCI43424

Eskelin, 2000, Tumor doubling times in metastatic malignant melanoma of the uvea: Tumor progression before and after treatment, Ophthalmology, 107, 1443, 10.1016/S0161-6420(00)00182-2

Callejo, 2007, Identification of circulating malignant cells and its correlation with prognostic factors and treatment in uveal melanoma. A prospective longitudinal study, Eye (Lond.), 21, 752, 10.1038/sj.eye.6702322

Schuster, 2007, Circulating tumor cells as prognostic factor for distant metastases and survival in patients with primary uveal melanoma, Clin. Cancer Res., 13, 1171, 10.1158/1078-0432.CCR-06-2329

Bowden, 1963, Malignant melanoma of unknown primary origin, Surg. Gynecol. Obstet., 117, 341

Giuliano, 1980, Clinical aspects of unknown primary melanoma, Ann. Surg., 191, 98, 10.1097/00000658-198001000-00018

Reintgen, 1983, Metastatic malignant melanoma with an unknown primary, Surg. Gynecol. Obstet., 156, 335

Stewart, 1931, Neurogenic sarcoma, Am. J. Cancer, 25, 1

Johnson, 1969, Benign nevus cells in the capsule of lymph nodes, Cancer, 23, 747, 10.1002/1097-0142(196903)23:3<747::AID-CNCR2820230331>3.0.CO;2-9

Ridolfi, 1977, Nevus cell aggregates associated with lymph nodes: Estimated frequency and clinical significance, Cancer, 39, 164, 10.1002/1097-0142(197701)39:1<164::AID-CNCR2820390127>3.0.CO;2-T

Baisden, 2000, HMB-45 immunohistochemical staining of sentinel lymph nodes: A specific method for enhancing detection of micrometastases in patients with melanoma, Am. J. Surg. Pathol., 24, 1140, 10.1097/00000478-200008000-00012

Holt, 2004, Nodal melanocytic nevi in sentinel lymph nodes. Correlation with melanoma-associated cutaneous nevi, Am. J. Clin. Pathol., 121, 58, 10.1309/Y5QAD623MYA21PUY

McCarthy, 1974, Naevus cells in lymph nodes, Pathology, 6, 351, 10.3109/00313027409077346

Carson, 1996, Nodal nevi and cutaneous melanomas, Am. J. Surg. Pathol., 20, 834, 10.1097/00000478-199607000-00006

Fisher, 1994, Benign lymph node inclusions mimicking metastatic carcinoma, J. Clin. Pathol., 47, 245, 10.1136/jcp.47.3.245

Bautista, 1994, Benign melanocytic nevus cells in axillary lymph nodes. A prospective incidence and immunohistochemical study with literature review, Am. J. Clin. Pathol., 102, 102, 10.1093/ajcp/102.1.102

Bieligk, 1999, Detection of Tyrosinase mRNA by reverse transcription-polymerase chain reaction in melanoma sentinel nodes, Ann. Surg. Oncol., 6, 232, 10.1007/s10434-999-0232-z

Starz, 2003, Tyrosinase RT-PCR as a supplement to histology for detecting melanoma and nevus cells in paraffin sections of sentinel lymph nodes, Mod. Pathol., 16, 920, 10.1097/01.MP.0000086074.55963.24

Taube, 2009, Benign nodal nevi frequently harbor the activating V600E Braf mutation, Am. J. Surg. Pathol., 33, 568, 10.1097/PAS.0b013e31818a64fb

Pinzani, 2010, Circulating benign nevus cells detected by ISET technique: Warning for melanoma molecular diagnosis, Arch. Dermatol., 146, 1120

Podsypanina, 2008, Seeding and propagation of untransformed mouse mammary cells in the lung, Science, 321, 1841, 10.1126/science.1161621

Awonuga, 2010, Pathogenesis of benign metastasizing leiomyoma: A review, Obstet. Gynecol. Surv., 65, 189, 10.1097/OGX.0b013e3181d60f93

