Melanoma Dissemination Research Articles

Melanoma stem cells and metastasis: mimicking hematopoietic cell trafficking?

Malignant melanoma is a highly metastatic cancer that bears responsibility for the majority of skin cancer-related deaths. Amidst the research efforts to better understand melanoma progression, there has been increasing evidence that hints at a role for a subpopulation of virulent cancer cells, termed malignant melanoma stem or initiating cells (MMICs), in metastasis formation. MMICs are characterized by their preferential ability to initiate and propagate tumor growth and their selective capacity for self-renewal and differentiation into less tumorigenic melanoma cells. The frequency of MMICs has been shown to correlate with poor clinical prognosis in melanoma. In addition, MMICs are enriched among circulating tumor cells in the peripheral blood of cancer patients, suggesting that MMICs may be a critical factor in the metastatic cascade. Although these links exist between MMICs and metastatic disease, the mechanisms by which MMICs may advance metastatic progression are only beginning to be elucidated. Recent studies have shown that MMICs express molecules critical for hematopoietic cell maintenance and trafficking, providing a possible explanation for how circulating MMICs could drive melanoma dissemination. We therefore propose that MMICs might fuel melanoma metastasis by exploiting homing mechanisms commonly utilized by hematopoietic cells. Here we review the biological properties of MMICs and the existing literature on their metastatic potential. We will discuss possible mechanisms by which MMICs might initiate metastases in the context of established knowledge of cancer stem cells in other cancers and of hematopoietic homing molecules, with a particular focus on selectins, integrins, chemokines and chemokine receptors known to be expressed by melanoma cells. Biological understanding of how these molecules might be utilized by MMICs to propel the metastatic cascade could critically impact the development of more effective therapies for advanced disease.

Predicting cell shapes in melanomas

Predicting cell shapes in melanomas

Circulating tumor DNA (ctDNA) in metastatic uveal melanoma (MUM): Correlation with outcome in 87 patients (pts) from Institut Curie

AbstractPurpose CtDNA can be detected in the plasma of MUM pts using a real‐time PCR based on the pyrophosphorolysis‐activated polymerization (bi‐PAP) targeting the most frequent GNAQ and GNA11 mutations present in 85% of UM (Madic et al, 2012).Methods May 2011‐March 2013:87 MUM pts were included in 3 prospective studies to assess the bi‐PAP assay and analyse clinical and outcome correlations.Results Median (med) age 57, primary tumor med diameter 15 mm; enucleation 32, proton beam 52, iodine disk 3. Enucleated eyes showed mostly mixed histotype and genomic high risk by array‐CGH: 8q gain and/or 3p loss. With a med disease free interval of 39 months (mo), 83 pts developed liver metastases first, with radiological miliary disease in 55; 4 had extra hepatic lesions without liver involvement. 35 pts were enrolled at the time of metastasis diagnostic. With a med follow‐up of 8 mo, 28 patients had disease progression and 34 died of metastasis. The med survival was 13 mo. Tumor samples were available in 82 pts, genotyping is ongoing for 8. GNAQ 626A>T or A>C, GNA11 626A>T and rare mutations were found in 9, 19, 26 is and 6 cases respectively; 14 were wild‐type tumors. CtDNA was detected in 51/54 samples (med 30 copies/ml, range 1‐11421) and correlated with the metastatic tumor burden as assessed by liver MRI (med 64 cm3, range 0.2‐7384). Correlation with progression‐free and overall survival will be presented.Conclusion ctDNA is a promising tool to assess the tumor burden and the micrometastatic dissemination of uveal melanoma, and a potential biomarker to evaluate the efficacy of targeted therapies in pts carrying GNA Q/11 mutated tumors.

Molecular Networks in Melanoma Invasion and Metastasis

Metastatic melanoma accounts for approximately 80% of skin cancer-related deaths. Up to now there has been no effective treatment for stage IV melanoma patients due to the complexity and dissemination potential of this disease. Melanomas are heterogeneous tumors in which conventional therapies fail to improve overall survival. Targeted therapies are being developed, but the final outcome can be hampered by the incomplete knowledge of the process of melanoma progression. Even if the intracellular pathways are similar, the interaction of the cells with the surrounding environment should be taken into consideration. This article seeks to highlight some of the advances in the understanding of the molecular mechanisms underlying melanoma dissemination.

