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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: closed (15 May 2020) | Viewed by 61951

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Dr. Malgorzata Czyz

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Department of Molecular Biology of Cancer, Medical University of Lodz, 92-215 Lodz, Poland
Interests: melanoma; genome; phenotype
Special Issues, Collections and Topics in MDPI journals

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Dear Colleagues,

Melanoma is highly heterogeneous, with cell subpopulations exerting transcriptionally distinct phenotypes. It is a consequence of diverse genetic alterations, but also of non-genomic changes often induced by the tumor microenvironment. These changes are integrated into the active modifications of multiple signaling pathways, including, but not limited to, the mitogen-activated protein kinase (MAPK) pathway and phosphoinositol-3-kinase (PI3K) pathway, which license melanoma cell survival, progression, and drug resistance. An analysis of the clinical samples derived from the melanoma patients that developed resistance to targeted therapies or immunotherapies created the opportunity to follow the changes in several critical signaling pathways.

This Special Issue of the International Journal of Molecular Sciences aims to bring together the state-of-the-art views and original research on “Signaling in Melanoma”. It will focus on the alterations in the signaling pathways that are crucial for melanoma initiation and progression, interactions of melanoma cells with the tumor microenvironment, and the development of resistance to targeted therapies and immunotherapies.

Dr. Malgorzata Czyz
Guest Editor

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Published Papers (10 papers)

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Research

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16 pages, 9593 KiB

Open AccessArticle

Inhibition Effect of Chloroquine and Integrin-Linked Kinase Knockdown on Translation in Melanoma Cells

by Dorota Gil, Piotr Laidler, Marta Zarzycka and Joanna Dulińska-Litewka

Int. J. Mol. Sci. 2021, 22(7), 3682; https://doi.org/10.3390/ijms22073682 - 1 Apr 2021

Cited by 5 | Viewed by 2909

Abstract

The twofold role of autophagy in cancer is often the therapeutic target. Numerous regulatory pathways are shared between autophagy and other molecular processes needed in tumorigenesis, such as translation or survival signaling. Thus, we have assumed that ILK knockdown should promote autophagy, and used together with chloroquine, an autophagy inhibitor, it could generate a better anticancer effect by dysregulation of common signaling pathways. Expression at the protein level was analyzed using Western Blot; siRNA transfection was done for ILK. Analysis of cell signaling pathways was monitored with phospho-specific antibodies. Melanoma cell proliferation was assessed with the crystal violet test, and migration was evaluated by scratch wound healing assays. Autophagy was monitored by the accumulation of its marker, LC3-II. Our data show that ILK knockdown by siRNA suppresses melanoma cell growth by inducing autophagy through AMPK activation, and simultaneously initiates apoptosis. We demonstrated that combinatorial treatment of melanoma cells with CQ and siILK has a stronger antitumor effect than monotherapy with either of these. It generates the synergistic antitumor effects by the decrease of translation of both global and oncogenic proteins synthesis. In our work, we point to the crosstalk between translation and autophagy regulation. Full article

(This article belongs to the Special Issue Signaling in Melanoma)

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14 pages, 3613 KiB

Open AccessArticle

LATS1 Is a Mediator of Melanogenesis in Response to Oxidative Stress and Regulator of Melanoma Growth

by Urszula Kazimierczak, Ewelina Dondajewska, Maria Zajaczkowska, Marianna Karwacka, Tomasz Kolenda and Andrzej Mackiewicz

Int. J. Mol. Sci. 2021, 22(6), 3108; https://doi.org/10.3390/ijms22063108 - 18 Mar 2021

Cited by 8 | Viewed by 2708

Abstract

The LATS1 kinase has been described as a tumor suppressor in various cancers. However, its role in melanoma has not been fully elucidated. There are several processes involved in tumorigenesis, including melanin production. Melanin content positively correlates with the level of reactive oxygen species (ROS) inside the cell. Accordingly, the purpose of the study was to assess the role of LATS1 in melanogenesis and oxidative stress and its influence on tumor growth. We have knocked down LATS1 in primary melanocytes and melanoma cells and found that its expression is crucial for melanin synthesis, ROS production, and oxidative stress response. We showed that LATS1 ablation significantly decreased the melanogenesis markers’ expression and melanin synthesis in melanocyte and melanoma cell lines. Moreover, silencing LATS1 resulted in enhanced oxidative stress. Reduced melanin content in LATS1 knocked down tumors was associated with increased tumor growth, pointing to melanin’s protective role in this process. The study demonstrated that LATS1 is highly engaged in melanogenesis and oxidative stress control and affects melanoma growth. Our results may find the implications in the diagnosis and treatment of pigmentation disorders, including melanoma. Full article

(This article belongs to the Special Issue Signaling in Melanoma)