Kopp, 2005, The bone marrow vascular niche: Home of HSC differentiation and mobilization, Physiology (Bethesda), 20, 349

Paku, 2000, Organ-specificity of the extravasation process: An ultrastructural study, Clin. Exp. Metastasis, 18, 481, 10.1023/A:1011858925376

Lalor, 2006, Human hepatic sinusoidal endothelial cells can be distinguished by expression of phenotypic markers related to their specialised functions in vivo, World J. Gastroenterol., 12, 5429, 10.3748/wjg.v12.i34.5429

Nicolson, 1988, Organ specificity of tumor metastasis: Role of preferential adhesion, invasion and growth of malignant cells at specific secondary sites, Cancer Metastasis Rev., 7, 143, 10.1007/BF00046483

Pasqualini, 1996, Organ targeting in vivo using phage display peptide libraries, Nature, 380, 364, 10.1038/380364a0

Schluter, 2006, Organ-specific metastatic tumor cell adhesion and extravasation of colon carcinoma cells with different metastatic potential, Am. J. Pathol., 169, 1064, 10.2353/ajpath.2006.050566

Rajotte, 1998, Molecular heterogeneity of the vascular endothelium revealed by in vivo phage display, J. Clin. Invest., 102, 430, 10.1172/JCI3008

Fidler, 1990, Host and tumour factors in cancer metastasis, Eur. J. Clin. Invest., 20, 481, 10.1111/j.1365-2362.1990.tb01889.x

Luzzi, 1998, Multistep nature of metastatic inefficiency: Dormancy of solitary cells after successful extravasation and limited survival of early micrometastases, Am. J. Pathol., 153, 865, 10.1016/S0002-9440(10)65628-3

Zlotnik, 2006, The chemokine and chemokine receptor superfamilies and their molecular evolution, Genome Biol., 7, 243, 10.1186/gb-2006-7-12-243

Richmond, 2009, The good and the bad of chemokines/chemokine receptors in melanoma, Pigment Cell Melanoma Res., 22, 175, 10.1111/j.1755-148X.2009.00554.x

Muller, 2001, Involvement of chemokine receptors in breast cancer metastasis, Nature, 410, 50, 10.1038/35065016

Wang, 2005, Chemokine receptor 7 activates phosphoinositide-3 kinase-mediated invasive and prosurvival pathways in head and neck cancer cells independent of EGFR, Oncogene, 24, 5897, 10.1038/sj.onc.1208740

Wittekind, 2000, Diagnosis and staging of lymph node metastasis, Recent Results Cancer Res., 157, 20, 10.1007/978-3-642-57151-0_3

Parker, 1996, Cancer statistics, 1996, CA Cancer J. Clin., 46, 5, 10.3322/canjclin.46.1.5

Dessureault, 2001, Improved staging of node-negative patients with intermediate to thick melanomas (>1 mm) with the use of lymphatic mapping and sentinel lymph node biopsy, Ann. Surg. Oncol., 8, 766, 10.1007/s10434-001-0766-1

Karkkainen, 2002, Lymphatic endothelium: A new frontier of metastasis research, Nat. Cell. Biol., 4, E2, 10.1038/ncb0102-e2

Dadras, 2003, Tumor lymphangiogenesis: A novel prognostic indicator for cutaneous melanoma metastasis and survival, Am. J. Pathol., 162, 1951, 10.1016/S0002-9440(10)64328-3

Jeltsch, 1997, Hyperplasia of lymphatic vessels in VEGF-C transgenic mice, Science, 276, 1423, 10.1126/science.276.5317.1423

Farzad, 1990, Lymphocyte subset alterations in nodes regional to human melanoma, Cancer Res., 50, 3585

Cochran, 2001, Sentinel lymph nodes show profound downregulation of antigen-presenting cells of the paracortex: Implications for tumor biology and treatment, Mod. Pathol., 14, 604, 10.1038/modpathol.3880358

Essner, 2006, Experimental frontiers for clinical applications: Novel approaches to understanding mechanisms of lymph node metastases in melanoma, Cancer Metastasis Rev., 25, 257, 10.1007/s10555-006-8506-4

