HomeList of TitleSearchContact Us
Open Journal of Hematology

ISSN: 2075-907X
Volume 3, 2012

Cell metastasis in Melanoma

Patrick A. Ott1, *, F. Stephen Hodi2, **
1 Division of Medical Oncology, Department of Medicine, New York University School of Medicine, New York University Cancer Institute, New York, NY, USA
2 Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA

DOI: 10.13055/ojhmt_3_S1_06.120221

Corresponding Address:
* Division of Medical Oncology, Department of Medicine, New York University School of Medicine, New York University Cancer Institute, New York, NY, USA; Email: patrick.ott@nyumc.org
** Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA; Email: stephen_hodi@dfci.harvard.edu


Cutaneous melanoma stands out as a model disease on which to study tumor progression and metastasis for several reasons. If undetected or diagnosed late, melanoma is a highly invasive tumor and almost invariably leads to metastatic spread. It tends to metastasize at a time when the tumor burden is low compared to other cancers, which is evident by the size (thickness) of the primary tumor being measured in millimeters. The fact that the majority of the almost 70,000 new melanomas diagnosed in the United States every year are detected when they are still curable, is presumably largely owed to its prominent site of origin, the skin. As a consequence, tissue from early stages of tumor development is relatively easily available for analysis, allowing for the investigation of the whole spectrum of tumor progression and the metastatic process in humans.

It is somewhat surprising that comparative genomic approaches to date have not yet consistently identified gene signatures reflecting genes or gene sets that are associated with metastasis or prognosis of melanoma. Nevertheless, tremendous progress has been made in recent years identifying mechanisms leading to metastasis in melanoma. In this review, we highlight some of the key molecules and pathways that have been discovered as drivers of metastatic progression in this disease.

© Ott et al.; licensee Ross Science Publishers
open-access license: ROSS Open Access articles will be distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc/3.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided that the original work will always be cited properly.

Article Processing History:
Receiving date: 29-12-2011
Acceptance date: 21-2-2012
Electronic publication date: 21-2-2012
Year of Publication: 2012


The incidence of melanoma continues to rise and it is expected that in 2011 almost 9,000 patients will die from this disease in the United States [1]. Despite recent exciting progress in the treatment of patients with advanced melanoma, such as the use of agents targeting oncogenic driver mutations and antibodies blocking immune-checkpoints such as CTLA-4 [2-4], the prognosis of most patients remains poor once the tumor has metastasized to distant organs. Most melanomas initially progress from an in situ to a radial growth phase (horizontal spread of small cell clusters within the epidermis and papillary dermis), subsequently to a vertical growth phase (vertical spread of nodules of tumor cells into the papillary dermis, reticular dermis, or subcutaneous tissue), which is associated with a higher tendency for metastatic spread. While many melanoma patients with metastases to the regional lymph node basin are still curable by surgical resection, lymph node metastasis is associated with increased risk for distant metastases and significantly decreased overall survival [5]. Metastasis is therefore the key prognostic factor limiting outcome in melanoma patients. As a result, it is critical to understand the molecular mechanisms that are responsible for the metastatic behavior of melanoma cells.

Organ-specific metastasis is guided by many different molecular mechanisms. The long-held view that only a small fraction of a primary melanoma has the potential for metastasis, has been called into question in recent years based on molecular profiling of tumors that identified gene signatures in primary tumors that are correlated with the probability of metastatic spread [6]. Several characteristics are required for the capacity of tumor cells to metastasize: motility, the ability to invade the adjacent tissue and enter into the circulation, to survive the transit, re-entry into tissue at a distant site, and colonize a distant organ while evading tumor surveillance [7]. In this mini-review we discuss recently described key pathways and molecules operational in the metastatic behavior of melanoma cells.