OP218: Immunohistochemical profile of primary oral malignant melanomas

Purpose Primary oral melanoma is an uncommon malignant tumor of melanocytic origin, with potentially aggressive capacity. Several immunohistochemical markers influencing invasiveness and metastatic dissemination of melanoma have been identified and used previously. Our aim was to analyze the immunohistochemical expression for cathepsin-D, c-kit, E-cadherin, cyclin D1, and MUM-1 in oral malignant melanomas. Material and Methods Immunoperoxidase staining was performed on formalin-fixed tissue specimens from oral melanoma specimens and oral melanocytic nevi lesions which were used as control group. The percentages of immunoreactive melanocytes were estimated and qualitatively abnormal immunoreactivity patterns were also tabulated. Results Cathepsin-D, c-kit, cyclin D1, and MUM-1 were highly expressed in oral melanomas, whereas negative or very weak expression of the above mentioned markers was recorded in oral melanocytic nevi lesions. E-cadherin was expressed uniform throughout the entire oral melanocytic nevi, whereas oral melanomas expressed heterogeneous E-cadherin staining. Furthermore oral melanomas showed qualitatively and quantitavely abnormal E-cadherin immunoreactivity, with gradual loss of staining and increasing lesional depth. The results indicate that cathepsin-D, c-kit, E-cadherin, cyclin D1, and MUM-1 may be involved in the development of oral melanomas, and eventually they may be useful in the differential diagnosis of oral malignant melanomas and oral melanocytic nevi lesions. Conclusions The above mentioned markers seems to correlate with oral melanoma development and have an important functional role in tumor development or progression. Melanoma has a wide spectrum of histologic features which mimic epithelial, hematologic, mesenchymal, and neural tumors. Immunohistochemistry has been the primary tool to distinguish melanomas from these other tumors. Use of immunohistochemical markers should therefore give additional information which cannot be determined by routine histopathology.

Abstract 1558: Imaging of metastatic B16F10 melanoma in mice using tumor-homing stem cells.

Abstract Tumors, like wounds, recruit cells from surrounding tissues and bone marrow. Some of these cells provide support and nutrition, while others participate in an inflammatory response. Bone marrow mesenchymal stem cells (MSCs) exhibit this tropism toward wounds and other areas of pathology. Consequently, stem cell technology for diagnostic and therapeutic purposes is an emerging field in cancer biology. Like bone marrow MSCs, mouse neural progenitor cells (NPCs) tend to migrate toward cancer sites. We found that these cells migrate toward B16F10 lung melanomas, making them very good candidates for delivery of chemotherapeutic drugs, genes of interest, and imaging contrast agents. Among imaging techniques, bioluminescent imaging is non-invasive. Gaussia luciferase (Gluc) is particularly useful, as it is non-toxic and has stronger luminescence than other known luciferases. In the presence of its substrate coelenterazine (coel), Gluc luminescence peaks near 470 nm. In this study, we engineered NPCs to secrete Gluc. These Gluc-engineered cells were injected systemically to C57BL/6 mice bearing metastatic B16F10 lung melanoma and mice were given coel intravenously. Imaging of the mice on the Caliper IVIS Lumina II showed bioluminescence in disseminated areas. The distribution of bioluminescence suggested that the engineered NPCs migrated to the tumor sites and secreted Gluc. In confirmation, necropsy revealed black metastatic tumors in the locations emitting bioluminescence. Although IV injection of metastatic B16F10 lung melanoma cells usually generates lung tumors, we found dissemination of melanoma in other parts of the body. The Gluc-expressing NPCs could find the tumors as early as 2 days post tumor-cell injection, long before tumors were palpable. Thus, this system offers promise for improving cancer diagnosis. For improved imaging, this bioluminescence system can be coupled with other fluorescent dyes for red shifted output. Finally, the same sensitivity and tumor tropism suggests that the NPCs could be useful delivery cells for tumor-targeted therapeutics. Citation Format: Tej B. Shrestha, Sivasai Balivada, Matthew Basel, Marla Pyle, Stefan H. Bossmann, Deryl L. Troyer. Imaging of metastatic B16F10 melanoma in mice using tumor-homing stem cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1558. doi:10.1158/1538-7445.AM2013-1558

