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Melanoma: Dark Tumor with Little Light for Metastasis Treatment
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Melanoma: Dark Tumor with Little Light for Metastasis Treatment

A special issue of Life (ISSN 2075-1729). This special issue belongs to the section "Cell Biology and Tissue Engineering".

Deadline for manuscript submissions: closed (10 December 2021) | Viewed by 27314

Special Issue Editor

Dr. Jiri Vachtenheim

E-Mail Website
Guest Editor
Institute of Medical Biochemistry and Laboratory Diagnostics, Department of Transcription and Cell Signaling, First Faculty of Medicine, Charles University Prague, Katerinska 32, 12108 Prague 2, Czech Republic
Interests: melanoma; MITF/TF; lung cancer; Hedgehog/GLI pathway; E1A oncoprotein; cancer stem cells; targeted therapy

Special Issue Information

Dear Colleagues,

Melanoma is an aggressive form of skin cancer. This insidious, resilient tumor originates from melanocytes—neural crest-derived cells endowed with high migration activity in embryonic development and reside in the epidermis of adults. This migration propensity is recapitulated in melanomas, which are highly metastatic when proceeding to later stages. Life-saving therapy is early surgery, mostly involving the additional removal of sentinel lymph nodes. Exposure to natural or artificial sunlight (UV) and genetic predisposition are risk factors for the development of melanoma. The tumor heterogeneity and individual melanoma cell phenotypes hamper effective therapy. Phenotype switching (epithelial–mesenchymal transition), a well-known process of phenotypic change that also appears in other cancers, contributes to melanoma heterogeneity. Microphthalmia-associated transcription factor (MITF) transcribes virtually all genes required for melanin formation, storage and transport. This is essential for maintaining melanoma cell identity. MITF is also essential for melanoma cell survival by activating the transcription of some antiapoptotic genes. MITF-high phenotype is considered to be pro-proliferative, while MITF-low melanoma cell subpopulations divide slowly but are more de-differentiated and invasive. More than half of melanomas harbor mutated BRAF oncogene and a smaller proportion contain mutated NRAS. Treatment is therefore concentrated to block the activated MAPK/ERK pathway by BRAF or NRAS inhibitors. However, typically, when mutated BRAF is targeted by dabrafenib, resistance appears after months and even “drug addiction” evolves. Therefore, combined therapy can be a solution and has been already tried. The molecular mechanisms that stand behind the melanoma resilience are not fully understood, and the most suitable combined targeted therapy is urgently needed for mutBRAF, mutNRAS and wt BRAF/NRAS tumors.

Authors are cordially invited to contribute original research papers or reviews to this Special Issue of Life.

Dr. Jiri Vachtenheim
Guest Editor

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Keywords

  • melanoma
  • MITF
  • BRAF
  • combined therapy
  • molecular targets

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Published Papers (8 papers)