Gene expression profiling

Different comparative genomic approaches such as microarray analysis, real-time PCR, and next generation sequencing have been employed to define transcriptional signatures of melanoma progression and metastasis. A large-scale gene expression analysis in melanoma was performed on melanoma cell lines with low versus high metastatic potential and identified differences in genes playing a role in extracellular matrix assembly and regulation of the actin-based cytoskeleton [8]. Gene expression profiling of primary melanomas and metastases from different sites using biostatistical and functional analyses revealed different gene clusters linked to melanoma aggressiveness, many genes also involved in the regulation of the cytoskeleton and the extracellular matrix [9]. More recently, gene expression profiling of more than one hundred primary melanomas revealed a set of 254 genes that were linked to the development of metastases. Many of the genes identified are coding for molecules that are members of functional groups such as cell cycle regulation, mitosis, and DNA replication [10]. Distinct gene expression signatures for different stages of melanoma progression have also been identified by comparative gene expression analysis of primary melanoma versus metastatic tissue, benign melanocytic nevi, and different subtypes of melanomas [11-12]. Of note, gene expression signatures observed in metastatic melanoma tissue were found in melanoma primaries of different origin, suggesting that metastatic signatures can be imprinted in the primary tumor, a notion that is different from the concept that only a small number of clones within a primary tumor have the ability to metastasize [11]. Nevertheless, the identification of a consistent, reproducible prognostic or metastatic gene signature has so far been elusive in melanoma. With rare exceptions, no overlapping genes have been reported in microarray studies published to date. Potential reasons for this include the heterogeneity of analyzed tissue (poorly characterized or mixed histology of primary tumors), variable sites of metastases, differing array platforms and biostatistical approaches, insufficient clinical annotation of samples, small patient cohorts, and lack of validation on independent data sets [13].


Human chemokines are a superfamily of secreted receptor ligands with many functions, most prominently the ability to induce cell migration. Chemokines or their receptors have been implicated in the control of metastatic spread, directing tumor cells towards specific tissues [14-17]. CXCR4 is widely expressed on many different cancers and the CXCL12–CXCR4 axis has been found to be of particular relevance for tumor cell migration to the lung, liver, and bone marrow [18]. CXCL12, the unique ligand for CXCR4, is highly expressed at sites of melanoma metastasis [19]. CXCR4 expression of primary melanomas was found to be associated with decreased time to progression and survival [20]; CXCR4 was also expressed in more than 50% of human melanoma metastases [21]. Even early in melanoma metastases from sentinel lymph nodes, CXCR4 expression was correlated with an increased risk for progression [22]. Transfection of the murine B16 melanoma line with CCR4 leads to increased metastases to the lung [23]. The adhesion of CXCR4 expressing B16 melanoma cells to endothelial cells was shown to be mediated in vitro and in vivo via beta 1 integrin through CXCL12 [24].

In addition to the CXCL12-CXCR4 axis, other chemokines contribute to site-specific melanoma metastasis. CCR7 has been demonstrated to directly control melanoma cell migration to the lymph nodes. A non-metastatic mouse melanoma line that did not express chemokine receptors metastasized to the lymph node upon transfection with CCR7 [25]. In B16 murine melanoma, there is evidence that CCR10 promotes lymph node metastasis, possibly by enhanced survival of melanoma cells in the lymph node because of immune evasion [26].

In humans, the CCR9/CCL25 axis was recently found to be critical in the migration of melanoma cells to the small intestine, potentially explaining the relatively high incidence of this somewhat unusual metastatic site for solid tumors that occurs more commonly in melanoma patients [27]. In this study, 88 of 102 (86.3%) patients with small bowel metastases expressed CCR9 as measured by qRT-PCR, whereas no CCR9 expression was detected in any of the 96 distant metastases from other sites. In a separate study, 64% of patients with expression of CCR9 in their primary melanomas and 45% of patients with expression of CCR9 in locoregional lymph node metastases ultimately developed small bowel metastases, suggesting that small bowel metastasis could be predicted by RT-PCR or immunohistochemistry (IHC) for CCR9 at an early stage in these patients [28].


The alteration of microRNA (miRNA) profiles is an attractive concept to account for metastatic potential of tumor cells, because miRNAs can control multiple target genes simultaneously. As a consequence, different cellular processes can be affected by one miRNA [29]. MiRNA signatures have been identified by expression profiling of different tumors and associated with tumor stage and prognosis [30]. Relatively high expression levels of miR-30b and -30d were recently found in metastatic melanoma tissue from 59 patients by miRNA array analysis and RT-PCR validation [31]. Of note, in a subset of 17 paired samples from the same patient, both miRNAs were significantly overexpressed in the metastatic tissue compared to the primary tumor. Furthermore, miR-30b and -30d expression in melanoma primaries was correlated with tumor thickness, nodular (more invasive) tumor type, and the rate of metastasis. Importantly, overexpression of miR-30d/30b increased melanoma invasiveness in vitro and metastatic potential in vivo in a B16 melanoma mouse model, whereas miR-30d/30b silencing produced the opposite effects. The effect was mediated predominantly by the GalNAc transferase GALNT7. Importantly, miR-30b/30d-mediated repression of GALNT7 resulted in increased production of the immunosuppressive cytokine IL-10 with accumulation of T-regulatory cells and decreased recruitment of CD3+ T cells, suggesting that miR-30b/30d-GALNT7 might be mechanistically involved in the immunosuppressive milieu of melanoma metastases.