The Calpain/Calpastatin System Has Opposing Roles in Growth and Metastatic Dissemination of Melanoma

Conventional calpains are ubiquitous cysteine proteases whose activity is promoted by calcium signaling and specifically limited by calpastatin. Calpain expression has been shown to be increased in human malignant cells, but the contribution of the calpain/calpastatin system in tumorigenesis remains unclear. It may play an important role in tumor cells themselves (cell growth, migration, and a contrario cell death) and/or in tumor niche (tissue infiltration by immune cells, neo-angiogenesis). In this study, we have used a mouse model of melanoma as a tool to gain further understanding of the role of calpains in tumor progression. To determine the respective importance of each target, we overexpressed calpastatin in tumor and/or host in isolation. Our data demonstrate that calpain inhibition in both tumor and host blunts tumor growth, while paradoxically increasing metastatic dissemination to regional lymph nodes. Specifically, calpain inhibition in melanoma cells limits tumor growth in vitro and in vivo but increases dissemination by amplifying cell resistance to apoptosis and accelerating migration process. Meanwhile, calpain inhibition restricted to host cells blunts tumor infiltration by immune cells and angiogenesis required for antitumor immunity, allowing tumor cells to escape tumor niche and disseminate. The development of highly specific calpain inhibitors with potential medical applications in cancer should take into account the opposing roles of the calpain/calpastatin system in initial tumor growth and subsequent metastatic dissemination.

A Role for Jag2 in Promoting Uveal Melanoma Dissemination and Growth

Controlling the spread of uveal melanoma is key to improving survival of patients with this common intraocular malignancy. The Notch ligand Jag2 has been shown to be upregulated in primary tumors that metastasize, and we therefore investigated its role in promoting invasion and clonogenic growth of uveal melanoma cells. mRNA and protein expression of Notch pathway components were measured using qPCR and Western blot in uveal melanoma cell lines. Expression of Jag2 ligand was upregulated using Jag2-GFP-MSCV constructs or downregulated by sh-Jag2 in the uveal melanoma cell lines Mel285, Mel290, 92.1, and OMM1, and the effects on growth and invasion were assessed. Jag2 was introduced into Mel285 and Mel290 cells, which have low baseline levels of both this ligand and Notch activity. Overall growth of the Jag2-expressing cultures increased somewhat, and a significant 3-fold increase in clonogenic growth in soft agar was also noted. Introduction of Jag2 increased motility in both wound-healing and transwell invasion assays. We also observed a significant increase in Jag2 and Hes1 mRNA in invasive OMM1 cells that had passed through a Matrigel-coated filter in the transwell assay when compared with noninvading cells. Loss-of-function studies performed in 92.1 and OMM1 lines using Jag2 shRNAs showed that downregulation of the ligand significantly suppressed cellular growth, invasion, and migration. Our data suggest that Jag2 may play an important role in promoting Notch activity, growth, and metastasis in uveal melanoma.

Safety of Pars Plana Vitrectomy in Eyes With Plaque-Irradiated Posterior Uveal Melanoma