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Research

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11 pages, 1093 KiB  
Article
Expression of Potential Targets for Cell-Based Therapies on Melanoma Cells
by Sophia B. Strobel, Devayani Machiraju, Ingrid Hülsmeyer, Jürgen C. Becker, Annette Paschen, Dirk Jäger, Winfried S. Wels, Michael Bachmann and Jessica C. Hassel
Life 2021, 11(4), 269; https://doi.org/10.3390/life11040269 - 24 Mar 2021
Cited by 10 | Viewed by 3608
Abstract
Tumor antigen-specific redirection of cytotoxic T cells (CTLs) or natural killer (NK) cells including chimeric antigen receptor (CAR-) and T cell receptor (TCR-) cell therapy is currently being evaluated in different tumor entities including melanoma. Expression of melanoma-specific antigen recognized by the respective [...] Read more.
Tumor antigen-specific redirection of cytotoxic T cells (CTLs) or natural killer (NK) cells including chimeric antigen receptor (CAR-) and T cell receptor (TCR-) cell therapy is currently being evaluated in different tumor entities including melanoma. Expression of melanoma-specific antigen recognized by the respective CAR or TCR directly or presented by HLA molecules is an indispensable prerequisite for this innovative therapy. In this study, we investigated in 168 FFPE tumor specimens of patients with stage I-IV melanoma the protein expression of HER2, TRP2, ABCB5, gp100, p53, and GD2 by immunohistochemistry (IHC). These results were correlated with clinical parameters. Membrane expression of HER2 and GD2 was also investigated in ten melanoma cell lines by flow cytometry for which corresponding tumors were analyzed by IHC. Our results demonstrated that gp100 was the most frequently overexpressed protein (61%), followed by TRP2 (50%), GD2 (38%), p53 (37%), ABCB5 (17%), and HER2 (3%). TRP2 expression was higher in primary tumors compared to metastases (p = 0.005). Accordingly, TRP2 and ABCB5 expression was significantly associated with lower tumor thickness of the primary (p = 0.013 and p = 0.025). There was no association between protein expression levels and survival in advanced melanoma patients. Flow cytometric analysis revealed abundant surface expression of GD2 and HER2 in all melanoma cell lines. The discordant HER2 expression in situ and in vitro suggests a tissue culture associated induction. In summary, our data support the use of gp100 and GD2 as a potential target for developing engineered TCR- or CAR-cell therapies, respectively, against melanoma. Full article
(This article belongs to the Special Issue Melanoma: Dark Tumor with Little Light for Metastasis Treatment)
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15 pages, 3925 KiB  
Article
Correlation between the Expression of Angiogenic Factors and Stem Cell Markers in Human Uveal Melanoma
by Klára Fodor, Éva Sipos, Nikoletta Dobos, János Nagy, Zita Steiber, Gábor Méhes, Kata Dull, Lóránt Székvölgyi, Andrew V. Schally and Gábor Halmos
Life 2020, 10(12), 310; https://doi.org/10.3390/life10120310 - 25 Nov 2020
Cited by 3 | Viewed by 2528
Abstract
Uveal melanoma (UM) is the most common malignant tumor of the eye with extremely high metastatic potential. UM tumor cells can disseminate only hematogenously, thus, angiogenic signals have a particular role in the prognosis of the disease. Although the presence of cancer stem [...] Read more.
Uveal melanoma (UM) is the most common malignant tumor of the eye with extremely high metastatic potential. UM tumor cells can disseminate only hematogenously, thus, angiogenic signals have a particular role in the prognosis of the disease. Although the presence of cancer stem cells (CSCs) in densely vascularized UMs has been reported previously, their role in the process of hematogenous spread of UM has not been studied. In this study, we investigated the regulation of angiogenesis in UM in correlation with the presence of CSCs. Seventy UM samples were collected to analyze the expression of CSC markers and angiogenic factors. The expression of CSC markers was studied by RT-PCR, Western blotting techniques and IHC-TMA technique. RT-PCR showed high expression of CSC markers, particularly nestin, FZD6 and SOX10 and somewhat lower expression of NGFR. The protein expression of FZD6, HIF-1α and VEGFA was further evaluated in 52 UM samples by the IHC-TMA technique. We report here for the first time a significant correlation between FZD6 and VEGFA expression in UM samples. The observed correlation between FZD6 and VEGFA suggests the presence of CSCs in UM that are associated with the vascularization process. Full article
(This article belongs to the Special Issue Melanoma: Dark Tumor with Little Light for Metastasis Treatment)
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16 pages, 2592 KiB  
Article
Cancer Stem Cells in Head and Neck Metastatic Malignant Melanoma Express Components of the Renin-Angiotensin System
by Sam Siljee, Tessa Pilkington, Helen D. Brasch, Nicholas Bockett, Josie Patel, Erin Paterson, Paul F. Davis and Swee T. Tan
Life 2020, 10(11), 268; https://doi.org/10.3390/life10110268 - 2 Nov 2020
Cited by 15 | Viewed by 3637
Abstract
Components of the renin-angiotensin system (RAS) are expressed by cancer stem cells (CSCs) in many cancer types. We here investigated expression of the RAS by the CSC subpopulations in human head and neck metastatic malignant melanoma (HNmMM) tissue samples and HNmMM-derived primary cell [...] Read more.
Components of the renin-angiotensin system (RAS) are expressed by cancer stem cells (CSCs) in many cancer types. We here investigated expression of the RAS by the CSC subpopulations in human head and neck metastatic malignant melanoma (HNmMM) tissue samples and HNmMM-derived primary cell lines. Immunohistochemical staining demonstrated expression of pro-renin receptor (PRR), angiotensin-converting enzyme (ACE), and angiotensin II receptor 2 (AT2R) in all; renin in one; and ACE2 in none of the 20 HNmMM tissue samples. PRR was localized to cells within the tumor nests (TNs), while AT2R was expressed by cells within the TNs and the peritumoral stroma (PTS). ACE was localized to the endothelium of the tumor microvessels within the PTS. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) detected transcripts for PRR, ACE, ACE2, and AT1R, in all the five HNmMM tissue samples and four HNmMM-derived primary cell lines; renin in one tissue sample and one cell line, and AT2R in none of the five HNmMM tissue samples and cell lines. Western blotting showed variable expression of ACE, PRR, and AT2R, but not ACE2, in six HNmMM tissue samples and two HNmMM-derived primary cell lines. Immunofluorescence staining of two HNmMM tissue samples demonstrated expression of PRR and AT2R by the SOX2+ CSCs within the TNs and the OCT4+ CSCs within the PTS, with ACE localized to the endothelium of the tumor microvessels within the PTS. Full article
(This article belongs to the Special Issue Melanoma: Dark Tumor with Little Light for Metastasis Treatment)
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Graphical abstract