Zhang, 2011, Chronic alcohol consumption decreases the percentage and number of NK cells in the peripheral lymph nodes and exacerbates B16BL6 melanoma metastasis into the draining lymph nodes, Cell Immunol., 266, 172, 10.1016/j.cellimm.2010.10.001

Haigh, 2001, Carbon dye histologically confirms the identity of sentinel lymph nodes in cutaneous melanoma, Cancer, 92, 535, 10.1002/1097-0142(20010801)92:3<535::AID-CNCR1352>3.0.CO;2-3

Nowecki, 2008, Sentinel node tumor burden according to the rotterdam criteria is the most important prognostic factor for survival in melanoma patients: A multicenter study in 388 patients with positive sentinel nodes, Ann. Surg., 248, 949, 10.1097/SLA.0b013e31818fefe0

Schmitz, 2010, Eortc melanoma group sentinel node protocol identifies high rate of submicrometastases according to rotterdam criteria, Eur. J. Cancer., 46, 2414, 10.1016/j.ejca.2010.06.003

Wiley, 2001, Expression of CC chemokine receptor-7 and regional lymph node metastasis of B16 murine melanoma, J. Natl. Cancer Inst., 93, 1638, 10.1093/jnci/93.21.1638

Takeuchi, 2004, Ccl21 chemokine regulates chemokine receptor Ccr7 bearing malignant melanoma cells, Clin. Cancer Res., 10, 2351, 10.1158/1078-0432.CCR-03-0195

Shields, 2007, Chemokine-mediated migration of melanoma cells towards lymphatics--a mechanism contributing to metastasis, Oncogene, 26, 2997, 10.1038/sj.onc.1210114

Hoon, 2006, Molecular mechanisms of metastasis, Cancer Metastasis Rev., 25, 203, 10.1007/s10555-006-8500-x

Kawada, 2004, Pivotal role of Cxcr3 in melanoma cell metastasis to lymph nodes, Cancer Res., 64, 4010, 10.1158/0008-5472.CAN-03-1757

Harpole, 1992, Analysis of 945 cases of pulmonary metastatic melanoma, J. Thorac. Cardiovasc. Surg., 103, 743, 10.1016/S0022-5223(19)34957-8

Barth, 1995, Prognostic factors in 1,521 melanoma patients with distant metastases, J. Am. Coll. Surg., 181, 193

Damsky, 2010, Mouse melanoma models and cell lines, Pigment Cell Melanoma Res., 23, 853, 10.1111/j.1755-148X.2010.00777.x

Johnson, 1991, Endothelial cell membrane vesicles in the study of organ preference of metastasis, Cancer Res., 51, 394

Zhu, 1991, Mediation of lung metastasis of murine melanomas by a lung-specific endothelial cell adhesion molecule, Proc. Natl. Acad. Sci. USA, 88, 9568, 10.1073/pnas.88.21.9568

Cheng, 2001, The breast cancer beta 4 integrin and endothelial human Clca2 mediate lung metastasis, J. Biol. Chem., 276, 25438, 10.1074/jbc.M100478200

Dittmar, 2008, Adhesion molecules and chemokines: The navigation system for circulating tumor (stem) cells to metastasize in an organ-specific manner, Clin. Exp. Metastasis, 25, 11, 10.1007/s10585-007-9095-5

Gassmann, 2004, Role of tumor cell adhesion and migration in organ-specific metastasis formation, Onkologie, 27, 577

Hynes, 2002, Integrins: Bidirectional, allosteric signaling machines, Cell, 110, 673, 10.1016/S0092-8674(02)00971-6

Pinon, P., and Wehrle-Haller, B. (2010). Integrins: Versatile receptors controling melanocyte adhesion, migration and proliferation. Pigment Cell Melanoma Res.

