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Slominski RM, Kim TK, Janjetovic Z, Brożyna AA, Podgorska E, Dixon KM, Mason RS, Tuckey RC, Sharma R, Crossman DK, Elmets C, Raman C, Jetten AM, Indra AK, Slominski AT. Malignant Melanoma: An Overview, New Perspectives, and Vitamin D Signaling. Cancers (Basel) 2024; 16:2262. [PMID: 38927967 PMCID: PMC11201527 DOI: 10.3390/cancers16122262] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2024] [Revised: 06/09/2024] [Accepted: 06/14/2024] [Indexed: 06/28/2024] Open
Abstract
Melanoma, originating through malignant transformation of melanin-producing melanocytes, is a formidable malignancy, characterized by local invasiveness, recurrence, early metastasis, resistance to therapy, and a high mortality rate. This review discusses etiologic and risk factors for melanoma, diagnostic and prognostic tools, including recent advances in molecular biology, omics, and bioinformatics, and provides an overview of its therapy. Since the incidence of melanoma is rising and mortality remains unacceptably high, we discuss its inherent properties, including melanogenesis, that make this disease resilient to treatment and propose to use AI to solve the above complex and multidimensional problems. We provide an overview on vitamin D and its anticancerogenic properties, and report recent advances in this field that can provide solutions for the prevention and/or therapy of melanoma. Experimental papers and clinicopathological studies on the role of vitamin D status and signaling pathways initiated by its active metabolites in melanoma prognosis and therapy are reviewed. We conclude that vitamin D signaling, defined by specific nuclear receptors and selective activation by specific vitamin D hydroxyderivatives, can provide a benefit for new or existing therapeutic approaches. We propose to target vitamin D signaling with the use of computational biology and AI tools to provide a solution to the melanoma problem.
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Affiliation(s)
- Radomir M. Slominski
- Department of Rheumatology and Clinical Immunology, Department of Medicine, School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA;
| | - Tae-Kang Kim
- Department of Dermatology, School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA; (T.-K.K.); (Z.J.); (E.P.); (C.E.); (C.R.)
| | - Zorica Janjetovic
- Department of Dermatology, School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA; (T.-K.K.); (Z.J.); (E.P.); (C.E.); (C.R.)
| | - Anna A. Brożyna
- Department of Human Biology, Institute of Biology, Faculty of Biological and Veterinary Sciences, Nicolaus Copernicus University, 87-100 Torun, Poland;
| | - Ewa Podgorska
- Department of Dermatology, School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA; (T.-K.K.); (Z.J.); (E.P.); (C.E.); (C.R.)
| | - Katie M. Dixon
- School of Medical Sciences, The University of Sydney, Sydney, NSW 2050, Australia; (K.M.D.); (R.S.M.)
| | - Rebecca S. Mason
- School of Medical Sciences, The University of Sydney, Sydney, NSW 2050, Australia; (K.M.D.); (R.S.M.)
| | - Robert C. Tuckey
- School of Molecular Sciences, University of Western Australia, Perth, WA 6009, Australia;
| | - Rahul Sharma
- Department of Biomedical Informatics and Data Science, School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA;
| | - David K. Crossman
- Department of Genetics and Bioinformatics, School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA;
| | - Craig Elmets
- Department of Dermatology, School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA; (T.-K.K.); (Z.J.); (E.P.); (C.E.); (C.R.)
| | - Chander Raman
- Department of Dermatology, School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA; (T.-K.K.); (Z.J.); (E.P.); (C.E.); (C.R.)
| | - Anton M. Jetten
- Cell Biology Section, NIEHS—National Institutes of Health, Research Triangle Park, NC 27709, USA;
| | - Arup K. Indra
- Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, OR 97331, USA
- Department of Dermatology, Oregon Health & Science University, Portland, OR 97239, USA
- Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA
| | - Andrzej T. Slominski
- Department of Dermatology, School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA; (T.-K.K.); (Z.J.); (E.P.); (C.E.); (C.R.)
- Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA
- Pathology and Laboratory Medicine Service, Veteran Administration Medical Center, Birmingham, AL 35233, USA
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Kuźbicki Ł, Brożyna AA. The markers auxiliary in differential diagnosis of early melanomas and benign nevi sharing some similar features potentially leading to misdiagnosis - a review of immunohistochemical studies. Cancer Invest 2022; 40:852-867. [PMID: 36214582 DOI: 10.1080/07357907.2022.2134415] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
Abstract
Although most melanocytic skin lesions are correctly diagnosed, numerous studies have shown interobserver disagreement. This review analyzes 20 molecules as immunohistochemical markers for distinguishing dysplastic and/or Spitz nevi from early melanomas (in situ, Clark level I or II and/or Breslow thickness at most 1 mm). The detected presence and/or level of tested molecules was significantly different in early melanomas than in dysplastic and Spitz nevi for six and seven potential markers, respectively. The most promising results were obtained for 5-hydroxymethylcytosine, cyclooxygenase-2 and PReferentially expressed Antigen in MElanoma whose levels were different in dysplastic and Spitz nevi compared to early melanomas.
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Affiliation(s)
- Łukasz Kuźbicki
- Department of Human Biology, Institute of Biology, Faculty of Biological and Veterinary Sciences, Nicolaus Copernicus University in Toruń, Toruń, Poland
| | - Anna A Brożyna
- Department of Human Biology, Institute of Biology, Faculty of Biological and Veterinary Sciences, Nicolaus Copernicus University in Toruń, Toruń, Poland
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Wang L, Wang L, Zhang Y, Zhao Z, Liu C, Li M, Liu J, Wang S, Yang D, Luo F, Yan J. LS-HB-Mediated Photodynamic Therapy Inhibits Proliferation and Induces Cell Apoptosis in Melanoma. Mol Pharm 2022; 19:2607-2619. [PMID: 35485954 DOI: 10.1021/acs.molpharmaceut.2c00302] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Chlorin e6-C-15-ethyl ester (LS-HB), a newly identified photosensitizer, was isolated from chlorin e6. The mechanism of tumor cell death induced by photodynamic therapy with LS-HB (LS-HB-PDT) is still unknown. Here, we investigated the photophysical properties of LS-HB, evaluated the antitumor effect on melanoma in vitro and in vivo, and explored its possible mechanisms. LS-HB not only has an optimal spectral band of red wavelength (660 nm) for photosensitization but also has favorable photostability. More importantly, LS-HB-PDT elicited a potent dose-dependent phototoxic effect in vitro. We discovered that LS-HB located in the mitochondria of B16F10 cells was able to generate excess reactive oxygen species, which subsequently resulted in mitochondrial membrane potential loss and induced apoptosis via caspase-9 and caspase-3 pathways. Moreover, PDT with LS-HB markedly inhibited the growth of melanoma in vivo. Therefore, LS-HB is expected to be an effective potential photosensitizer in antitumor therapy.
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Affiliation(s)
- Lanlan Wang
- Cancer Research Center, School of Medicine, Xiamen University, Xiamen, Fujian 361102, China
| | - Li Wang
- Cancer Research Center, School of Medicine, Xiamen University, Xiamen, Fujian 361102, China
| | - Yang Zhang
- Fuzhou Neuro-Psychiatric Hospital Affiliated to Fujian Medical University, Fuzhou, Fujian 350008, China
| | - Zhiyu Zhao
- Cancer Research Center, School of Medicine, Xiamen University, Xiamen, Fujian 361102, China
| | - Cong Liu
- Cancer Research Center, School of Medicine, Xiamen University, Xiamen, Fujian 361102, China
| | - Mengqi Li
- Cancer Research Center, School of Medicine, Xiamen University, Xiamen, Fujian 361102, China
| | - Jiajing Liu
- Cancer Research Center, School of Medicine, Xiamen University, Xiamen, Fujian 361102, China
| | - Shengyu Wang
- Cancer Research Center, School of Medicine, Xiamen University, Xiamen, Fujian 361102, China
| | - Dong Yang
- Cancer Research Center, School of Medicine, Xiamen University, Xiamen, Fujian 361102, China
| | - Fanghong Luo
- Cancer Research Center, School of Medicine, Xiamen University, Xiamen, Fujian 361102, China
| | - Jianghua Yan
