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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 December 2017) | Viewed by 79997

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Special Issue Editors

Prof. Dr. Andrzej Slominski

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Guest Editor

Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
Interests: dermatopathology; skin pigmentation; neuroendocrinology of the skin; photobiology; melanoma; steroidogenesis; vitamin D; sterols; melatonin; stress response mechanisms
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Prof. Dr. Marcus W. Bosenberg

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Guest Editor

Department of Dermatology, Yale University School of Medicine, New Haven, CT, USA
Interests: melanoma; cancer genetics; epigenetics; metabolism; cancer immunology

Prof. Dr. David M. Kaetzel

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Guest Editor

Department of Biochemistry and Molecular Biology, Greenebaum Cancer Center, School of Medicine, University of Maryland-Baltimore, Baltimore, MD, USA
Interests: UV-induced melanoma; metastasis; metastasis suppressor genes; melanoma biomarkers; growth factors; transcriptional regulation; DNA repair; stem cell biology

Special Issue Information

Dear Colleagues,

Malignant melanoma represents a significant problem in the human population, exhibiting the highest mortality rate of all skin cancers as well as a high incidence across different age groups. When the disease is localized to the skin (in situ, or is at the radial growth phase), cures are usually achieved by surgical excision. However, melanomas gain metastatic potential upon entering the vertical growth phase, indicating the importance of early and accurate histopathological diagnosis. Melanomas localized to the skin at stage II and metastatic melanomas (stages III and IV) represent particularly difficult challenges for therapy. Despite impressive recent progress in development of new therapies for metastatic disease (targeted therapy, immunotherapy, etc.), prospects for long-term survival remain grim for most patients due to acquired resistance to these agents. Moreover, these therapies are limited by adverse side effects and their high costs. Clearly the need is great for development of new strategies for advanced melanoma with long-term efficacy, improved toxicity profiles and lower costs. In this regard, a key element for progress is the utilization of appropriate animal models. Several models for human melanoma have been developed in rodents and other animals that recapitulate advanced, metastatic forms of the disease and can be employed for these efforts. This issue reviews the current state-of-the-art for experimental animal models of human melanoma, and outlines potential approaches for their application to the development of novel strategies for effective management and cure of this devastating disease.

Prof. Dr. Andrzej Slominski
Prof. Dr. Marcus W. Bosenberg
Prof. Dr. David M. Kaetzel
Guest Editors

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Keywords

Rodent models
Melanoma
Metastasis
Genetically engineered mouse models (GEMMs)
Metastasis suppressor and driver genes
Melanoma patient derived xenografts (PDXs)

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Published Papers (11 papers)

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Research

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24 pages, 9492 KiB

Open AccessArticle

Non-Metastatic Cutaneous Melanoma Induces Chronodisruption in Central and Peripheral Circadian Clocks

by Leonardo Vinícius Monteiro De Assis, Maria Nathália Moraes, Keila Karoline Magalhães-Marques, Gabriela Sarti Kinker, Sanseray Da Silveira Cruz-Machado and Ana Maria De Lauro Castrucci

Int. J. Mol. Sci. 2018, 19(4), 1065; https://doi.org/10.3390/ijms19041065 - 3 Apr 2018

Cited by 35 | Viewed by 6158

Abstract

The biological clock has received increasing interest due to its key role in regulating body homeostasis in a time-dependent manner. Cancer development and progression has been linked to a disrupted molecular clock; however, in melanoma, the role of the biological clock is largely unknown. We investigated the effects of the tumor on its micro- (TME) and macro-environments (TMaE) in a non-metastatic melanoma model. C57BL/6J mice were inoculated with murine B16-F10 melanoma cells and 2 weeks later the animals were euthanized every 6 h during 24 h. The presence of a localized tumor significantly impaired the biological clock of tumor-adjacent skin and affected the oscillatory expression of genes involved in light- and thermo-reception, proliferation, melanogenesis, and DNA repair. The expression of tumor molecular clock was significantly reduced compared to healthy skin but still displayed an oscillatory profile. We were able to cluster the affected genes using a human database and distinguish between primary melanoma and healthy skin. The molecular clocks of lungs and liver (common sites of metastasis), and the suprachiasmatic nucleus (SCN) were significantly affected by tumor presence, leading to chronodisruption in each organ. Taken altogether, the presence of non-metastatic melanoma significantly impairs the organism’s biological clocks. We suggest that the clock alterations found in TME and TMaE could impact development, progression, and metastasis of melanoma; thus, making the molecular clock an interesting pharmacological target. Full article