17 pages, 2821 KiB  
Article
Novel Methylation Patterns Predict Outcome in Uveal Melanoma
by Sarah Tadhg Ferrier and Julia Valdemarin Burnier
Life 2020, 10(10), 248; https://doi.org/10.3390/life10100248 - 20 Oct 2020
Cited by 9 | Viewed by 2844
Abstract
Uveal melanoma (UM) is the most common intraocular tumor in adults. Despite effective local treatments, 50% of patients develop metastasis. Better ways to determine prognosis are needed as well as new therapeutic targets. Epigenetic changes are important events driving cancer progression; however, few [...] Read more.
Uveal melanoma (UM) is the most common intraocular tumor in adults. Despite effective local treatments, 50% of patients develop metastasis. Better ways to determine prognosis are needed as well as new therapeutic targets. Epigenetic changes are important events driving cancer progression; however, few studies exist on methylation changes in UM. Our aim was to identify methylation events associated with UM prognosis. Matched clinical, genetic, and methylation data for 80 UM cases were obtained from The Cancer Genome Atlas (TCGA). Top differentially methylated loci were sorted through hierarchical clustering based on methylation patterns, and these patterns were compared to tumor characteristics, genomic aberrations, and patient outcome. Hierarchical clustering revealed two distinct groups. These classifications effectively separated high and low-risk cases, with significant differences between groups in patient survival (p < 0.0001) and correlation with known prognostic factors. Major differences in methylation of specific genes, notably NFIA, HDAC4, and IL12RB2, were also seen. The methylation patterns identified in this study indicate potential novel prognostic indicators of UM and highlight the power of methylation changes in predicting outcome. The methylation events enriched in the high-risk group suggest that epigenetic modulating drugs may be useful in reducing metastatic potential, and that specific differentially methylated loci could act as biomarkers of therapeutic response. Full article
(This article belongs to the Special Issue Melanoma: Dark Tumor with Little Light for Metastasis Treatment)
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14 pages, 3328 KiB  
Article
Ephrin Receptors (Eph): EphA1, EphA5, and EphA7 Expression in Uveal Melanoma—Associations with Clinical Parameters and Patient Survival
by Malgorzata Gajdzis, Stamatios Theocharis, Pawel Gajdzis, Nathalie Cassoux, Sophie Gardrat, Piotr Donizy, Jerzy Klijanienko and Radoslaw Kaczmarek
Life 2020, 10(10), 225; https://doi.org/10.3390/life10100225 - 30 Sep 2020
Cited by 11 | Viewed by 2571
Abstract
Uveal melanoma is the most common primary intraocular malignancy in adults. The development of distant metastases is associated with a poor prognosis. Ephrine receptors (Eph) are the largest subpopulation of tyrosine kinase receptors. They play an important role in processes related to the [...] Read more.
Uveal melanoma is the most common primary intraocular malignancy in adults. The development of distant metastases is associated with a poor prognosis. Ephrine receptors (Eph) are the largest subpopulation of tyrosine kinase receptors. They play an important role in processes related to the formation and progression of cancer. The aim of the study was to evaluate the expression of ephrin receptors EphA1, EphA5, and EphA7 in uveal melanoma and its associations with clinicopathological parameters, overall survival, and disease-free survival. The study included 94 previously untreated patients who underwent enucleation due to uveal melanoma. High expression of EphA1 was positively correlated with a smaller tumor size, less frequent extra-scleral extension, lower mitotic activity, and more frequent vitreous hemorrhage. High expression of EphA5 was associated with less frequent chromosome 3 loss, absence of distant metastases, and more frequent vitreous hemorrhage. High expression of EphA7 was associated with a more frequent primary tumor location in the posterior pole. High EphA5 expression was associated with longer overall survival time. The above findings indicate that high expression of EphA1 and EphA5 can be considered a beneficial prognostic factor in uveal melanoma. Full article
(This article belongs to the Special Issue Melanoma: Dark Tumor with Little Light for Metastasis Treatment)
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Review