Conversely, another miRNA, miR-211, whose expression is restricted to the melanocyte lineage, was recently linked to decreased invasiveness and reduced migration of melanoma cells. IGF2R, TGFBR2, and NFAT5, whose role in melanomagenesis had been previously established, demonstrated inversely correlated expression with miR-211 and were identified as miR-211 biological target genes [32].


Tumor cells have the ability to disrupt the physiologically tight control of extracellular matrix proteases, allowing for proteolytic activity on basement membranes and extracellular matrices. The activity of matrix metalloproteinases (MMP) has been associated with cancer metastasis and results not only in increased tissue invasion, but also in the generation of bioactive peptides. One of these peptides, cryptic collagen epitope HU177, has been related to angiogenesis and tumor growth in vivo [33]. Increased serum titers against HU177 in patients with primary melanomas have been associated with increased tumor thickness, increased recurrence rates, and poor survival, suggesting its likely relevance in the metastatic process [34-35].

Both MMP-8 and MMP-27 are frequently mutated in melanoma; wild-type MMP-8 is associated with decreased melanoma progression suggesting that it is a tumor suppressor gene [36]. MMP-19 expression correlates with increased invasion, migratory behavior and early metastasis of melanoma cells, whereas MMP-9 expression was decreased with increasing thickness of melanomas [37-38]. MMP-1 and MMP-2 have also been linked to melanoma progression [39-40] Interestingly, MMP-2 specific CD4+ T cells, exhibiting a detrimental inflammatory Th2 profile (secreting mainly TNF-α, IL-4, and Il-13) were recently found in tumor infiltrating lymphocytes of melanoma patients [41]. Comprehensive mutational analysis of another metalloproteinase family, ADAMTS, found that ADAMTS-18 is highly mutated in melanoma patients and linked to increased proliferation, cell migration, and metastasis [42].


TGF-beta is secreted by tumor cells and different cell types within the tumor microenvironment and promotes invasion and metastasis through various auto- and paracrine loops (in contrast to its anti-proliferative, tumor suppressive role in early carcinogenesis) [43]. It induces epithelial mesenchymal transition, leading to tumor invasion and ultimately metastasis through changes in the expression of cell-cell adhesion molecules and the activity of metalloproteinases [44]. Increased TGF-beta 1 and 2 plasma levels have been found in patients with metastatic melanoma. TGF-beta signaling through the Smad pathway has been linked to increased extracellular matrix invasiveness, increased anchorage independent growth, and the production of pro-metastatic molecules such as osteopontin, IL-11, and CXCR-4. The transcription factor GLI2, whose activation to a great extent depends on autocrine TGF-beta signaling, was recently found to mediate critical steps in melanoma progression, such as loss of E-cadherin and transition to N-cadherin expression, mesenchymal transition, and increased invasiveness of melanoma cells [45]. Since GLI2 is a critical substrate that is necessary for response of the hedgehog (HH) pathway, cross-talk between the TGF-beta and HH pathways may induce a positive feedback loop, promoting tumor progression and metastasis [46]. TGF-beta leads to MMP-2 upregulation in several cancers and expression of the two proteins has been found to be correlated in plasma from advanced melanoma patients [47]. Intravital imaging and microarray analysis of B16 melanoma tumors demonstrated that TGF-beta signaling can reverse features that are characteristics of differentiated melanocytes and increase cell motility [48].

Melanoma metastasis and embryonic development

Increasing evidence for a link between embryonic development and metastasis has recently emerged in melanoma. Several melanocyte developmental transcription factors, such as TWIST, YANG, SLUG, and MITF, have been found to be critically important for metastatic progression in this disease. MITF is a member of the micropthalmia-related transcription factors which are important for growth, differentiation, expression of melanogenic enzymes, and survival of melanocytes. It is considered a lineage-specific master regulator of melanocytic differentiation. In melanoma, it was identified as a “lineage addiction” oncogene and found to be amplified in 10-20% of melanomas [49-50]. MITF amplification correlated with BRAF mutation, p16 inactivation, and was found to be more common in metastatic melanoma. It was also linked to decreased overall survival of melanoma patients. The contrasting roles of MITF in melanocytes versus tumor cells remain largely unexplained. The “phenotype switching” model attempts to reconcile the contrasting MITF activities by linking two distinct transcriptional melanoma cell signatures with either high MITF expression (proliferative) versus low MITF expression (invasive) [51].