Bartolome, 2009, The chemokine receptor Cxcr4 and the metalloproteinase Mt1-Mmp are mutually required during melanoma metastasis to lungs, Am. J. Pathol., 174, 602, 10.2353/ajpath.2009.080636

Murakami, 2002, Expression of CXC chemokine receptor-4 enhances the pulmonary metastatic potential of murine B16 melanoma cells, Cancer Res., 62, 7328

Cardones, 2003, Cxcr4 enhances adhesion of B16 tumor cells to endothelial cells in vitro and in vivo via beta(1) integrin, Cancer Res., 63, 6751

Kim, 2006, Chemokine receptor Cxcr4 expression in patients with melanoma and colorectal cancer liver metastases and the association with disease outcome, Ann. Surg., 244, 113, 10.1097/01.sla.0000217690.65909.9c

Kim, 2008, Inhibition of the Cxcr4/Cxcl12 chemokine pathway reduces the development of murine pulmonary metastases, Clin. Exp. Metastasis, 25, 201, 10.1007/s10585-007-9133-3

Tucci, 2007, Involvement of E-cadherin, beta-catenin, Cdc42 and Cxcr4 in the progression and prognosis of cutaneous melanoma, Br. J. Dermatol., 157, 1212, 10.1111/j.1365-2133.2007.08246.x

Platta, 2010, Current treatment strategies for brain metastasis and complications from therapeutic techniques: A review of current literature, Am. J. Clin. Oncol., 33, 398, 10.1097/COC.0b013e318194f744

Budman, 1978, The current causes of death in patients with malignant melanoma, Eur. J. Cancer, 14, 327, 10.1016/0014-2964(78)90201-3

Balch, 1983, A multifactorial analysis of melanoma. IV. Prognostic factors in 200 melanoma patients with distant metastases (stage III), J. Clin. Oncol., 1, 126, 10.1200/JCO.1983.1.2.126

Moore, 1983, Patterned distribution of metastases from malignant melanoma in humans, Cancer Res., 43, 3427

Palmieri, 2007, The biology of metastasis to a sanctuary site, Clin. Cancer Res., 13, 1656, 10.1158/1078-0432.CCR-06-2659

Madajewicz, 1984, Malignant melanoma brain metastases. Review of Roswell Park Memorial Institute experience, Cancer, 53, 2550, 10.1002/1097-0142(19840601)53:11<2550::AID-CNCR2820531129>3.0.CO;2-B

Sampson, 1998, Demographics, prognosis, and therapy in 702 patients with brain metastases from malignant melanoma, J. Neurosurg., 88, 11, 10.3171/jns.1998.88.1.0011

Fidler, 1999, The biology of melanoma brain metastasis, Cancer Metastasis Rev., 18, 387, 10.1023/A:1006329410433

Zhang, 2009, Transforming growth factor-beta2 is a molecular determinant for site-specific melanoma metastasis in the brain, Cancer Res., 69, 828, 10.1158/0008-5472.CAN-08-2588

Menter, 1995, The role of trophic factors and autocrine/paracrine growth factors in brain metastasis, Clin. Exp. Metastasis, 13, 67, 10.1007/BF00133612

Denkins, 2004, Brain metastases in melanoma: Roles of neurotrophins, Neuro. Oncol., 6, 154, 10.1215/S115285170300067X

Nicolson, 1996, Brain metastasis: Role of trophic, autocrine, and paracrine factors in tumor invasion and colonization of the central nervous system, Curr. Top. Microbiol. Immunol., 213(Pt 2), 89

Marchetti, 1993, Nerve growth factor effects on human and mouse melanoma cell invasion and heparanase production, Int. J. Cancer, 55, 692, 10.1002/ijc.2910550430

Marchetti, 1996, Neurotrophin stimulation of human melanoma cell invasion: Selected enhancement of heparanase activity and heparanase degradation of specific heparan sulfate subpopulations, Cancer Res., 56, 2856

Vlodavsky, 2001, Molecular properties and involvement of heparanase in cancer metastasis and angiogenesis, J. Clin. Invest., 108, 341, 10.1172/JCI13662

Ridgway, 2010, Modulation of Gef-H1 induced signaling by heparanase in brain metastatic melanoma cells, J. Cell Biochem., 111, 1299, 10.1002/jcb.22854