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21 pages, 2353 KiB

Open AccessArticle

17-Aminogeldanamycin Inhibits Constitutive Nuclear Factor-Kappa B (NF-κB) Activity in Patient-Derived Melanoma Cell Lines

by Mariusz L. Hartman, Magdalena Rogut, Aleksandra Mielczarek-Lewandowska, Michal Wozniak and Malgorzata Czyz

Int. J. Mol. Sci. 2020, 21(11), 3749; https://doi.org/10.3390/ijms21113749 - 26 May 2020

Cited by 8 | Viewed by 3377

Abstract

Melanoma remains incurable skin cancer, and targeting heat shock protein 90 (HSP90) is a promising therapeutic approach. In this study, we investigate the effect of 17-aminogeldanamycin, a potent HSP90 inhibitor, on nuclear factor-kappa B (NF-κB) activity in BRAF^V600E and NRAS^Q61R patient-derived melanoma cell lines. We performed time-lapse microscopy and flow cytometry to monitor changes in cell confluence and viability. The NF-κB activity was determined by immunodetection of phospho-p65 and assessment of expression of NF-κB-dependent genes by quantitative real-time polymerase chain reaction (qRT-PCR), Western blotting, and enzyme-linked immunosorbent assay (ELISA). Constitutive activity of p65/NF-κB was evident in all melanoma cell lines. Differences in its level might be associated with genetic alterations in CHUK, IL1B, MAP3K14, NFKBIE, RIPK1, and TLR4, while differences in transcript levels of NF-κB-inducible genes revealed by PCR array might result from the contribution of other regulatory mechanisms. 17-Aminogeldanamycin markedly diminished the level of phospho-p65, but the total p65 protein level was unaltered, indicating that 17-aminogeldanamycin inhibited activation of p65/NF-κB. This conclusion was supported by significantly reduced expression of selected NF-κB-dependent genes: cyclin D1 (CCND1), C-X-C motif chemokine ligand 8 (CXCL8), and vascular endothelial growth factor (VEGF), as shown at transcript and protein levels, as well as secretion of IL-8 and VEGF. Our study indicates that 17-aminogeldanamycin can be used for efficient inhibition of NF-κB activity and the simultaneous diminution of IL-8 and VEGF levels in the extracellular milieu of melanoma. Full article

(This article belongs to the Special Issue Signaling in Melanoma)

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11 pages, 2272 KiB

Open AccessArticle

β3-Adrenoreceptor Blockade Induces Stem Cells Differentiation in Melanoma Microenvironment

by Maura Calvani, Gennaro Bruno, Annalisa Dabraio, Angela Subbiani, Francesca Bianchini, Filippo Fontani, Gabriella Casazza, Marina Vignoli, Francesco De Logu, Stefano Frenos, Luca Filippi and Claudio Favre

Int. J. Mol. Sci. 2020, 21(4), 1420; https://doi.org/10.3390/ijms21041420 - 20 Feb 2020

Cited by 20 | Viewed by 3493

Abstract

Although there is an increasing evidence that cancer stem cell (CSC) niches in the tumor microenvironment (TME) plays a crucial role in sustaining solid tumors progression, several molecular players involved in this regulation still remain unknown. The role of β-adrenergic signaling in enhancing tumor growth through β2-adrenoreceptors (β2-ARs) has been confirmed in different cancer models, but the role played by the β3-adrenergic receptor (β3-AR) has recently emerged. Previous studies showed that β3-AR promotes cancer growth through the activation of different stromal cells in the TME, and leads to melanoma malignancy progression through inflammation, angiogenesis, and immunotolerance. Here we show that in B16 melanoma-bearing mice, the pharmacological β3-AR blockade is able to reduce the expression of CSC markers, and to induce a differentiated phenotype of hematopoietic subpopulations in TME. In particular, cytofluorimetric analysis (FACS) of the tumor mass shows that β3-AR antagonist SR59230A promotes hematopoietic differentiation as indicated by increased ratios of lymphoid/hematopoietic stem cells (HSCs) and of myeloid progenitor cells/HSCs, and increases the number of Ter119 and natural killer (NK) precursor cells, and of granulocyte precursors, indicating active hematopoiesis within the tumor tissue. Moreover, pharmacological antagonism of β3-AR induces mesenchymal stem cell (MSC) differentiation into adipocytes subtracting a potential renewal of the stem compartment by these cells. Here we demonstrate that β3-AR blockade in the TME by inducing the differentiation of different stromal cells at the expense of stemness traits could possibly have a favorable effect on the control of melanoma progression. Full article

(This article belongs to the Special Issue Signaling in Melanoma)

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14 pages, 2693 KiB

Open AccessArticle

Topical MTII Therapy Suppresses Melanoma Through PTEN Upregulation and Cyclooxygenase II Inhibition

by Jian-Ching Wu, Han-En Tsai, Yi-Hsiang Hsiao, Ji-Syuan Wu, Chieh-Shan Wu and Ming-Hong Tai