- Cancer Research Center, School of Medicine, Xiamen University, Xiamen, Fujian 361102, China
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Jung E, Shim I, An J, Ji MS, Jangili P, Chi SG, Kim JS. Phenylthiourea-Conjugated BODIPY as an Efficient Photosensitizer for Tyrosinase-Positive Melanoma-Targeted Photodynamic Therapy. ACS APPLIED BIO MATERIALS 2021; 4:2120-2127. [PMID: 35014340 DOI: 10.1021/acsabm.0c01322] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Melanoma is the most threatening form of metastatic skin cancer that develops from melanocytes and causes a large majority of deaths due to poor therapeutic prognosis. It has significant limitations in treatment because it shows great resistance to chemotherapy, radiotherapy, and other therapeutic methods. A noninvasive and clinically accepted therapeutic modality, photodynamic therapy (PDT), is a promising treatment option, but it is limitedly applied for melanoma skin cancer treatment. This is because most of the photosensitizers are unlikely to be expected to have a remarkable effect on melanoma due to drug efflux by melanin pigmentation and intrinsic antioxidant defense mechanisms. Moreover, melanin is a dominant absorber in the spectral region of 500-600 nm that can cause the decreased photoreaction efficiency of photosensitizers. Herein, to overcome these drawbacks, we have developed a phenylthiourea-conjugated BODIPY photosensitizer (PTUBDP) for tyrosinase-positive melanoma-targeted PDT. In light of our results, it exhibited an enhanced cytotoxic efficacy compared to BDP, a parallel PDT agent that absence of phenylthiourea unit. PTUBDP shows outstanding effects of increased oxidative stress by an enhanced cellular uptake of the tyrosinase positive melanoma cell line (B16F10). This work presents increased therapeutic efficacy through the combined therapeutic approach, enabling enhanced reactive oxygen species (ROS) generation as well as overcoming the critical limitations of melanoma.
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Affiliation(s)
- Eugeine Jung
- Department of Chemistry, Korea University, Seoul 02841, Korea
- Department of Life Sciences, Korea University, Seoul 02841, Korea
| | - Inseob Shim
- Department of Chemistry, Korea University, Seoul 02841, Korea
| | - Jusung An
- Department of Chemistry, Korea University, Seoul 02841, Korea
| | - Myung Sun Ji
- Department of Chemistry, Korea University, Seoul 02841, Korea
| | | | - Sung-Gil Chi
- Department of Life Sciences, Korea University, Seoul 02841, Korea
| | - Jong Seung Kim
- Department of Chemistry, Korea University, Seoul 02841, Korea
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Naik PP. Cutaneous Malignant Melanoma: A Review of Early Diagnosis and Management. World J Oncol 2021; 12:7-19. [PMID: 33738001 PMCID: PMC7935621 DOI: 10.14740/wjon1349] [Citation(s) in RCA: 71] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2020] [Accepted: 12/23/2020] [Indexed: 02/06/2023] Open
Abstract
Cutaneous melanoma (CM) is a malignant tumor formed from pigment-producing cells called melanocytes. It is one of the most aggressive and fatal forms of skin malignancy. In the last decades, CM's incidence has gradually risen, with 351,880 new cases in 2015. Since the 1960s, its incidence has increased steadily, in 2019, with approximately 96,000 new cases. A greater understanding of early diagnosis and management of CM is urgently needed because of the high mortality rates due to metastatic melanoma. Timely detection of melanoma is crucial for successful treatment, but diagnosis with histopathology may also pose a significant challenge to this objective. Early diagnosis and management are essential and contribute to better survival rates of the patient. To better control this malignancy, such information is expected to be particularly useful in the early detection of possible metastatic lesions and the development of new therapeutic approaches. This article reviews the available information on the early diagnosis and management of CM and discusses such information's potential in facilitating the future prospective.
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Affiliation(s)
- Piyu Parth Naik
- Department of Dermatology, Saudi German Hospitals and Clinics, Hessa Street 331 West, Al Barsha 3, Exit 36 Sheikh Zayed Road, Opposite of American School, Dubai, United Arab Emirates.