Nodal, a member of the TGF-beta superfamily, was recently identified as a signaling pathway in melanoma that is linked to an aggressive phenotype. Inhibiting Nodal signaling reduced invasiveness of melanoma cells as well as their ability to form vascular networks on a three-dimensional collagen matrix. Furthermore, Nodal was expressed in 60% of human melanoma skin metastases, whereas it was absent in the primary tumors as measured by IHC [52]. The prominence of this pathway at the interface of embryonic and tumorigenic pathways also underscores the importance of the TGF-beta superfamily in the metastatic process of melanoma [52].

A comparative oncogenomics approach was used to identify NEDD9 (Neural precursor cell expressed, developmentally downregulated), a member of the family of adapter molecules, as an important melanoma metastasis gene [53-54]. The Nedd9 protein is a component of the focal adhesion complex, which is critical for cell invasion and was shown to play an important role in cell invasion and the development of metastases in melanoma. Using quantitative RT-PCR and IHC on tissue microarrays, overexpression of NEDD9 at the transcript and protein levels was confirmed in 35%–52% of human metastatic melanomas.

Most recently, in a conditional melanoma mouse model based on melanocyte-specific PTEN loss and the BRAFV600E activating mutation, the β-catenin/wnt signaling pathway was identified as a critical mediator of metastasis [55]. Importantly, the genetic alterations and cellular phenotypes studied in this mouse model were very similar to human melanoma.


In conclusion, the spectrum of biological processes and molecules implicated in melanoma cell metastasis is extensive. Gene expression profiling studies of primary and metastatic melanomas including a recent meta-analysis have not produced a uniform signature that would be suitable as a predictive or prognostic marker. Future approaches in this arena need to control more stringently for homogeneous clinicopathological staging of the patient cohorts under investigation, consistently include independent validation cohorts, and provide sufficient clinical outcome data. Rapidly evolving new technologies such as comparative genomic approaches and the identification of new classes of molecules such as miRNAs have lead to the discovery of novel molecules, many of whom are potential drug targets or candidates for biomarkers. Unexpected associations such as the role of matrix metalloproteinases in the immune response to melanoma open up potential new avenues for therapeutic intervention. Further advancement in our understanding of melanoma genomic alterations interactions with host factors in the tumor microenvironment such as immune responses will provide additional opportunities for therapeutic intervention.


The authors have no conflict of interest.