To determine the long-term safety of pars plana vitrectomy (PPV) in eyes with plaque-irradiated posterior uveal melanoma. In this retrospective case series, patients with plaque-irradiated posterior uveal melanoma subsequently underwent PPV for vitreous hemorrhage. The main outcome measures are the rates of intraocular melanoma dissemination, extrascleral extension of melanoma, local melanoma recurrence, and systemic melanoma metastasis after PPV. Forty-seven eyes of 47 patients underwent PPV for vitreous hemorrhage after iodine 125-labeled plaque radiotherapy for choroidal melanoma. The mean interval between the onset of vitreous hemorrhage and PPV was 13 (median, 10; range, 0-52) months. The mean time from PPV to last follow-up was 5 (range, 0.5-16) years. There were no cases of intraocular melanoma dissemination or extrascleral extension of melanoma. One patient (2%) developed local choroidal melanoma recurrence (2 years after PPV and 5 years after initial plaque radiotherapy) and was successfully managed with transpupillary thermotherapy. Systemic melanoma metastasis occurred in 4 patients (9%) during a mean interval of 5 years after plaque radiotherapy. During follow-up, 43 patients (91%) were alive without systemic metastasis and 4 patients (9%) were alive with metastasis. Management of vitreous hemorrhage by PPV in eyes with previously irradiated uveal melanoma appears to be safe and without increased risk for intraocular, local, orbital, or systemic dissemination of the tumor.

High endothelial venules (HEVs) in human melanoma lesions

The presence of tumor-infiltrating lymphocytes (TILs) is a strong prognostic parameter for local dissemination and overall survival in melanoma. Lymphocyte migration from blood into peripheral tissues is mainly regulated by vascular endothelium. However, the blood vessels and mechanisms governing the recruitment of TILs in melanoma tumors remain poorly understood. Here, we show that high endothelial venules (HEVs), specialized blood vessels for lymphocyte extravasation into lymphoid tissues, are frequently found in melanoma tumors and are associated with high levels of lymphocyte infiltration. The analysis of 225 primary melanomas revealed that lymphocytes specifically infiltrated HEV-rich areas of melanoma tumors and that the density of MECA-79+ HEVs was variable among patients and strongly correlated with CD3+, CD8+ and CD20+ TIL densities. Inflammatory (CCL5, CXCL9, CXCL10 and CXCL11) and lymphoid (CCL21, CCL19 and CXCL13) chemokines as well as TH1 and naïve T-cell genes were overexpressed in melanoma samples with high densities of tumor HEVs. Mature dendritic cells (mDCs) were frequently found around tumor HEVs and densities of HEVs and DC-LAMP+ mDCs within tumor stroma were strongly correlated. DCs which maintain HEVs in lymph nodes, may thus also contribute to the regulation of HEVs in melanomas. Finally, we found significantly higher densities of tumor HEVs in melanomas with tumor regression, low Clark level of invasion and thin Breslow thickness (all p < 0.001). The strong association between tumor HEVs, TILs, mDCs and clinical parameters of melanoma, supports a critical role for HEVs in limiting malignant melanoma development through both naïve and effector T-lymphocyte recruitment and activation.

Bilateral choroidal metastases as presentation of dissemination of cutaneous malignant melanoma

AbstractPurpose To report the case of a patient with bilateral choroidal mestastases as the first sign of dissemination of cutaneous malignant melanoma.Methods A 47‐year‐old Caucasian male presented to our emergency department with rapid‐onset blurred vision in his right eye (RE). Ophthalmoscopic examination revealed multiple pigmented placoid lesions located in the posterior pole and half periphery of the retina of both eyes and a serous macular detachment in RE. Optical coherence tomography confirmed the macular neurosensory detachment in the RE Since clinical suspicion of choroidal metastases, we referred the patient to the Oncology Department for systematic study. After an exhaustive study, they concluded that it was a dissemination of a cutaneous malignant melanoma with bilateral choroidal metastases, liver and spleen metastases.Results The patient underwent palliative treatment with chemotherapy with improvement of the visual acuity and reduction of the macular neurosensory detachment in the RE. Nevertheless the patient died months later of the diagnosis of cutaneous melanoma dissemination.Conclusion Dissemination of cutaneous melanoma to the choroid is rare and is a major prognostic factor. In general the treatment of ocular metastases is palliative, because the presence of metastases indicates hematogenous spread of tumor. The objectives are therefore to maximize the quality of life and restore or preserve vision.