Izraely, 2010, Chemokine-chemokine receptor axes in melanoma brain metastasis, Immunol. Lett., 130, 107, 10.1016/j.imlet.2009.12.003

Xie, 2006, Activation of Stat3 in human melanoma promotes brain metastasis, Cancer Res., 66, 3188, 10.1158/0008-5472.CAN-05-2674

Perides, 2006, The fibrinolytic system facilitates tumor cell migration across the blood-brain barrier in experimental melanoma brain metastasis, BMC Cancer, 6, 56, 10.1186/1471-2407-6-56

Brasfield, 1964, Metastatic melanoma: A clinicopathological study, Cancer, 17, 1323, 10.1002/1097-0142(196410)17:10<1323::AID-CNCR2820171015>3.0.CO;2-N

Lee, 1980, Malignant melanoma: Patterns of metastasis, CA Cancer J. Clin., 30, 137, 10.3322/canjclin.30.3.137

Song, 1997, Liver metastasis formation by Laminin-1 peptide (lqvqlsir)-adhesion selected B16-F10 melanoma cells, Int. J. Cancer, 71, 436, 10.1002/(SICI)1097-0215(19970502)71:3<436::AID-IJC22>3.0.CO;2-C

Fantuzzi, 2000, IL-18 regulates IL-1beta-dependent hepatic melanoma metastasis via vascular cell adhesion molecule-1, Proc. Natl. Acad. Sci. USA, 97, 734, 10.1073/pnas.97.2.734

Carrascal, 2003, Interleukin-18 binding protein reduces B16 melanoma hepatic metastasis by neutralizing adhesiveness and growth factors of sinusoidal endothelium, Cancer Res., 63, 491

Fon, 1981, Skeletal metastases of melanoma: Radiographic, scintigraphic, and clinical review, AJR Am. J. Roentgenol., 137, 103, 10.2214/ajr.137.1.103

Stewart, 1978, Skeletal metastases of melanoma, J. Bone Joint Surg. Am., 60, 645, 10.2106/00004623-197860050-00009

Mohammad, K.S., Javelaud, D., Fournier, P.G., Niewolna, M., McKenna, C.R., Peng, X.H., Duong, V., Dunn, L.K., Mauviel, A., and Guise, T.A. (2010). The transforming growth factor-{beta} receptor I kinase inhibitor SD-208 reduces the development and progression of melanoma bone metastases. Cancer Res.

Finck, 1983, Ldh and melanoma, Cancer, 51, 840, 10.1002/1097-0142(19830301)51:5<840::AID-CNCR2820510516>3.0.CO;2-7

Feun, 1982, The natural history of resectable metastatic melanoma (stage IVa melanoma), Cancer, 50, 1656, 10.1002/1097-0142(19821015)50:8<1656::AID-CNCR2820500833>3.0.CO;2-L

Morales, 1999, Ctack, a skin-associated chemokine that preferentially attracts skin-homing memory T cells, Proc. Natl. Acad. Sci. USA, 96, 14470, 10.1073/pnas.96.25.14470

Murakami, 2003, Immune evasion by murine melanoma mediated through CC chemokine receptor-10, J. Exp. Med., 198, 1337, 10.1084/jem.20030593

Murakami, 2004, Chemokine receptors and melanoma metastasis, J Dermatol. Sci., 36, 71, 10.1016/j.jdermsci.2004.03.002

Simonetti, 2006, Potential role of Ccl27 and Ccr10 expression in melanoma progression and immune escape, Eur. J. Cancer, 42, 1181, 10.1016/j.ejca.2006.01.043

2008, Organ selectivity in metastasis: Regulation by chemokines and their receptors, Clin. Exp. Metastasis, 25, 345, 10.1007/s10585-007-9097-3

Amersi, 2008, Activation of Ccr9/Ccl25 in cutaneous melanoma mediates preferential metastasis to the small intestine, Clin. Cancer Res., 14, 638, 10.1158/1078-0432.CCR-07-2025