Int. J. Mol. Sci. 2020, 21(2), 681; https://doi.org/10.3390/ijms21020681 - 20 Jan 2020

Cited by 4 | Viewed by 4664

Abstract

Melanotan II (MTII), a synthetic analogue of the alpha-melanocyte stimulating hormone (α-MSH), has been applied for skin tanning in humans. However, the carcinogenic consequence of topical MTII has been equivocal. This study aims to delineate the anti-neoplastic efficacy and mechanism of MTII using the B16-F10 melanoma model in vitro and in vivo. It was found that, despite a lack of influence on proliferation, MTII potently inhibited the migration, invasion, and colony-forming capability of melanoma cells. Moreover, topical MTII application significantly attenuated the tumor progression in mice bearing established melanoma. Histological analysis revealed that MTII therapy induced apoptosis while inhibiting the proliferation and neovaluarization in melanoma tissues. By immunoblot and immunohistochemical analysis, it was found that MTII dose-dependently increased the phosphatase and tensin homolog (PTEN) protein level while reducing PTEN phosphorylation, which resulted in the inhibition of AKT/nuclear factor kappa B (NFκB) signaling. Consistently, MTII treatment inhibited cyclooxygenase II (COX-2) expression and prostaglandin E2 (PGE2) production in melanoma cells. Finally, studies of antibody neutralization suggest that the melanocortin 1 receptor (MC1R) plays a critical role in MTII-induced PTEN upregulation and melanoma suppression. Together, these results indicate that MTII elicits PTEN upregulation via MC1R, thereby suppressing melanoma progression through downregulating COX-2/PGE2 signaling. Hence, topical MTII therapy may facilitate a novel therapeutic strategy against melanoma. Full article

(This article belongs to the Special Issue Signaling in Melanoma)

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Review

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31 pages, 2857 KiB

Open AccessReview

WNT Signaling in Melanoma

by Anna Gajos-Michniewicz and Malgorzata Czyz

Int. J. Mol. Sci. 2020, 21(14), 4852; https://doi.org/10.3390/ijms21144852 - 9 Jul 2020

Cited by 148 | Viewed by 13351

Abstract

WNT-signaling controls important cellular processes throughout embryonic development and adult life, so any deregulation of this signaling can result in a wide range of pathologies, including cancer. WNT-signaling is classified into two categories: β-catenin-dependent signaling (canonical pathway) and β-catenin-independent signaling (non-canonical pathway), the latter can be further divided into WNT/planar cell polarity (PCP) and calcium pathways. WNT ligands are considered as unique directional growth factors that contribute to both cell proliferation and polarity. Origin of cancer can be diverse and therefore tissue-specific differences can be found in WNT-signaling between cancers, including specific mutations contributing to cancer development. This review focuses on the role of the WNT-signaling pathway in melanoma. The current view on the role of WNT-signaling in cancer immunity as well as a short summary of WNT pathway-related drugs under investigation are also provided. Full article

(This article belongs to the Special Issue Signaling in Melanoma)

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21 pages, 542 KiB

Open AccessReview

Targeted Therapy in Melanoma and Mechanisms of Resistance

by Anna M. Czarnecka, Ewa Bartnik, Michał Fiedorowicz and Piotr Rutkowski

Int. J. Mol. Sci. 2020, 21(13), 4576; https://doi.org/10.3390/ijms21134576 - 27 Jun 2020

Cited by 118 | Viewed by 10555

Abstract

The common mutation BRAFV600 in primary melanomas activates the mitogen-activated protein kinase/extracellular-signal-regulated kinase (MAPK/ERK) pathway and the introduction of proto-oncogene B-Raf (BRAF) and mitogen-activated protein kinase kinase (MEK) inhibitors (BRAFi and MEKi) was a breakthrough in the treatment of these cancers. However, 15–20% of tumors harbor primary resistance to this therapy, and moreover, patients develop acquired resistance to treatment. Understanding the molecular phenomena behind resistance to BRAFi/MEKis is indispensable in order to develop novel targeted therapies. Most often, resistance develops due to either the reactivation of the MAPK/ERK pathway or the activation of alternative kinase signaling pathways including phosphatase and tensin homolog (PTEN), neurofibromin 1 (NF-1) or RAS signaling. The hyperactivation of tyrosine kinase receptors, such as the receptor of the platelet-derived growth factor β (PDFRβ), insulin-like growth factor 1 receptor (IGF-1R) and the receptor for hepatocyte growth factor (HGF), lead to the induction of the AKT/3-phosphoinositol kinase (PI3K) pathway. Another pathway resulting in BRAFi/MEKi resistance is the hyperactivation of epidermal growth factor receptor (EGFR) signaling or the deregulation of microphthalmia-associated transcription factor (MITF). Full article