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Cecchi R, De Gaudio C, Buralli L, Innocenti S. Lymphatic Mapping and Sentinel Lymph Node Biopsy in the Management of Primary Cutaneous Melanoma: Report of a Single-centre Experience. TUMORI JOURNAL 2019; 92:113-7. [PMID: 16724689 DOI: 10.1177/030089160609200205] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Aims and Background Lymphatic mapping and sentinel lymph node biopsy provide important prognostic data in patients with early stage melanoma and are crucial in guiding the management of the tumor. We report our experience with lymphatic mapping and sentinel lymph node biopsy in a group of patients with primary cutaneous melanoma and discuss recent concepts and controversies on its use. Patients and Methods A total of 111 patients with stage I-II AJCC primary cutaneous melanoma underwent lymphatic mapping and sentinel lymph node biopsy from December 1999 through December 2004 using a standardized technique of preoperative lymphoscintigraphy and biopsy guided by blue dye injection in addition to a hand-held gamma probe. After removal, sentinel lymph nodes were submitted to serial sectioning and permanent preparations for histological and immunohistochemical examination. Complete lymph node dissection was performed only in patients with tumor-positive sentinel lymph nodes. Results Sentinel lymph nodes were identified and removed in all patients (detection rate of 100%), and metastases were found in 17 cases (15.3%). The incidence of metastasis in sentinel lymph nodes was 2.1%, 15.9%, 35.2%, and 41.6% for melanomas < or 1.0, 1.01-2.0, 2.01-4.0, and > 4.0 mm in thickness, respectively. Complete lymph node dissection was performed in 15 of 17 patients with positive sentinel lymph nodes, and metastases in non-sentinel lymph nodes were detected in only 2 cases (11.7%). Recurrences were more frequently observed in patients with a positive than in those with negative sentinel lymph node (41.1% vs 5.3% at a median follow-up of 31.5 months, P<0.001). The false-negative rate was 2.1%. Conclusions Our study confirms that lymphatic mapping and sentinel lymph node biopsy allow accurate staging and yield relevant prognostic information in patients with early stage melanoma.
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Affiliation(s)
- Roberto Cecchi
- Cutaneous Surgery Service, Pistoia Hospital, Pistoia, Italy.
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Mancera N, Smalley KSM, Margo CE. Melanoma of the eyelid and periocular skin: Histopathologic classification and molecular pathology. Surv Ophthalmol 2019; 64:272-288. [PMID: 30578807 DOI: 10.1016/j.survophthal.2018.12.002] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Revised: 12/12/2018] [Accepted: 12/12/2018] [Indexed: 12/29/2022]
Abstract
Cutaneous melanoma, a potentially lethal malignancy of the periocular skin, represents only a small proportion of the roughly 87,000 new cases of cutaneous melanoma diagnosed annually in the United States. Most of our understanding of melanoma of the eyelid skin is extrapolated from studies of cutaneous melanoma located elsewhere. Recent years have witnessed major breakthroughs in molecular biology and genomics of cutaneous melanoma, some of which have led to the development of targeted therapies. The molecular insights have also kindled interest in rethinking how cutaneous melanomas are classified and assessed for risk. We provide a synopsis of the epidemiology, histopathologic classification, and clinical experience of eyelid melanoma since 1990 and then review major advances in the molecular biology of cutaneous melanoma, exploring how this impacts our understanding of classification and predicting risk.
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Affiliation(s)
- Norberto Mancera
- Department of Ophthalmology, Morsani College of Medicine, University of South Florida, Tampa, Florida, USA.
| | - Keiran S M Smalley
- Departments of Tumor Biology, The Moffitt Cancer Center & Research Institute, Tampa, Florida, USA; Cutaneous Oncology The Moffitt Cancer Center & Research Institute, Tampa, Florida, USA
| | - Curtis E Margo
- Department of Ophthalmology, Morsani College of Medicine, University of South Florida, Tampa, Florida, USA; Department of Pathology and Cell Biology, Morsani College of Medicine, University of South Florida, Tampa, Florida, USA
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Baldea I, Giurgiu L, Teacoe ID, Olteanu DE, Olteanu FC, Clichici S, Filip GA. Photodynamic Therapy in Melanoma - Where do we Stand? Curr Med Chem 2019; 25:5540-5563. [PMID: 29278205 DOI: 10.2174/0929867325666171226115626] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2017] [Revised: 11/21/2017] [Accepted: 11/29/2017] [Indexed: 12/19/2022]
Abstract
BACKGROUND Malignant melanoma is one of the most aggressive malignant tumors, with unpredictable evolution. Despite numerous therapeutic options, like chemotherapy, BRAF inhibitors and immunotherapy, advanced melanoma prognosis remains severe. Photodynamic therapy (PDT) has been successfully used as the first line or palliative therapy for the treatment of lung, esophageal, bladder, non melanoma skin and head and neck cancers. However, classical PDT has shown some drawbacks that limit its clinical application in melanoma. OBJECTIVE The most important challenge is to overcome melanoma resistance, due to melanosomal trapping, presence of melanin, enhanced oxidative stress defense, defects in the apoptotic pathways, immune evasion, neoangiogenesis stimulation. METHOD In this review we considered: (1) main signaling molecular pathways deregulated in melanoma as potential targets for personalized therapy, including PDT, (2) results of the clinical studies regarding PDT of melanoma, especially advanced metastatic stage, (3) progresses made in the design of anti-melanoma photosensitizers (4) inhibition of tumor neoangiogenesis, as well as (5) advantages of the derived therapies like photothermal therapy, sonodynamic therapy. RESULTS PDT represents a promising alternative palliative treatment for advanced melanoma patients, mainly due to its minimal invasive character and low side effects. Efficient melanoma PDT requires: (1) improved, tumor targeted, NIR absorbing photosensitizers, capable of inducing high amounts of different ROS inside tumor and vasculature cells, possibly allowing a theranostic approach; (2) an efficient adjuvant immune therapy. CONCLUSION Combination of PDT with immune stimulation might be the key to overcome the melanoma resistance and to obtain better, sustainable clinical results.