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13 pages, 1043 KiB  
Review
Many Distinct Ways Lead to Drug Resistance in BRAF- and NRAS-Mutated Melanomas
by Jiri Vachtenheim and Lubica Ondrušová
Life 2021, 11(5), 424; https://doi.org/10.3390/life11050424 - 5 May 2021
Cited by 5 | Viewed by 3152
Abstract
Advanced melanoma is a relentless tumor with a high metastatic potential. The combat of melanoma by using the targeted therapy is impeded because several major driver mutations fuel its growth (predominantly BRAF and NRAS). Both these mutated oncogenes strongly activate the MAPK [...] Read more.
Advanced melanoma is a relentless tumor with a high metastatic potential. The combat of melanoma by using the targeted therapy is impeded because several major driver mutations fuel its growth (predominantly BRAF and NRAS). Both these mutated oncogenes strongly activate the MAPK (MEK/ERK) pathway. Therefore, specific inhibitors of these oncoproteins or MAPK pathway components or their combination have been used for tumor eradication. After a good initial response, resistant cells develop almost universally and need the drug for further expansion. Multiple mechanisms, sometimes very distant from the MAPK pathway, are responsible for the development of resistance. Here, we review many of the mechanisms causing resistance and leading to the dismal final outcome of mutated BRAF and NRAS therapy. Very heterogeneous events lead to drug resistance. Due to this, each individual mechanism would be in fact needed to be determined for a personalized therapy to treat patients more efficiently and causally according to molecular findings. This procedure is practically impossible in the clinic. Other approaches are therefore needed, such as combined treatment with more drugs simultaneously from the beginning of the therapy. This could eradicate tumor cells more rapidly and greatly diminish the possibility of emerging mechanisms that allow the evolution of drug resistance. Full article
(This article belongs to the Special Issue Melanoma: Dark Tumor with Little Light for Metastasis Treatment)
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25 pages, 1089 KiB  
Review
The Tumor and Host Immune Signature, and the Gut Microbiota as Predictive Biomarkers for Immune Checkpoint Inhibitor Response in Melanoma Patients
by Katarzyna Tomela, Bernadeta Pietrzak, Marcin Schmidt and Andrzej Mackiewicz
Life 2020, 10(10), 219; https://doi.org/10.3390/life10100219 - 25 Sep 2020
Cited by 13 | Viewed by 3951
Abstract
There are various melanoma treatment strategies that are based on immunological responses, among which immune checkpoint inhibitors (ICI) are relatively novel form. Nowadays, anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and anti-programmed death-1 (PD-1) antibodies represent a standard treatment for metastatic melanoma. Although there are [...] Read more.
There are various melanoma treatment strategies that are based on immunological responses, among which immune checkpoint inhibitors (ICI) are relatively novel form. Nowadays, anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and anti-programmed death-1 (PD-1) antibodies represent a standard treatment for metastatic melanoma. Although there are remarkable curative effects in responders to ICI therapy, up to 70% of melanoma patients show resistance to this treatment. This low response rate is caused by innate as well as acquired resistance, and some aspects of treatment resistance are still unknown. Growing evidence shows that gut microbiota and bacterial metabolites, such as short-chain fatty acids (SCFAs), affect the efficacy of immunotherapy. Various bacterial species have been indicated as potential biomarkers of anti-PD-1 or anti-CTLA-4 therapy efficacy in melanoma, next to biomarkers related to molecular and genetic tumor characteristics or the host immunological response, which are detected in patients’ blood. Here, we review the current status of biomarkers of response to ICI melanoma therapies, their pre-treatment predictive values, and their utility as on-treatment monitoring tools in order to select a relevant personalized therapy on the basis of probability of the best clinical outcome. Full article
(This article belongs to the Special Issue Melanoma: Dark Tumor with Little Light for Metastasis Treatment)
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15 pages, 340 KiB  
Review
Treatment of Advanced Melanoma: Past, Present and Future
by Taku Fujimura, Yumi Kambayashi, Kentaro Ohuchi, Yusuke Muto and Setsuya Aiba
Life 2020, 10(9), 208; https://doi.org/10.3390/life10090208 - 16 Sep 2020
Cited by 23 | Viewed by 3771
Abstract
Therapeutic options for treating advanced melanoma are progressing rapidly. Until six years ago, the regimen for treating advanced melanoma mainly comprised cytotoxic agents such as dacarbazine, and type I interferons. Since 2014, anti-programmed cell death 1 (PD1) antibodies have become recognized as anchor [...] Read more.
Therapeutic options for treating advanced melanoma are progressing rapidly. Until six years ago, the regimen for treating advanced melanoma mainly comprised cytotoxic agents such as dacarbazine, and type I interferons. Since 2014, anti-programmed cell death 1 (PD1) antibodies have become recognized as anchor drugs for treating advanced melanoma with or without additional combination drugs such as ipilimumab. In addition, v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) kinase inhibitors in combination with mitogen-activated protein kinase kinase (MEK) inhibitors are among the most promising chemotherapeutic regimens for treating advanced BRAF-mutant melanoma, especially in patients with low tumor burden. Since anti-PD1 antibodies are widely applicable for the treatment of both BRAF wild-type and mutated advanced melanomas, several clinical trials for drugs in combination with anti-PD1 antibodies are ongoing. This review focuses on the development of the anti-melanoma therapies available today, and discusses the clinical trials of novel regimens for the treatment of advanced melanoma. Full article
(This article belongs to the Special Issue Melanoma: Dark Tumor with Little Light for Metastasis Treatment)
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