(This article belongs to the Special Issue Signaling in Melanoma)

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20 pages, 986 KiB

Open AccessReview

Biological Factors behind Melanoma Response to Immune Checkpoint Inhibitors

by Magdalena Olbryt, Marcin Rajczykowski and Wiesława Widłak

Int. J. Mol. Sci. 2020, 21(11), 4071; https://doi.org/10.3390/ijms21114071 - 6 Jun 2020

Cited by 31 | Viewed by 4608

Abstract

Modern immunotherapy together with targeted therapy has revolutionized the treatment of advanced melanoma. Inhibition of immune checkpoints significantly improved the median overall survival and gave hope to many melanoma patients. However, this treatment has three serious drawbacks: high cost, serious side effects, and an effectiveness limited only to approximately 50% of patients. Some patients do not derive any or short-term benefit from this treatment due to primary or secondary resistance. The response to immunotherapy depends on many factors that fall into three main categories: those associated with melanoma cells, those linked to a tumor and its microenvironment, and those classified as individual ontogenic and physiological features of the patient. The first category comprises expression of PD-L1 and HLA proteins on melanoma cells as well as genetic/genomic metrics such as mutational load, (de)activation of specific signaling pathways and epigenetic factors. The second category is the inflammatory status of the tumor: “hot” versus “cold” (i.e., high versus low infiltration of immune cells). The third category comprises metabolome and single nucleotide polymorphisms of specific genes. Here we present up-to-date data on those biological factors influencing melanoma response to immunotherapy with a special focus on signaling pathways regulating the complex process of anti-tumor immune response. We also discuss their potential predictive capacity. Full article

(This article belongs to the Special Issue Signaling in Melanoma)

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24 pages, 1952 KiB

Open AccessReview

The MNK1/2-eIF4E Axis as a Potential Therapeutic Target in Melanoma

by Sathyen A. Prabhu, Omar Moussa, Wilson H. Miller, Jr. and Sonia V. del Rincón

Int. J. Mol. Sci. 2020, 21(11), 4055; https://doi.org/10.3390/ijms21114055 - 5 Jun 2020

Cited by 20 | Viewed by 5297

Abstract

Melanoma is a type of skin cancer that originates in the pigment-producing cells of the body known as melanocytes. Most genetic aberrations in melanoma result in hyperactivation of the mitogen activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) pathways. We and others have shown that a specific protein synthesis pathway known as the MNK1/2-eIF4E axis is often dysregulated in cancer. The MNK1/2-eIF4E axis is a point of convergence for these signaling pathways that are commonly constitutively activated in melanoma. In this review we consider the functional implications of aberrant mRNA translation in melanoma and other malignancies. Moreover, we discuss the consequences of inhibiting the MNK1/2-eIF4E axis on the tumor and tumor-associated cells, and we provide important avenues for the utilization of this treatment modality in combination with other targeted and immune-based therapies. The past decade has seen the increased development of selective inhibitors to block the action of the MNK1/2-eIF4E pathway, which are predicted to be an effective therapy regardless of the melanoma subtype (e.g., cutaneous, acral, and mucosal). Full article

(This article belongs to the Special Issue Signaling in Melanoma)

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29 pages, 2289 KiB

Open AccessReview

Non-Apoptotic Cell Death Signaling Pathways in Melanoma

by Mariusz L. Hartman

Int. J. Mol. Sci. 2020, 21(8), 2980; https://doi.org/10.3390/ijms21082980 - 23 Apr 2020

Cited by 38 | Viewed by 9647

Abstract

Resisting cell death is a hallmark of cancer. Disturbances in the execution of cell death programs promote carcinogenesis and survival of cancer cells under unfavorable conditions, including exposition to anti-cancer therapies. Specific modalities of regulated cell death (RCD) have been classified based on different criteria, including morphological features, biochemical alterations and immunological consequences. Although melanoma cells are broadly equipped with the anti-apoptotic machinery and recurrent genetic alterations in the components of the RAS/RAF/MEK/ERK signaling markedly contribute to the pro-survival phenotype of melanoma, the roles of autophagy-dependent cell death, necroptosis, ferroptosis, pyroptosis, and parthanatos have recently gained great interest. These signaling cascades are involved in melanoma cell response and resistance to the therapeutics used in the clinic, including inhibitors of BRAF^mut and MEK1/2, and immunotherapy. In addition, the relationships between sensitivity to non-apoptotic cell death routes and specific cell phenotypes have been demonstrated, suggesting that plasticity of melanoma cells can be exploited to modulate response of these cells to different cell death stimuli. In this review, the current knowledge on the non-apoptotic cell death signaling pathways in melanoma cell biology and response to anti-cancer drugs has been discussed. Full article

(This article belongs to the Special Issue Signaling in Melanoma)

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