[1] SEER Cancer Statistics Review. National Cancer Institute. . 2011
[2] Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, Dummer R, Garbe C, Testori A, Maio M, Hogg D, Lorigan P, Lebbe C, Jouary T, Schadendorf D, Ribas A, O'Day SJ, Sosman JA, Kirkwood JM, Eggermont AM, Dreno B, Nolop K, Li J, Nelson B, Hou J, Lee RJ, Flaherty KT, McArthur GA. BRIM-3 Study Group. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011; 364: 2507–16. [PMID: 21639808] [PMCID: PMC3549296] [DOI: 10.1056/NEJMoa1103782]
[3] Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, Akerley W, van den Eertwegh AJ, Lutzky J, Lorigan P, Vaubel JM, Linette GP, Hogg D, Ottensmeier CH, Lebbé C, Peschel C, Quirt I, Clark JI, Wolchok JD, Weber JS, Tian J, Yellin MJ, Nichol GM, Hoos A, Urba WJ. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010; 363: 711–23. [PMID: 20525992] [PMCID: PMC3549297] [DOI: 10.1056/NEJMoa1003466]
[4] Robert C, Thomas L, Bondarenko I, O'Day S, Weber J, Garbe C, Lebbe C, Baurain JF, Testori A, Grob JJ, Davidson N, Richards J, Maio M, Hauschild A, Miller WH Jr, Gascon P, Lotem M, Harmankaya K, Ibrahim R, Francis S, Chen TT, Humphrey R, Hoos A, Wolchok JD. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011; 364: 2517–26. [PMID: 21639810] [DOI: 10.1056/NEJMoa1104621]
[5] Dickson PV, Gershenwald JE. Staging and prognosis of cutaneous melanoma. Surg Oncol Clin N Am. 2011; 20: 1–17. [PMID: 21111956] [PMCID: PMC3221385] [DOI: 10.1016/j.soc.2010.09.007]
[6] Weigelt B, Peterse JL, van 't Veer LJ. Breast cancer metastasis: markers and models. Nat Rev Cancer. 2005; 5: 591–602. [PMID: 16056258] [DOI: 10.1038/nrc1670]
[7] Fidler IJ. The pathogenesis of cancer metastasis: the 'seed and soil' hypothesis revisited. Nat Rev Cancer. 2003; 3: 453–8. [PMID: 12778135] [DOI: 10.1038/nrc1098]
[8] Clark EA, Golub TR, Lander ES, Hynes RO. Genomic analysis of metastasis reveals an essential role for RhoC. Nature. 2000; 406: 532–5. [PMID: 10952316] [DOI: 10.1038/35020106]
[9] Bittner M, Meltzer P, Chen Y, Jiang Y, Seftor E, Hendrix M, Radmacher M, Simon R, Yakhini Z, Ben-Dor A, Sampas N, Dougherty E, Wang E, Marincola F, Gooden C, Lueders J, Glatfelter A, Pollock P, Carpten J, Gillanders E, Leja D, Dietrich K, Beaudry C, Berens M, Alberts D, Sondak V. Molecular classification of cutaneous malignant melanoma by gene expression profiling. Nature. 2000; 406: 536–40. [PMID: 10952317] [DOI: 10.1038/35020115]
[10] Winnepenninckx V, Lazar V, Michiels S, Dessen P, Stas M, Alonso SR, Avril MF, Ortiz Romero PL, Robert T, Balacescu O, Eggermont AM, Lenoir G, Sarasin A, Tursz T, van den Oord JJ, Spatz A. Melanoma Group of the European Organization for Research and Treatment of Cancer. Gene expression profiling of primary cutaneous melanoma and clinical outcome. J Natl Cancer Inst. 2006; 98: 472–82. [PMID: 16595783] [DOI: 10.1093/jnci/djj103]
[11] Haqq C, Nosrati M, Sudilovsky D, Crothers J, Khodabakhsh D, Pulliam BL, Federman S, Miller JR 3rd, Allen RE, Singer MI, Leong SP, Ljung BM, Sagebiel RW, Kashani-Sabet M. The gene expression signatures of melanoma progression. Proc Natl Acad Sci U S A. 2005; 102: 6092–7. [PMID: 15833814] [PMCID: PMC1087936] [DOI: 10.1073/pnas.0501564102]
[12] Jaeger J, Koczan D, Thiesen HJ, Ibrahim SM, Gross G, Spang R, Kunz M. Gene expression signatures for tumor progression, tumor subtype, and tumor thickness in laser-microdissected melanoma tissues. Clin Cancer Res. 2007; 13: 806–15. [PMID: 17289871] [DOI: 10.1158/1078-0432.CCR-06-1820]
[13] Tímár J, Gyorffy B, Rásó E. Gene signature of the metastatic potential of cutaneous melanoma: too much for too little?. Clin Exp Metastasis. 2010; 27: 371–87. [PMID: 20177751] [DOI: 10.1007/s10585-010-9307-2]
[14] Balkwill F. The significance of cancer cell expression of the chemokine receptor CXCR4. Semin Cancer Biol. 2004; 14: 171–9. [PMID: 15246052] [DOI: 10.1016/j.semcancer.2003.10.003]