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Affiliation(s)
- Ioana Baldea
- Physiology Department, University of Medicine and Pharmacy, Iuliu Hatieganu, Cluj-Napoca, Romania
| | - Lorin Giurgiu
- Physiology Department, University of Medicine and Pharmacy, Iuliu Hatieganu, Cluj-Napoca, Romania
| | - Ioana Diana Teacoe
- Physiology Department, University of Medicine and Pharmacy, Iuliu Hatieganu, Cluj-Napoca, Romania
| | - Diana Elena Olteanu
- Physiology Department, University of Medicine and Pharmacy, Iuliu Hatieganu, Cluj-Napoca, Romania
| | - Florin Catalin Olteanu
- Industrial Engineering and Management Department, Transylvania University, Brasov, Romania
| | - Simona Clichici
- Physiology Department, University of Medicine and Pharmacy, Iuliu Hatieganu, Cluj-Napoca, Romania
| | - Gabriela Adriana Filip
- Physiology Department, University of Medicine and Pharmacy, Iuliu Hatieganu, Cluj-Napoca, Romania
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P Santos I, van Doorn R, Caspers PJ, Bakker Schut TC, Barroso EM, Nijsten TEC, Noordhoek Hegt V, Koljenović S, Puppels GJ. Improving clinical diagnosis of early-stage cutaneous melanoma based on Raman spectroscopy. Br J Cancer 2018; 119:1339-1346. [PMID: 30410059 PMCID: PMC6265324 DOI: 10.1038/s41416-018-0257-9] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2018] [Revised: 08/06/2018] [Accepted: 08/17/2018] [Indexed: 12/31/2022] Open
Abstract
Background Clinical diagnosis of early melanoma (Breslow thickness less than 0.8 mm) is crucial to disease-free survival. However, it is subjective and can be exceedingly difficult, leading to missed melanomas, or unnecessary excision of benign pigmented skin lesions. An objective technique is needed to improve the diagnosis of early melanoma. Methods We have developed a method to improve diagnosis of (thin) melanoma, based on Raman spectroscopy. In an ex vivo study in a tertiary referral (pigmented lesions) centre, high-wavenumber Raman spectra were collected from 174 freshly excised melanocytic lesions suspicious for melanoma. Measurements were performed on multiple locations within the lesions. A diagnostic model was developed and validated on an independent data set of 96 lesions. Results Approximately 60% of the melanomas included in this study were melanomas in situ. The invasive melanomas had an average Breslow thickness of 0.89 mm. The diagnostic model correctly classified all melanomas (including in situ) with a specificity of 43.8%, and showed a potential improvement of the number needed to treat from 6.0 to 2.7, at a sensitivity of 100%. Conclusion This work signifies an important step towards accurate and objective clinical diagnosis of melanoma and in particular melanoma with Breslow thickness <0.8 mm.