(This article belongs to the Special Issue Animal Models of Melanoma)

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13 pages, 8949 KiB

Open AccessArticle

Visualization and Quantitative 3D Analysis of Intraocular Melanoma and Its Vascularization in a Hamster Eye

by Bartosz Leszczyński, Martyna Śniegocka, Andrzej Wróbel, Roman Pędrys, Małgorzata Szczygieł, Bożena Romanowska-Dixon, Krystyna Urbańska and Martyna Elas

Int. J. Mol. Sci. 2018, 19(2), 332; https://doi.org/10.3390/ijms19020332 - 24 Jan 2018

Cited by 6 | Viewed by 4873

Abstract

A tumor vasculature network undergoes intense growth and rebuilding during tumor growth. Traditionally, vascular networks are histologically examined using parameters such as vessel density determined from two-dimensional slices of the tumor. Two-dimensional probing of a complicated three-dimensional (3D) structure only provides partial information. Therefore, we propose the use of microcomputed tomography (micro-CT) imaging to analyze the evolution of a tumor vasculature in an experimental ocular tumor model. A Bomirski Hamster Melanoma was implanted in the anterior chamber of a hamster eye. Ultrasound (US) imaging of the same tumor was performed in vivo, and the vascular results obtained using the two methods were compared. Normal ocular tissues, a tumor, and a tumor vascular structure were revealed with high accuracy using micro-CT. The vessels that grew within the tumor were chaotic, leaky, and contained many convoluted micro-vessels and embolizations. They comprised 20–38% of the tumor mass. The blood flow in the larger functional vessels was in the range from 10 to 25 mm/s, as determined by in vivo Doppler US. The micro-CT imaging of the hamster eyeball enabled both qualitative and quantitative 3D analyses of the globe at a histological level. Although the presented images were obtained ex vivo, micro-CT noninvasive imaging is being developed intensively, and high-resolution in vivo imaging is feasible. Full article

(This article belongs to the Special Issue Animal Models of Melanoma)

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1631 KiB

Open AccessArticle

Dermal Delivery of Constructs Encoding Cre Recombinase to Induce Skin Tumors in Pten^LoxP/LoxP;Braf^CA/+ Mice

by Marcel A. Deken, Ji-Ying Song, Jules Gadiot, Adriaan D. Bins, Paula Kroon, Inge Verbrugge and Christian U. Blank

Int. J. Mol. Sci. 2016, 17(12), 2149; https://doi.org/10.3390/ijms17122149 - 20 Dec 2016

Cited by 1 | Viewed by 7221

Abstract

Current genetically-engineered mouse melanoma models are often based on Tyr::CreER^T2-controlled MAPK pathway activation by the BRAF^V600E mutation and PI3K pathway activation by loss of PTEN. The major drawback of these models is the occurrence of spontaneous tumors caused by leakiness of the Tyr::CreER^T2 system, hampering long-term experiments. To address this problem, we investigated several approaches to optimally provide local delivery of Cre recombinase, including injection of lentiviral particles, DNA tattoo administration and particle-mediated gene transfer, to induce melanomas in Pten^LoxP/LoxP;Braf^CA/+ mice lacking the Tyr::CreER^T2 allele. We found that dermal delivery of the Cre recombinase gene under the control of a non-specific CAG promoter induced the formation of melanomas, but also keratoacanthoma and squamous cell carcinomas. Delivery of Cre recombinase DNA under the control of melanocyte-specific promoters in Pten^LoxP/LoxP;Braf^CA/+ mice resulted in sole melanoma induction. The growth rate and histological features of the induced tumors were similar to 4-hydroxytamoxifen-induced tumors in Tyr::CreER^T2;Pten^LoxP/LoxP;Braf^CA/+ mice, while the onset of spontaneous tumors was prevented completely. These novel induction methods will allow long-term experiments in mouse models of skin malignancies. Full article