Duband, 1995, Epithelium-mesenchyme transition during neural crest development, Acta. Anat. (Basel), 154, 63, 10.1159/000147752

Kalluri, 2009, The basics of epithelial-mesenchymal transition, J. Clin. Invest., 119, 1420, 10.1172/JCI39104

Tarin, 2005, The fallacy of epithelial mesenchymal transition in neoplasia, Cancer Res., 65, 5996, 10.1158/0008-5472.CAN-05-0699

Talmadge, 2010, AACR centennial series: The biology of cancer metastasis: Historical perspective, Cancer Res., 70, 5649, 10.1158/0008-5472.CAN-10-1040

Tsuji, 2009, Epithelial-mesenchymal transition and cell cooperativity in metastasis, Cancer Res., 69, 7135, 10.1158/0008-5472.CAN-09-1618

Yilmaz, 2010, Mechanisms of motility in metastasizing cells, Mol. Cancer Res., 8, 629, 10.1158/1541-7786.MCR-10-0139

Palmieri, 2009, Main roads to melanoma, J. Transl. Med., 7, 86, 10.1186/1479-5876-7-86

Kuphal, 2009, Recent progress in understanding the pathology of malignant melanoma, J. Pathol., 219, 400, 10.1002/path.2617

Nash, 2007, Requirement of Kiss1 secretion for multiple organ metastasis suppression and maintenance of tumor dormancy, J. Natl. Cancer Inst., 99, 309, 10.1093/jnci/djk053

Xu, 2006, Gpr56, an atypical G protein-coupled receptor, binds tissue transglutaminase, Tg2, and inhibits melanoma tumor growth and metastasis, Proc. Natl. Acad. Sci. USA, 103, 9023, 10.1073/pnas.0602681103

Shevde, 2002, Suppression of human melanoma metastasis by the metastasis suppressor gene, Brms1, Exp. Cell Res., 273, 229, 10.1006/excr.2001.5452

Kim, 2006, Comparative oncogenomics identifies Nedd9 as a melanoma metastasis gene, Cell, 125, 1269, 10.1016/j.cell.2006.06.008

Kang, 2003, A multigenic program mediating breast cancer metastasis to bone, Cancer Cell, 3, 537, 10.1016/S1535-6108(03)00132-6

Minn, 2005, Genes that mediate breast cancer metastasis to lung, Nature, 436, 518, 10.1038/nature03799

Bos, 2009, Genes that mediate breast cancer metastasis to the brain, Nature, 459, 1005, 10.1038/nature08021

Nguyen, 2009, Wnt/Tcf signaling through Lef1 and Hoxb9 mediates lung adenocarcinoma metastasis, Cell, 138, 51, 10.1016/j.cell.2009.04.030

Kabbarah, 2010, Integrative genome comparison of primary and metastatic melanomas, PLoS One, 5, e10770, 10.1371/journal.pone.0010770

Bittner, 2000, Molecular classification of cutaneous malignant melanoma by gene expression profiling, Nature, 406, 536, 10.1038/35020115

Winnepenninckx, 2006, Melanoma Group of the European Organization for R.; Treatment of C. Gene expression profiling of primary cutaneous melanoma and clinical outcome, J. Natl. Cancer Inst., 98, 472, 10.1093/jnci/djj103

John, 2008, Predicting clinical outcome through molecular profiling in stage III melanoma, Clin. Cancer Res., 14, 5173, 10.1158/1078-0432.CCR-07-4170

Jonsson, 2010, Gene expression profiling-based identification of molecular subtypes in stage IV melanomas with different clinical outcome, Clin. Cancer Res., 16, 3356, 10.1158/1078-0432.CCR-09-2509

Timar, 2010, Gene signature of the metastatic potential of cutaneous melanoma: Too much for too little?, Clin. Exp. Metastasis, 27, 371, 10.1007/s10585-010-9307-2

Pleasance, 2010, A comprehensive catalogue of somatic mutations from a human cancer genome, Nature, 463, 191, 10.1038/nature08658