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Affiliation(s)
- Inês P Santos
- Department of Dermatology, Erasmus MC, Erasmus University Medical Center Rotterdam, Rotterdam, Netherlands
| | - Remco van Doorn
- Department of Dermatology, Leiden University Medical Center, Leiden, Netherlands
| | - Peter J Caspers
- Department of Dermatology, Erasmus MC, Erasmus University Medical Center Rotterdam, Rotterdam, Netherlands
| | - Tom C Bakker Schut
- Department of Dermatology, Erasmus MC, Erasmus University Medical Center Rotterdam, Rotterdam, Netherlands
| | - Elisa M Barroso
- Department of Oral & Maxillofacial Surgery, Special Dental Care, and Orthodontics, Erasmus MC, Erasmus University Medical Center Rotterdam, Rotterdam, Netherlands
| | - Tamar E C Nijsten
- Department of Dermatology, Erasmus MC, Erasmus University Medical Center Rotterdam, Rotterdam, Netherlands
| | - Vincent Noordhoek Hegt
- Department of Pathology, Erasmus MC, Erasmus University Medical Center Rotterdam, Rotterdam, Netherlands
| | - Senada Koljenović
- Department of Pathology, Erasmus MC, Erasmus University Medical Center Rotterdam, Rotterdam, Netherlands
| | - Gerwin J Puppels
- Department of Dermatology, Erasmus MC, Erasmus University Medical Center Rotterdam, Rotterdam, Netherlands.
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Büch TRH, Büch EAM, Boekhoff I, Steinritz D, Aigner A. Role of Chemosensory TRP Channels in Lung Cancer. Pharmaceuticals (Basel) 2018; 11:ph11040090. [PMID: 30248976 PMCID: PMC6316293 DOI: 10.3390/ph11040090] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2018] [Revised: 09/16/2018] [Accepted: 09/18/2018] [Indexed: 12/25/2022] Open
Abstract
Transient receptor potential (TRP) channels represent a large family of cation channels and many members of the TRP family have been shown to act as polymodal receptor molecules for irritative or potentially harmful substances. These chemosensory TRP channels have been extensively characterized in primary sensory and neuronal cells. However, in recent years the functional expression of these proteins in non-neuronal cells, e.g., in the epithelial lining of the respiratory tract has been confirmed. Notably, these proteins have also been described in a number of cancer types. As sensor molecules for noxious compounds, chemosensory TRP channels are involved in cell defense mechanisms and influence cell survival following exposure to toxic substances via the modulation of apoptotic signaling. Of note, a number of cytostatic drugs or drug metabolites can activate these TRP channels, which could affect the therapeutic efficacy of these cytostatics. Moreover, toxic inhalational substances with potential involvement in lung carcinogenesis are well established TRP activators. In this review, we present a synopsis of data on the expression of chemosensory TRP channels in lung cancer cells and describe TRP agonists and TRP-dependent signaling pathways with potential relevance to tumor biology. Furthermore, we discuss a possible role of TRP channels in the non-genomic, tumor-promoting effects of inhalational carcinogens such as cigarette smoke.
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Affiliation(s)
- Thomas R H Büch
- Rudolf Boehm-Institute for Pharmacology and Toxicology, Clinical Pharmacology, Leipzig University, Haertelstrasse 16-18, D-04107 Leipzig, Germany.
| | - Eva A M Büch
- Rudolf Boehm-Institute for Pharmacology and Toxicology, Clinical Pharmacology, Leipzig University, Haertelstrasse 16-18, D-04107 Leipzig, Germany.
| | - Ingrid Boekhoff
- Walther Straub Institute of Pharmacology and Toxicology, Ludwig-Maximilian University, D-80336 Munich, Germany.
| | - Dirk Steinritz
- Walther Straub Institute of Pharmacology and Toxicology, Ludwig-Maximilian University, D-80336 Munich, Germany.
- Bundeswehr Institute of Pharmacology and Toxicology, Neuherbergstr. 11, D-80937 Munich, Germany.
| | - Achim Aigner
- Rudolf Boehm-Institute for Pharmacology and Toxicology, Clinical Pharmacology, Leipzig University, Haertelstrasse 16-18, D-04107 Leipzig, Germany.