(This article belongs to the Special Issue Animal Models of Melanoma)

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Review

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18 pages, 615 KiB

Open AccessReview

Cutaneous Melanoma—A Long Road from Experimental Models to Clinical Outcome: A Review

by Dorina Coricovac, Cristina Dehelean, Elena-Alina Moaca, Iulia Pinzaru, Tiberiu Bratu, Dan Navolan and Ovidiu Boruga

Int. J. Mol. Sci. 2018, 19(6), 1566; https://doi.org/10.3390/ijms19061566 - 24 May 2018

Cited by 60 | Viewed by 7736

Abstract

Cutaneous melanoma is a complex disorder characterized by an elevated degree of heterogeneity, features that place it among the most aggressive types of cancer. Although significant progress was recorded in both the understanding of melanoma biology and genetics, and in therapeutic approaches, this malignancy still represents a major problem worldwide due to its high incidence and the lack of a curative treatment for advanced stages. This review offers a survey of the most recent information available regarding the melanoma epidemiology, etiology, and genetic profile. Also discussed was the topic of cutaneous melanoma murine models outlining the role of these models in understanding the molecular pathways involved in melanoma initiation, progression, and metastasis. Full article

(This article belongs to the Special Issue Animal Models of Melanoma)

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15 pages, 1162 KiB

Open AccessReview

Spatiotemporal Labeling of Melanocytes in Mice

by Sarah Preston, Shweta Aras and M. Raza Zaidi

Int. J. Mol. Sci. 2018, 19(5), 1469; https://doi.org/10.3390/ijms19051469 - 15 May 2018

Cited by 5 | Viewed by 7164

Abstract

Melanocytes are pigment producing cells in the skin that give rise to cutaneous malignant melanoma, which is a highly aggressive and the deadliest form of skin cancer. Studying melanocytes in vivo is often difficult due to their small proportion in the skin and the lack of specific cell surface markers. Several genetically-engineered mouse models (GEMMs) have been created to specifically label the melanocyte compartment. These models give both spatial and temporal control over the expression of a cellular ‘beacon’ that has an added benefit of inducible expression that can be activated on demand. Two powerful models that are discussed in this review include the melanocyte-specific, tetracycline-inducible green fluorescent protein expression system (iDct-GFP), and the fluorescent ubiquitination-based cell cycle indicator (FUCCI) model that allows for the monitoring of the cell-cycle. These two systems are powerful tools in studying melanocyte and melanoma biology. We discuss their current uses and how they could be employed to help answer unresolved questions in the fields of melanocyte and melanoma biology. Full article

(This article belongs to the Special Issue Animal Models of Melanoma)

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29 pages, 2978 KiB

Open AccessReview

Transplantable Melanomas in Hamsters and Gerbils as Models for Human Melanoma. Sensitization in Melanoma Radiotherapy—From Animal Models to Clinical Trials

by Martyna Śniegocka, Ewa Podgórska, Przemysław M. Płonka, Martyna Elas, Bożena Romanowska-Dixon, Małgorzata Szczygieł, Michał A. Żmijewski, Mirosława Cichorek, Anna Markiewicz, Anna A. Brożyna, Andrzej T. Słominski and Krystyna Urbańska

Int. J. Mol. Sci. 2018, 19(4), 1048; https://doi.org/10.3390/ijms19041048 - 1 Apr 2018

Cited by 32 | Viewed by 7330

Abstract

The focus of the present review is to investigate the role of melanin in the radioprotection of melanoma and attempts to sensitize tumors to radiation by inhibiting melanogenesis. Early studies showed radical scavenging, oxygen consumption and adsorption as mechanisms of melanin radioprotection. Experimental models of melanoma in hamsters and in gerbils are described as well as their use in biochemical and radiobiological studies, including a spontaneously metastasizing ocular model. Some results from in vitro studies on the inhibition of melanogenesis are presented as well as radio-chelation therapy in experimental and clinical settings. In contrast to cutaneous melanoma, uveal melanoma is very successfully treated with radiation, both using photon and proton beams. We point out that the presence or lack of melanin pigmentation should be considered, when choosing therapeutic options, and that both the experimental and clinical data suggest that melanin could be a target for radiosensitizing melanoma cells to increase efficacy of radiotherapy against melanoma. Full article