Disseminated tumour cells in bone marrow of patients with uveal melanoma

Approximately 50% of patients with uveal melanomas develop metastases. Thus, it is important to improve our understanding of how melanoma metastases develop. As part of a uveal melanoma micrometastasis study, we compared the detection rates of immunomagnetically selected (IMS) tumour cells in bone marrow (BM) with positively stained tumour cells using immunocytochemistry (ICC). Bone marrow mononuclear cells were isolated. Immunocytochemistry cytospin preparations were immunocytochemically stained in parallel with two different melanoma antibodies, 9.2.27 and HMB45. Using IMS, melanoma cells were selected from BM mononuclear cell fractions using immunomagnetic beads coated with the 9.2.27 antibody and identified by light microscopy. In cytospin preparations from 226 patients, melanoma cells were detected in 24 (10.6%), 10 with 9.2.27 and 17 with the HMB45 antibody. In three cases, we found positive cells with both antibodies. Six of the 226 (2.6%) patients that stained positively with ICC died with metastatic disease, all also positive with IMS. Sixty-six (29.2%) patients had positive BM samples with IMS at the first examination. Immunomagnetic selection (IMS) was positive in 36.8% of the 57 patients who later developed clinical metastases. Twenty-one IMS-positive patients and 31 IMS-negative patients died of metastases, in total 52 of 226 patients (23.0%). The mortality rate of melanoma metastasis was 24% (6/24) after at least 4 ½ years in ICC-positive patients compared to 38.5% (20/52) in IMS-positive patients. The presence of melanoma cells in BM of patients with uveal melanoma is documented in our study with IMS and ICC. Immunomagnetically selected is more sensitive than ICC in detecting tumour cells in BM. However, statistically, we did not find any prognostic impact of the presence of melanoma cells in BM.

Chronology of Metastasis in Cutaneous Melanoma: Growth Rate Model

In humans, it is not possible to obtain experimental evidence of when a cancer begins to metastasize. The purpose of this study was to estimate the time of onset of metastatic dissemination in cutaneous melanoma using a model based on its growth rate (GR). The critical time of onset of metastatic dissemination below which no cases of fatal melanomas were seen may be described with a potential function in which this time is inversely proportional to the GR. The critical time of development beyond which a melanoma may metastasize presents great variation. This time was just 1 month for those melanomas with a fast GR, whereas it was over 5 years for those with a very slow GR. Quantitatively, the fastest-growing melanomas began metastasizing with a greater thickness than the slowest-growing melanomas. A correlation exists between the critical time of onset of metastatic potential and the GR of the melanoma. These results may well have relevance to the understanding of mechanisms of tumor dissemination and for the design of future studies on melanomas, irrespective of whether they are basic studies on biomolecular mechamisms or clinical studies.

Bilateral Choroidal Metastases as Presentation of Dissemination of Cutaneous Malignant Melanoma

Case Report. A 47-year-old man presented with blurred vision in the right eye. Ophthalmoscopic examination showed several placoid, pigmented lesions in the posterior pole and midperiphery of the retina of both eyes. Results. Patient referred a cutaneous malignant melanoma on the back skin removed 6 years ago. A systemic workup revealed multiple metastases in liver and spleen. After an exhaustive study we concluded that it was a dissemination of a cutaneous malignant melanoma with bilateral choroidal metastases, liver and spleen metastases. The patient obtained clinical ocular improvement after palliative chemotherapy, although he died in the following months. Pathological examination of the lesions confirmed the diagnosis of choroidal metastases from a malignant cutaneous melanoma. Conclusions. Monitoring patients who have had cutaneous malignant melanoma is very important, since melanoma metastases may occur even many years after the diagnosis of the primary tumor. Choroidal metastases from cutaneous melanoma are uncommon but we should be aware because their appearance worsens prognosis.

SPARC Promotes Cathepsin B-Mediated Melanoma Invasiveness through a Collagen I/α2β1 Integrin Axis