Harbour, 2010, Frequent mutation of Bap1 in metastasizing uveal melanomas, Science, 3, 1410, 10.1126/science.1194472

Chin, 2006, Malignant melanoma: Genetics and therapeutics in the genomic era, Genes Dev., 20, 2149, 10.1101/gad.1437206

Davies, 2002, Mutations of the Braf gene in human cancer, Nature, 417, 949, 10.1038/nature00766

Dhomen, 2009, Braf signaling and targeted therapies in melanoma, Hematol. Oncol. Clin. North Am., 23, 529, 10.1016/j.hoc.2009.04.001

Ugurel, 2007, B-raf and N-ras mutations are preserved during short time in vitro propagation and differentially impact prognosis, PLoS One, 2, e236, 10.1371/journal.pone.0000236

Akslen, 2005, Braf and Nras mutations are frequent in nodular melanoma but are not associated with tumor cell proliferation or patient survival, J. Invest. Dermatol., 125, 312, 10.1111/j.0022-202X.2005.23788.x

Egyhazi, 2006, Nras and Braf mutations in melanoma tumours in relation to clinical characteristics: A study based on mutation screening by pyrosequencing, Melanoma Res., 16, 471, 10.1097/01.cmr.0000232300.22032.86

Sharma, 2006, Targeting mitogen-activated protein kinase/extracellular signal-regulated kinase kinase in the mutant (V600E) B-raf signaling cascade effectively inhibits melanoma lung metastases, Cancer Res., 66, 8200, 10.1158/0008-5472.CAN-06-0809

Oler, 2008, Gene expression profiling of papillary thyroid carcinoma identifies transcripts correlated with Braf mutational status and lymph node metastasis, Clin. Cancer Res., 14, 4735, 10.1158/1078-0432.CCR-07-4372

Basolo, 2010, Correlation between the Braf V600E mutation and tumor invasiveness in papillary thyroid carcinomas smaller than 20 millimeters: Analysis of 1060 cases, J. Clin. Endocrinol. Metab., 95, 4197, 10.1210/jc.2010-0337

Rozenberg, 2010, Metastasis in an orthotopic murine model of melanoma is independent of Ras/Raf mutation, Melanoma Res., 20, 361, 10.1097/CMR.0b013e328336ee17

Guldberg, 1997, Disruption of the Mmac1/Pten gene by deletion or mutation is a frequent event in malignant melanoma, Cancer Res., 57, 3660

Tsao, 1998, Identification of Pten/Mmac1 alterations in uncultured melanomas and melanoma cell lines, Oncogene, 16, 3397, 10.1038/sj.onc.1201881

Forbes, S.A., Bhamra, G., Bamford, S., Dawson, E., Kok, C., Clements, J., Menzies, A., Teague, J.W., Futreal, P.A., and Stratton, M.R. (2008). The catalogue of somatic mutations in cancer (cosmic). Curr. Protoc. Hum. Genet., Chapter 10, Unit 10 11.

Zhou, 2000, Epigenetic Pten silencing in malignant melanomas without Pten mutation, Am. J. Pathol., 157, 1123, 10.1016/S0002-9440(10)64627-5

Mirmohammadsadegh, 2006, Epigenetic silencing of the Pten gene in melanoma, Cancer Res., 66, 6546, 10.1158/0008-5472.CAN-06-0384

Stewart, 2002, PI3 kinase blockade by Ad-Pten inhibits invasion and induces apoptosis in RGP and metastatic melanoma cells, Mol. Med., 8, 451, 10.1007/BF03402025

Dankort, 2009, Braf(V600E) cooperates with Pten loss to induce metastatic melanoma, Nat. Genet., 41, 544, 10.1038/ng.356

Nogueira, 2010, Cooperative interactions of Pten deficiency and Ras activation in melanoma metastasis, Oncogene, 29, 6222, 10.1038/onc.2010.349

Reya, 2001, Stem cells, cancer, and cancer stem cells, Nature, 414, 105, 10.1038/35102167

Dalerba, 2007, Cancer stem cells: Models and concepts, Annu. Rev. Med., 58, 267, 10.1146/annurev.med.58.062105.204854