(This article belongs to the Special Issue Animal Models of Melanoma)

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21 pages, 506 KiB

Open AccessReview

Strengths and Weaknesses of Pre-Clinical Models for Human Melanoma Treatment: Dawn of Dogs’ Revolution for Immunotherapy

by Giuseppina Barutello, Valeria Rolih, Maddalena Arigoni, Lidia Tarone, Laura Conti, Elena Quaglino, Paolo Buracco, Federica Cavallo and Federica Riccardo

Int. J. Mol. Sci. 2018, 19(3), 799; https://doi.org/10.3390/ijms19030799 - 10 Mar 2018

Cited by 36 | Viewed by 7968

Abstract

Despite several therapeutic advances, malignant melanoma still remains a fatal disease for which novel and long-term curative treatments are needed. The successful development of innovative therapies strongly depends on the availability of appropriate pre-clinical models. For this purpose, several mouse models holding the promise to provide insight into molecular biology and clinical behavior of melanoma have been generated. The most relevant ones and their contribution for the advancement of therapeutic approaches for the treatment of human melanoma patients will be here summarized. However, as models, mice do not recapitulate all the features of human melanoma, thus their strengths and weaknesses need to be carefully identified and considered for the translation of the results into the human clinics. In this panorama, the concept of comparative oncology acquires a priceless value. The revolutionary importance of spontaneous canine melanoma as a translational model for the pre-clinical investigation of melanoma progression and treatment will be here discussed, with a special consideration to the development of innovative immunotherapeutic approaches. Full article

(This article belongs to the Special Issue Animal Models of Melanoma)

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19 pages, 8260 KiB

Open AccessReview

Naturally Occurring Canine Melanoma as a Predictive Comparative Oncology Model for Human Mucosal and Other Triple Wild-Type Melanomas

by Belen Hernandez, Hibret A. Adissu, Bih-Rong Wei, Helen T. Michael, Glenn Merlino and R. Mark Simpson

Int. J. Mol. Sci. 2018, 19(2), 394; https://doi.org/10.3390/ijms19020394 - 30 Jan 2018

Cited by 92 | Viewed by 9834

Abstract

Melanoma remains mostly an untreatable fatal disease despite advances in decoding cancer genomics and developing new therapeutic modalities. Progress in patient care would benefit from additional predictive models germane for human disease mechanisms, tumor heterogeneity, and therapeutic responses. Toward this aim, this review documents comparative aspects of human and naturally occurring canine melanomas. Clinical presentation, pathology, therapies, and genetic alterations are highlighted in the context of current basic and translational research in comparative oncology. Somewhat distinct from sun exposure-related human cutaneous melanomas, there is growing evidence that a variety of gene copy number alterations and protein structure/function mutations play roles in canine melanomas, in circumstances more analogous to human mucosal melanomas and to some extent other melanomas with murine sarcoma viral oncogene homolog B (BRAF), Neuroblastoma RAS Viral (V-Ras) Oncogene Homolog (NRAS), and neurofibromin 1 tumor suppressor NF1 triple wild-type genotype. Gaps in canine genome annotation, as well as an insufficient number and depth of sequences covered, remain considerable barriers to progress and should be collectively addressed. Preclinical approaches can be designed to include canine clinical trials addressing immune modulation as well as combined-targeted inhibition of Rat Sarcoma Superfamily/Mitogen-activated protein kinase (RAS/MAPK) and/or Phosphatidylinositol-3-Kinase/Protein Kinase B/Mammalian target of rapamycin (PI3K/AKT/mTOR) signal transduction, pathways frequently activated in both human and canine melanomas. Future investment should be aimed towards improving understanding of canine melanoma as a predictive preclinical surrogate for human melanoma and for mutually benefiting these uniquely co-dependent species. Full article

(This article belongs to the Special Issue Animal Models of Melanoma)

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6429 KiB

Open AccessReview

Patient-Derived Orthotopic Xenograft (PDOX) Models of Melanoma

by Robert M. Hoffman

Int. J. Mol. Sci. 2017, 18(9), 1875; https://doi.org/10.3390/ijms18091875 - 31 Aug 2017