In melanoma, the extracellular protein SPARC (secreted protein acidic and rich in cysteine) is related to tumor progression. Some of the evidence that links SPARC to melanoma progression indicates that SPARC may be involved in the acquisition of mesenchymal traits that favor metastatic dissemination. However, no molecular pathways that link extracellular SPARC to a mesenchymal phenotype have been described. In this study, global protein expression analysis of the melanoma secretome following enforced downregulation of SPARC expression led us to elucidate a new molecular mechanism by which SPARC promotes cathepsin B-mediated melanoma invasiveness using collagen I and α2β1 integrins as mediators. Interestingly, we also found that the transforming growth factor (TGF)-β1 contribution to cathepsin B-mediated invasion is highly SPARC dependent. In addition, induction of the E-cadherin to N-cadherin switch by SPARC enabled melanoma cells to transmigrate across an endothelial layer through a mechanism independent to that of enhancing invasion. Finally, SPARC also enhanced the extracellular expression of other proteins involved in epithelial-mesenchymal transformation, such as family with sequence similarity 3, member C/interleukin-like EMT-inducer. Our findings demonstrate a previously unreported molecular pathway for SPARC activity on invasion and support an active role of SPARC in the mesenchymal transformation that contributes to melanoma dissemination.

Vascular endothelial growth factor regulates melanoma cell adhesion and growth in the bone marrow microenvironment via tumor cyclooxygenase-2

BackgroundHuman melanoma frequently colonizes bone marrow (BM) since its earliest stage of systemic dissemination, prior to clinical metastasis occurrence. However, how melanoma cell adhesion and proliferation mechanisms are regulated within bone marrow stromal cell (BMSC) microenvironment remain unclear. Consistent with the prometastatic role of inflammatory and angiogenic factors, several studies have reported elevated levels of cyclooxygenase-2 (COX-2) in melanoma although its pathogenic role in bone marrow melanoma metastasis is unknown.MethodsHerein we analyzed the effect of cyclooxygenase-2 (COX-2) inhibitor celecoxib in a model of generalized BM dissemination of left cardiac ventricle-injected B16 melanoma (B16M) cells into healthy and bacterial endotoxin lipopolysaccharide (LPS)-pretreated mice to induce inflammation. In addition, B16M and human A375 melanoma (A375M) cells were exposed to conditioned media from basal and LPS-treated primary cultured murine and human BMSCs, and the contribution of COX-2 to the adhesion and proliferation of melanoma cells was also studied.ResultsMice given one single intravenous injection of LPS 6 hour prior to cancer cells significantly increased B16M metastasis in BM compared to untreated mice; however, administration of oral celecoxib reduced BM metastasis incidence and volume in healthy mice, and almost completely abrogated LPS-dependent melanoma metastases. In vitro, untreated and LPS-treated murine and human BMSC-conditioned medium (CM) increased VCAM-1-dependent BMSC adherence and proliferation of B16M and A375M cells, respectively, as compared to basal medium-treated melanoma cells. Addition of celecoxib to both B16M and A375M cells abolished adhesion and proliferation increments induced by BMSC-CM. TNFα and VEGF secretion increased in the supernatant of LPS-treated BMSCs; however, anti-VEGF neutralizing antibodies added to B16M and A375M cells prior to LPS-treated BMSC-CM resulted in a complete abrogation of both adhesion- and proliferation-stimulating effect of BMSC on melanoma cells. Conversely, recombinant VEGF increased adherence to BMSC and proliferation of both B16M and A375M cells, compared to basal medium-treated cells, while addition of celecoxib neutralized VEGF effects on melanoma. Recombinant TNFα induced B16M production of VEGF via COX-2-dependent mechanism. Moreover, exogenous PGE2 also increased B16M cell adhesion to immobilized recombinant VCAM-1.ConclusionsWe demonstrate the contribution of VEGF-induced tumor COX-2 to the regulation of adhesion- and proliferation-stimulating effects of TNFα, from endotoxin-activated bone marrow stromal cells, on VLA-4-expressing melanoma cells. These data suggest COX-2 neutralization as a potential anti-metastatic therapy in melanoma patients at high risk of systemic and bone dissemination due to intercurrent infectious and inflammatory diseases.

A novel function of junctional adhesion molecule-C in mediating melanoma cell metastasis.