Quintana, 2008, Efficient tumour formation by single human melanoma cells, Nature, 456, 593, 10.1038/nature07567

Schatton, 2008, Identification of cells initiating human melanomas, Nature, 451, 345, 10.1038/nature06489

Held, 2010, Characterization of melanoma cells capable of propagating tumors from a single cell, Cancer Res., 70, 388, 10.1158/0008-5472.CAN-09-2153

Boiko, 2010, Human melanoma-initiating cells express neural crest nerve growth factor receptor CD271, Nature, 466, 133, 10.1038/nature09161

Roesch, 2010, A temporarily distinct subpopulation of slow-cycling melanoma cells is required for continuous tumor growth, Cell, 141, 583, 10.1016/j.cell.2010.04.020

Quintana, 2010, Phenotypic heterogeneity among tumorigenic melanoma cells from patients that is reversible and not hierarchically organized, Cancer Cell, 18, 510, 10.1016/j.ccr.2010.10.012

Mani, 2008, The epithelial-mesenchymal transition generates cells with properties of stem cells, Cell, 133, 704, 10.1016/j.cell.2008.03.027

Garzon, 2009, MicroRNAs in cancer, Annu. Rev. Med., 60, 167, 10.1146/annurev.med.59.053006.104707

Ma, 2007, Tumour invasion and metastasis initiated by microRNA-10b in breast cancer, Nature, 449, 682, 10.1038/nature06174

Segura, 2009, Aberrant miR-182 expression promotes melanoma metastasis by repressing Foxo3 and microphthalmia-associated transcription factor, Proc. Natl. Acad. Sci. USA, 106, 1814, 10.1073/pnas.0808263106

Bemis, 2008, MicroRNA-137 targets microphthalmia-associated transcription factor in melanoma cell lines, Cancer Res., 68, 1362, 10.1158/0008-5472.CAN-07-2912

Felicetti, 2008, The promyelocytic leukemia zinc finger-microRNA-221/-222 pathway controls melanoma progression through multiple oncogenic mechanisms, Cancer Res., 68, 2745, 10.1158/0008-5472.CAN-07-2538

Schultz, 2008, MicroRNA let-7b targets important cell cycle molecules in malignant melanoma cells and interferes with anchorage-independent growth, Cell Res., 18, 549, 10.1038/cr.2008.45

Eichten, 2006, Paradoxical roles of the immune system during cancer development, Nat. Rev. Cancer, 6, 24, 10.1038/nrc1782

Melnikova, 2009, Inflammation and melanoma metastasis, Pigment Cell Melanoma Res., 22, 257, 10.1111/j.1755-148X.2009.00570.x

DeNardo, 2010, Interactions between lymphocytes and myeloid cells regulate pro- versus anti-tumor immunity, Cancer Metastasis Rev., 29, 309, 10.1007/s10555-010-9223-6

Qian, 2010, Macrophage diversity enhances tumor progression and metastasis, Cell, 141, 39, 10.1016/j.cell.2010.03.014

Brauer, 2010, Characteristics associated with early and late melanoma metastases, Cancer, 116, 415, 10.1002/cncr.24724

Alexandrescu, 2010, Immunotherapy for melanoma: Current status and perspectives, J. Immunother., 33, 570, 10.1097/CJI.0b013e3181e032e8

Lee, 2007, Microenvironmental influences in melanoma progression, J. Cell. Biochem., 101, 862, 10.1002/jcb.21204

Kaplan, 2005, Vegfr1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche, Nature, 438, 820, 10.1038/nature04186

Kaplan, 2006, Bone marrow cells in the ‘pre-metastatic niche’: Within bone and beyond, Cancer Metastasis Rev., 25, 521, 10.1007/s10555-006-9036-9

Geiger, 2009, Metastasis mechanisms, Biochim. Biophys. Acta, 1796, 293

Damsky, W.E., Jr.; Bosenberg, M. Department of Dermatology, Yale School of Medicine. Unpublished data, 2010.