Cited by 29 | Viewed by 7521

Abstract

Metastatic melanoma is a recalcitrant tumor. Although “targeted” and immune therapies have been highly touted, only relatively few patients have had durable responses. To overcome this problem, our laboratory has established the melanoma patient-derived orthotopic xenograft (PDOX) model with the use of surgical orthotopic implantation (SOI). Promising results have been obtained with regard to identifying effective approved agents and experimental therapeutics, as well as combinations of the two using the melanoma PDOX model. Full article

(This article belongs to the Special Issue Animal Models of Melanoma)

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2515 KiB

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The HGF/SF Mouse Model of UV-Induced Melanoma as an In Vivo Sensor for Metastasis-Regulating Gene

by M. Kathryn Leonard, Nidhi Pamidimukkala, Gemma S. Puts, Devin E. Snyder, Andrzej T. Slominski and David M. Kaetzel

Int. J. Mol. Sci. 2017, 18(8), 1647; https://doi.org/10.3390/ijms18081647 - 28 Jul 2017

Cited by 6 | Viewed by 4992

Abstract

Cutaneous malignant melanoma is an aggressive and potentially lethal form of skin cancer, particularly in its advanced and therapy-resistant stages, and the need for novel therapeutics and prognostic tools is acute. Incidence of melanoma has steadily increased over the past few decades, with exposure to the genome-damaging effects of ultraviolet radiation (UVR) well-recognized as a primary cause. A number of genetically-engineered mouse models (GEMMs) have been created that exhibit high incidence of spontaneous and induced forms of melanoma, and a select subset recapitulates its progression to aggressive and metastatic forms. These GEMMs hold considerable promise for providing insights into advanced stages of melanoma, such as potential therapeutic targets and prognostic markers, and as in vivo systems for testing of novel therapies. In this review, we summarize how the HGF/SF transgenic mouse has been used to reveal metastasis-regulating activity of four different genes (CDK4^R24C, survivin and NME1/NME2) in the context of UV-induced melanoma. We also discuss how these models can potentially yield new strategies for clinical management of melanoma in its most aggressive forms. Full article

(This article belongs to the Special Issue Animal Models of Melanoma)

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Open AccessCase Report

Pigmented Epithelioid Melanocytoma (PEM)/Animal Type Melanoma (ATM): Quest for an Origin. Report of One Unusual Case Indicating Follicular Origin and Another Arising in an Intradermal Nevus

by Ashley Tarasen, J. Andrew Carlson, M. Kathryn Leonard, Glenn Merlino, David Kaetzel and Andrzej T. Slominski

Int. J. Mol. Sci. 2017, 18(8), 1769; https://doi.org/10.3390/ijms18081769 - 15 Aug 2017

Cited by 6 | Viewed by 7411

Abstract

Pigmented epithelioid melanocytoma (PEM) is a tumor encompassing epithelioid blue nevus of Carney complex (EBN of CNC) and was previously termed animal-type melanoma. Histologically PEMs are heavily pigmented spindled and epithelioid dermal melanocytic tumors with infiltrative borders, however, their origin remains unclear. Stem cells for the epidermis and hair follicle are located in the bulge area of the hair follicle with the potential to differentiate into multiple lineages. Multiple cutaneous carcinomas, including follicular cutaneous squamous cell carcinoma (FSCC), are thought to arise from stem cells in the follicular bulge. We present two cases of PEM/ATM in a 63 year-old male on the scalp with follicular origin and a 72 year-old female on the upper back arising in an intradermal nevus. Biopsy of both cases revealed a proliferation of heavily pigmented dermal nests of melanocytes with atypia. The Case 1 tumor was in continuation with the outer root sheath of the hair follicle in the bulge region. Case 2 arose in an intradermal melanocytic nevus. Rare mitotic figures, including atypical mitotic figures, were identified in both cases. We present two cases of PEM, with histologic evidence suggesting two origins: one from the follicular bulb and one from an intradermal nevus. Full article

(This article belongs to the Special Issue Animal Models of Melanoma)

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