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Bayci AWL, Baker DA, Somerset AE, Turkoglu O, Hothem Z, Callahan RE, Mandal R, Han B, Bjorndahl T, Wishart D, Bahado-Singh R, Graham SF, Keidan R. Metabolomic identification of diagnostic serum-based biomarkers for advanced stage melanoma. Metabolomics 2018; 14:105. [PMID: 30830422 DOI: 10.1007/s11306-018-1398-9] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2018] [Accepted: 07/18/2018] [Indexed: 01/02/2023]
Abstract
INTRODUCTION Melanoma is a highly aggressive malignancy and is currently one of the fastest growing cancers worldwide. While early stage (I and II) disease is highly curable with excellent prognosis, mortality rates rise dramatically after distant spread. We sought to identify differences in the metabolome of melanoma patients to further elucidate the pathophysiology of melanoma and identify potential biomarkers to aid in earlier detection of recurrence. METHODS Using 1H NMR and DI-LC-MS/MS, we profiled serum samples from 26 patients with stage III (nodal metastasis) or stage IV (distant metastasis) melanoma and compared their biochemical profiles with 46 age- and gender-matched controls. RESULTS We accurately quantified 181 metabolites in serum using a combination of 1H NMR and DI-LC-MS/MS. We observed significant separation between cases and controls in the PLS-DA scores plot (permutation test p-value = 0.002). Using the concentrations of PC-aa-C40:3, DL-carnitine, octanoyl-L-carnitine, ethanol, and methylmalonyl-L-carnitine we developed a diagnostic algorithm with an AUC (95% CI) = 0.822 (0.665-0.979) with sensitivity and specificity of 100 and 56%, respectively. Furthermore, we identified arginine, proline, tryptophan, glutamine, glutamate, glutathione and ornithine metabolism to be significantly perturbed due to disease (p < 0.05). CONCLUSION Targeted metabolomic analysis demonstrated significant differences in metabolic profiles of advanced stage (III and IV) melanoma patients as compared to controls. These differences may represent a potential avenue for the development of multi-marker serum-based assays for earlier detection of recurrences, allow for newer, more effective targeted therapy when tumor burden is less, and further elucidate the pathophysiologic changes that occur in melanoma.
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Affiliation(s)
- A W L Bayci
- Department of General Surgery, Beaumont Health, Royal Oak, MI, USA
| | - D A Baker
- Department of General Surgery, Beaumont Health, Royal Oak, MI, USA.
- Department of Surgery, Beaumont Health, 3601 W. 13 Mile Rd., Royal Oak, MI, 48073, USA.
| | - A E Somerset
- Department of General Surgery, Beaumont Health, Royal Oak, MI, USA
| | - O Turkoglu
- Department of Obstetrics and Gynecology, Beaumont Health, Royal Oak, MI, USA
| | - Z Hothem
- Department of General Surgery, Beaumont Health, Royal Oak, MI, USA
| | - R E Callahan
- Department of General Surgery, Beaumont Health, Royal Oak, MI, USA
| | - R Mandal
- Department of Biological and Computing Sciences, University of Alberta Edmonton, Edmonton, AB, Canada
| | - B Han
- Department of Biological and Computing Sciences, University of Alberta Edmonton, Edmonton, AB, Canada
| | - T Bjorndahl
- Department of Biological and Computing Sciences, University of Alberta Edmonton, Edmonton, AB, Canada
| | - D Wishart
- Department of Biological and Computing Sciences, University of Alberta Edmonton, Edmonton, AB, Canada
| | - R Bahado-Singh
- Department of Obstetrics and Gynecology, Beaumont Health, Royal Oak, MI, USA
| | - S F Graham
- Department of Obstetrics and Gynecology, Beaumont Health, Royal Oak, MI, USA
| | - R Keidan
- Department of General Surgery, Beaumont Health, Royal Oak, MI, USA
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12
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Śniegocka M, Podgórska E, Płonka PM, Elas M, Romanowska-Dixon B, Szczygieł M, Żmijewski MA, Cichorek M, Markiewicz A, Brożyna AA, Słominski AT, Urbańska K. Transplantable Melanomas in Hamsters and Gerbils as Models for Human Melanoma. Sensitization in Melanoma Radiotherapy-From Animal Models to Clinical Trials. Int J Mol Sci 2018; 19:E1048. [PMID: 29614755 PMCID: PMC5979283 DOI: 10.3390/ijms19041048] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2017] [Revised: 03/27/2018] [Accepted: 03/28/2018] [Indexed: 12/18/2022] Open
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.