[15] Balkwill F. Cancer and the chemokine network. Nat Rev Cancer. 2004; 4: 540–50. [PMID: 15229479] [DOI: 10.1038/nrc1388]
[16] Moser B, Wolf M, Walz A, Loetscher P. Chemokines: multiple levels of leukocyte migration control. Trends Immunol. 2004; 25: 75–84. [PMID: 15102366] [DOI: 10.1016/j.it.2003.12.005]
[17] Zlotnik A. Chemokines in neoplastic progression. Semin Cancer Biol. 2004; 14: 181–5. [PMID: 15246053] [DOI: 10.1016/j.semcancer.2003.10.004]
[18] Zlotnik A, Burkhardt AM, Homey B. Homeostatic chemokine receptors and organ-specific metastasis. Nat Rev Immunol. 2011; 11: 597–606. [PMID: 21866172] [DOI: 10.1038/nri3049]
[19] Müller A, Homey B, Soto H, Ge N, Catron D, Buchanan ME, McClanahan T, Murphy E, Yuan W, Wagner SN, Barrera JL, Mohar A, Verástegui E, Zlotnik A. Involvement of chemokine receptors in breast cancer metastasis. Nature. 2001; 410: 50–6. [PMID: 11242036] [DOI: 10.1038/35065016]
[20] Scala S, Ottaiano A, Ascierto PA, Cavalli M, Simeone E, Giuliano P, Napolitano M, Franco R, Botti G, Castello G. Expression of CXCR4 predicts poor prognosis in patients with malignant melanoma. Clin Cancer Res. 2005; 11: 1835–41. [PMID: 15756007] [DOI: 10.1158/1078-0432.CCR-04-1887]
[21] Scala S, Giuliano P, Ascierto PA, Ieranò C, Franco R, Napolitano M, Ottaiano A, Lombardi ML, Luongo M, Simeone E, Castiglia D, Mauro F, De Michele I, Calemma R, Botti G, Caracò C, Nicoletti G, Satriano RA, Castello G. Human melanoma metastases express functional CXCR4. Clin Cancer Res. 2006; 12: 2427–33. [PMID: 16638848] [DOI: 10.1158/1078-0432.CCR-05-1940]
[22] Franco R, Cantile M, Scala S, Catalano E, Cerrone M, Scognamiglio G, Pinto A, Chiofalo MG, Caracò C, Anniciello AM, Abbruzzese A, Caraglia M, Botti G. Histomorphologic parameters and CXCR4 mRNA and protein expression in sentinel node melanoma metastasis are correlated to clinical outcome. Cancer Biol Ther. 2010; 9: 423–9. [PMID: 20061818] [DOI: 10.4161/cbt.9.6.10996]
[23] Murakami T, Maki W, Cardones AR, Fang H, Tun Kyi A, Nestle FO, Hwang ST. Expression of CXC chemokine receptor-4 enhances the pulmonary metastatic potential of murine B16 melanoma cells. Cancer Res. 2002; 62: 7328–34. [PMID: 12499276]
[24] Cardones AR, Murakami T, Hwang ST. CXCR4 enhances adhesion of B16 tumor cells to endothelial cells in vitro and in vivo via beta(1) integrin. Cancer Res. 2003; 63: 6751–7. [PMID: 14583470]
[25] Wiley HE, Gonzalez EB, Maki W, Wu MT, Hwang ST. Expression of CC chemokine receptor-7 and regional lymph node metastasis of B16 murine melanoma. J Natl Cancer Inst. 2001; 93: 1638–43. [PMID: 11698568] [DOI: 10.1093/jnci/93.21.1638]
[26] Murakami T, Cardones AR, Finkelstein SE, Restifo NP, Klaunberg BA, Nestle FO, Castillo SS, Dennis PA, Hwang ST. Immune evasion by murine melanoma mediated through CC chemokine receptor-10. J Exp Med. 2003; 198: 1337–47. [PMID: 14581607] [PMCID: PMC2194242] [DOI: 10.1084/jem.20030593]
[27] Amersi FF, Terando AM, Goto Y, Scolyer RA, Thompson JF, Tran AN, Faries MB, Morton DL, Hoon DS. Activation of CCR9/CCL25 in cutaneous melanoma mediates preferential metastasis to the small intestine. Clin Cancer Res. 2008; 14: 638–45. [PMID: 18245522] [PMCID: PMC2760931] [DOI: 10.1158/1078-0432.CCR-07-2025]
[28] van den Oord J. The CCR9-CCL25 axis mediates melanoma metastasis to the small intestine. Nat Clin Pract Oncol. 2008; 5: 440–1. [PMID: 18577981] [DOI: 10.1038/ncponc1174]
[29] Gupta GP, Massagué J. Cancer metastasis: building a framework. Cell. 2006; 127: 679–95. [PMID: 17110329] [DOI: 10.1016/j.cell.2006.11.001]
[30] Calin GA, Croce CM. MicroRNA signatures in human cancers. Nat Rev Cancer. 2006; 6: 857–66. [PMID: 17060945] [DOI: 10.1038/nrc1997]