Hematogenous dissemination of melanoma is a life-threatening complication of this malignant tumor. Here, we identified junctional adhesion molecule-C (JAM-C) as a novel player in melanoma metastasis to the lung. JAM-C expression was identified in human and murine melanoma cell lines, in human malignant melanoma, as well as in metastatic melanoma including melanoma lung metastasis. JAM-C expressed on both murine B16 melanoma cells as well as on endothelial cells promoted the transendothelial migration of the melanoma cells. We generated mice with inactivation of JAM-C. JAM-C(-/-) mice as well as endothelial-specific JAM-C-deficient mice displayed significantly decreased B16 melanoma cell metastasis to the lung, whereas treatment of mice with soluble JAM-C prevented melanoma lung metastasis. Together, JAM-C represents a novel therapeutic target for melanoma metastasis.

Ultraviolet exposure of melanoma cells induces fibroblast activation protein-α in fibroblasts: Implications for melanoma invasion

Fibroblast activation protein-α (FAP-α) promotes tumor growth and cell invasiveness through extracellular matrix degradation. How ultraviolet radiation (UVR), the major risk factor for malignant melanoma, influences the expression of FAP-α is unknown. We examined the effect of UVR on FAP-α expression in melanocytes, keratinocytes and fibroblasts from the skin and in melanoma cells. UVR induces upregulation of FAP-α in fibroblasts, melanocytes and primary melanoma cells (PM) whereas keratinocytes and metastatic melanoma cells remained FAP-α negative. UVA and UVB stimulated FAP-α-driven migration and invasion in fibroblasts, melanocytes and PM. In co-culture systems UVR of melanocytes, PM and cells from regional metastases upregulated FAP-α in fibroblasts but only supernatants from non-irradiated PM were able to induce FAP-α in fibroblasts. Further, UV-radiated melanocytes and PM significantly increased FAP-α expression in fibroblasts through secretory crosstalk via Wnt5a, PDGF-BB and TGF-β1. Moreover, UV radiated melanocytes and PM increased collagen I invasion and migration of fibroblasts. The FAP-α/DPPIV inhibitor Gly-ProP(OPh)2 significantly decreased this response implicating FAP-α/DPPIV as an important protein complex in cell migration and invasion. These experiments suggest a functional association between UVR and FAP-α expression in fibroblasts, melanocytes and melanoma cells implicating that UVR of malignant melanoma converts fibroblasts into FAP-α expressing and ECM degrading fibroblasts thus facilitating invasion and migration. The secretory crosstalk between melanoma and tumor surrounding fibroblasts is mediated via PDGF-BB, TGF-β1 and Wnt5a and these factors should be evaluated as targets to reduce FAP-α activity and prevent early melanoma dissemination.

Cutaneous melanoma: A model to study cancer metastasis

Nodal status in melanoma is a critically important prognostic factor for patient outcome. The survival rate drops to <10% when melanoma has spread beyond the regional lymph nodes and includes visceral involvement. In general, the process of melanoma metastasis is progressive in that dissemination of melanoma from the primary site to the regional lymph nodes occurs prior to systemic disease. The goal of this review article is to describe melanoma as a clinical model to study cancer metastasis. A future challenge is to develop a molecular taxonomy to subgroup melanoma patients at various stages of tumor progression for more accurate targeted treatment.

Uveal melanoma: neither fish nor fowl?

Abstract Purpose To outline recent development and future research avenues for molecular mechanisms in uveal melanoma Methods Review of pertinent literature and unpublished personal data Results While most eyes with uveal melanoma now can be treated with one or more of a range of sight‐conserving options, overall patient survival has not improved during recent years. It remains clear that overall survival for patients with uveal melanoma can only be improved if effective treatment for disseminated disease can be offered and that such treatment need to be provided early in the disease progression. The molecular mechanisms involved in uveal melanoma appear to be distinctly different from those identified in cutaneous melanoma. Although much progress has been made in mapping the pathways likely to play a role in uveal melanoma initiation, progression and dissemination has been made in recent years, much remains to be unravelled. Targeted therapy combined with early detection of disseminated disease or the identification of patients at high risk of tumour spread is likely to impact prognosis in the next decade to come. Conclusion Recent progress in identifying molecular mechanisms involved in uveal melanoma initiation, progression and dissemination has been significant. The next decade is likely to see the translation of this knowledge to effective treatment which may result in improved patient survival.