[31] Segura MF, Belitskaya-Lévy I, Rose AE, Zakrzewski J, Gaziel A, Hanniford D, Darvishian F, Berman RS, Shapiro RL, Pavlick AC, Osman I, Hernando E. Melanoma MicroRNA signature predicts post-recurrence survival. Clin Cancer Res. 2010; 16: 1577–86. [PMID: 20179230] [DOI: 10.1158/1078-0432.CCR-09-2721]
[32] Levy C, Khaled M, Iliopoulos D, Janas MM, Schubert S, Pinner S, Chen PH, Li S, Fletcher AL, Yokoyama S, Scott KL, Garraway LA, Song JS, Granter SR, Turley SJ, Fisher DE, Novina CD. Intronic miR-211 assumes the tumor suppressive function of its host gene in melanoma. Mol Cell. 2010; 40: 841–9. [PMID: 21109473] [PMCID: PMC3004467] [DOI: 10.1016/j.molcel.2010.11.020]
[33] Cretu A, Roth JM, Caunt M, Akalu A, Policarpio D, Formenti S, Gagne P, Liebes L, Brooks PC. Disruption of endothelial cell interactions with the novel HU177 cryptic collagen epitope inhibits angiogenesis. Clin Cancer Res. 2007; 13: 3068–78. [PMID: 17505010] [DOI: 10.1158/1078-0432.CCR-06-2342]
[34] Hamilton HK, Rose AE, Christos PJ, Shapiro RL, Berman RS, Mazumdar M, Ma MW, Krich D, Liebes L, Brooks PC, Osman I. Increased shedding of HU177 correlates with worse prognosis in primary melanoma. J Transl Med. 2010; 8: 19. [PMID: 20178639] [PMCID: PMC2837640] [DOI: 10.1186/1479-5876-8-19]
[35] Ng B, Zakrzewski J, Warycha M, Christos PJ, Bajorin DF, Shapiro RL, Berman RS, Pavlick AC, Polsky D, Mazumdar M, Montgomery A, Liebes L, Brooks PC, Osman I. Shedding of distinct cryptic collagen epitope (HU177) in sera of melanoma patients. Clin Cancer Res. 2008; 14: 6253–8. [PMID: 18829505] [DOI: 10.1158/1078-0432.CCR-07-4992]
[36] Palavalli LH, Prickett TD, Wunderlich JR, Wei X, Burrell AS, Porter-Gill P, Davis S, Wang C, Cronin JC, Agrawal NS, Lin JC, Westbroek W, Hoogstraten-Miller S, Molinolo AA, Fetsch P, Filie AC, O'Connell MP, Banister CE, Howard JD, Buckhaults P, Weeraratna AT, Brody LC, Rosenberg SA, Samuels Y. Analysis of the matrix metalloproteinase family reveals that MMP8 is often mutated in melanoma. Nat Genet. 2009; 41: 518–20. [PMID: 19330028] [PMCID: PMC2748394] [DOI: 10.1038/ng.340]
[37] Müller M, Beck IM, Gadesmann J, Karschuk N, Paschen A, Proksch E, Djonov V, Reiss K, Sedlacek R. MMP19 is upregulated during melanoma progression and increases invasion of melanoma cells. Mod Pathol. 2010; 23: 511–21. [PMID: 20098411] [DOI: 10.1038/modpathol.2009.183]
[38] Simonetti O, Lucarini G, Brancorsini D, Nita P, Bernardini ML, Biagini G, Offidani A. Immunohistochemical expression of vascular endothelial growth factor, matrix metalloproteinase 2, and matrix metalloproteinase 9 in cutaneous melanocytic lesions. Cancer. 2002; 95: 1963–70. [PMID: 12404291] [DOI: 10.1002/cncr.10888]
[39] Airola K, Karonen T, Vaalamo M, Lehti K, Lohi J, Kariniemi AL, Keski-Oja J, Saarialho-Kere UK. Expression of collagenases-1 and -3 and their inhibitors TIMP-1 and -3 correlates with the level of invasion in malignant melanomas. Br J Cancer. 1999; 80: 733–43. [PMID: 10360651] [PMCID: PMC2362286] [DOI: 10.1038/sj.bjc.6690417]
[40] Hofmann UB, Westphal JR, Waas ET, Zendman AJ, Cornelissen IM, Ruiter DJ, van Muijen GN. Matrix metalloproteinases in human melanoma cell lines and xenografts: increased expression of activated matrix metalloproteinase-2 (MMP-2) correlates with melanoma progression. Br J Cancer. 1999; 81: 774–82. [PMID: 10555745] [PMCID: PMC2374291] [DOI: 10.1038/sj.bjc.6690763]
[41] Godefroy E, Manches O, Dréno B, Hochman T, Rolnitzky L, Labarrière N, Guilloux Y, Goldberg J, Jotereau F, Bhardwaj N. Matrix metalloproteinase-2 conditions human dendritic cells to prime inflammatory T(H)2 cells via an IL-12- and OX40L-dependent pathway. Cancer Cell. 2011; 19: 333–46. [PMID: 21397857] [PMCID: PMC3073826] [DOI: 10.1016/j.ccr.2011.01.037]
[42] Wei X, Prickett TD, Viloria CG, Molinolo A, Lin JC, Cardenas-Navia I, Cruz P, Rosenberg SA, Davies MA, Gershenwald JE, López-Otín C, Samuels Y. NISC Comparative Sequencing Program. Mutational and functional analysis reveals ADAMTS18 metalloproteinase as a novel driver in melanoma. Mol Cancer Res. 2010; 8: 1513–25. [PMID: 21047771] [PMCID: PMC3058631] [DOI: 10.1158/1541-7786.MCR-10-0262]
[43] Massagué J. TGFbeta in Cancer. Cell. 2008; 134: 215–30. [PMID: 18662538] [PMCID: PMC3512574] [DOI: 10.1016/j.cell.2008.07.001]
[44] Meulmeester E, Ten Dijke P. The dynamic roles of TGF-beta in cancer. J Pathol. 2011; 223: 205–18. [PMID: 20957627] [DOI: 10.1002/path.2785]
[45] Alexaki VI, Javelaud D, Van Kempen LC, Mohammad KS, Dennler S, Luciani F, Hoek KS, Juàrez P, Goydos JS, Fournier PJ, Sibon C, Bertolotto C, Verrecchia F, Saule S, Delmas V, Ballotti R, Larue L, Saiag P, Guise TA, Mauviel A. GLI2-mediated melanoma invasion and metastasis. J Natl Cancer Inst. 2010; 102: 1148–59. [PMID: 20660365] [PMCID: PMC2914763] [DOI: 10.1093/jnci/djq257]
[46] Javelaud D, Alexaki VI, Dennler S, Mohammad KS, Guise TA, Mauviel A. TGF-beta/SMAD/GLI2 signaling axis in cancer progression and metastasis. Cancer Res. 2011; 71: 5606–10. [PMID: 21862631] [PMCID: PMC3165102] [DOI: 10.1158/0008-5472.CAN-11-1194]
[47] Malaponte G, Zacchia A, Bevelacqua Y, Marconi A, Perrotta R, Mazzarino MC, Cardile V, Stivala F. Co-regulated expression of matrix metalloproteinase-2 and transforming growth factor-beta in melanoma development and progression. Oncol Rep. 2010; 24: 81–7. [PMID: 20514447] [DOI: 10.3892/or_00000831]
[48] Pinner S, Jordan P, Sharrock K, Bazley L, Collinson L, Marais R, Bonvin E, Goding C, Sahai E. Intravital imaging reveals transient changes in pigment production and Brn2 expression during metastatic melanoma dissemination. Cancer Res. 2009; 69: 7969–77. [PMID: 19826052] [PMCID: PMC2763120] [DOI: 10.1158/0008-5472.CAN-09-0781]
[49] Garraway LA, Widlund HR, Rubin MA, Getz G, Berger AJ, Ramaswamy S, Beroukhim R, Milner DA, Granter SR, Du J, Lee C, Wagner SN, Li C, Golub TR, Rimm DL, Meyerson ML, Fisher DE, Sellers WR. Integrative genomic analyses identify MITF as a lineage survival oncogene amplified in malignant melanoma. Nature. 2005; 436: 117–22. [PMID: 16001072] [DOI: 10.1038/nature03664]
[50] Weinstein IB, Joe AK. Mechanisms of disease: Oncogene addiction--a rationale for molecular targeting in cancer therapy. Nat Clin Pract Oncol. 2006; 3: 448–57. [PMID: 16894390] [DOI: 10.1038/ncponc0558]
[51] Hoek KS, Eichhoff OM, Schlegel NC, Döbbeling U, Kobert N, Schaerer L, Hemmi S, Dummer R. In vivo switching of human melanoma cells between proliferative and invasive states. Cancer Res. 2008; 68: 650–6. [PMID: 18245463] [DOI: 10.1158/0008-5472.CAN-07-2491]
[52] Topczewska JM, Postovit LM, Margaryan NV, Sam A, Hess AR, Wheaton WW, Nickoloff BJ, Topczewski J, Hendrix MJ. Embryonic and tumorigenic pathways converge via Nodal signaling: role in melanoma aggressiveness. Nat Med. 2006; 12: 925–32. [PMID: 16892036] [DOI: 10.1038/nm1448]
[53] Tomlins SA, Chinnaiyan AM. Of mice and men: cancer gene discovery using comparative oncogenomics. Cancer Cell. 2006; 10: 2–4. [PMID: 16843259] [DOI: 10.1016/j.ccr.2006.06.013]
[54] Kim M, Gans JD, Nogueira C, Wang A, Paik JH, Feng B, Brennan C, Hahn WC, Cordon-Cardo C, Wagner SN, Flotte TJ, Duncan LM, Granter SR, Chin L. Comparative oncogenomics identifies NEDD9 as a melanoma metastasis gene. Cell. 2006; 125: 1269–81. [PMID: 16814714] [DOI: 10.1016/j.cell.2006.06.008]
[55] Damsky WE, Curley DP, Santhanakrishnan M, Rosenbaum LE, Platt JT, Gould Rothberg BE, Taketo MM, Dankort D, Rimm DL, McMahon M, Bosenberg M. beta-Catenin Signaling Controls Metastasis in Braf-Activated Pten-Deficient Melanomas. Cancer Cell. 2011; 20: 741–54. [PMID: 22172720] [PMCID: PMC3241928] [DOI: 10.1016/j.ccr.2011.10.030]
2012 Ross Science Publishers