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Affiliation(s)
- Martyna Śniegocka
- Department of Biophysics, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University in Kraków, 31-007 Kraków, Poland.
| | - Ewa Podgórska
- Department of Biophysics, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University in Kraków, 31-007 Kraków, Poland.
| | - Przemysław M Płonka
- Department of Biophysics, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University in Kraków, 31-007 Kraków, Poland.
| | - Martyna Elas
- Department of Biophysics, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University in Kraków, 31-007 Kraków, Poland.
| | - Bożena Romanowska-Dixon
- Department of Ophthalmology and Ocular Oncology, Medical College of Jagiellonian University in Kraków, 31-007 Kraków, Poland.
| | - Małgorzata Szczygieł
- Department of Biophysics, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University in Kraków, 31-007 Kraków, Poland.
| | - Michał A Żmijewski
- Department of Histology, Medical University of Gdansk, 80-210 Gdańsk, Poland.
| | - Mirosława Cichorek
- Department of Embryology, Medical University of Gdansk, 80-210 Gdańsk, Poland.
| | - Anna Markiewicz
- Department of Ophthalmology and Ocular Oncology, Medical College of Jagiellonian University in Kraków, 31-007 Kraków, Poland.
| | - Anna A Brożyna
- Department of Tumor Pathology and Pathomorphology, Faculty of Health Sciences, Nicolaus Copernicus University Collegium Medicum in Bydgoszcz, Oncology Centre-Prof. Franciszek Łukaszczyk Memorial Hospital, 85-796 Bydgoszcz, Poland.
- Department of Dermatology, Comprehensive Cancer Center Cancer Chemoprevention Program, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
| | - Andrzej T Słominski
- Department of Dermatology, Comprehensive Cancer Center Cancer Chemoprevention Program, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
- VA Medical Center, Birmingham, AL 35294, USA.
| | - Krystyna Urbańska
- Department of Biophysics, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University in Kraków, 31-007 Kraków, Poland.
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13
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Slominski AT, Brożyna AA, Skobowiat C, Zmijewski MA, Kim TK, Janjetovic Z, Oak AS, Jozwicki W, Jetten AM, Mason RS, Elmets C, Li W, Hoffman RM, Tuckey RC. On the role of classical and novel forms of vitamin D in melanoma progression and management. J Steroid Biochem Mol Biol 2018; 177:159-170. [PMID: 28676457 PMCID: PMC5748362 DOI: 10.1016/j.jsbmb.2017.06.013] [Citation(s) in RCA: 67] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2017] [Revised: 06/19/2017] [Accepted: 06/23/2017] [Indexed: 12/31/2022]
Abstract
Melanoma represents a significant clinical problem affecting a large segment of the population with a relatively high incidence and mortality rate. Ultraviolet radiation (UVR) is an important etiological factor in malignant transformation of melanocytes and melanoma development. UVB, while being a full carcinogen in melanomagenesis, is also necessary for the cutaneous production of vitamin D3 (D3). Calcitriol (1,25(OH)2D3) and novel CYP11A1-derived hydroxyderivatives of D3 show anti-melanoma activities and protective properties against damage induced by UVB. The former activities include inhibitory effects on proliferation, plating efficiency and anchorage-independent growth of cultured human and rodent melanomas in vitro, as well as the in vivo inhibition of tumor growth by 20(OH)D3 after injection of human melanoma cells into immunodeficient mice. The literature indicates that low levels of 25(OH)D3 are associated with more advanced melanomas and reduced patient survivals, while single nucleotide polymorphisms of the vitamin D receptor or the D3 binding protein gene affect development or progression of melanoma, or disease outcome. An inverse correlation of VDR and CYP27B1 expression with melanoma progression has been found, with low or undetectable levels of these proteins being associated with poor disease outcomes. Unexpectedly, increased expression of CYP24A1 was associated with better melanoma prognosis. In addition, decreased expression of retinoic acid orphan receptors α and γ, which can also bind vitamin D3 hydroxyderivatives, showed positive association with melanoma progression and shorter disease-free and overall survival. Thus, inadequate levels of biologically active forms of D3 and disturbances in expression of the target receptors, or D3 activating or inactivating enzymes, can affect melanomagenesis and disease progression. We therefore propose that inclusion of vitamin D into melanoma management should be beneficial for patients, at least as an adjuvant approach. The presence of multiple hydroxyderivatives of D3 in skin that show anti-melanoma activity in experimental models and which may act on alternative receptors, will be a future consideration when planning which forms of vitamin D to use for melanoma therapy.
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Affiliation(s)
- Andrzej T Slominski
- Department of Dermatology, Birmingham, AL, 35294, USA; Comprehensive Cancer Center, Cancer Chemoprevention Program, Birmingham, AL, 35294, USA; Nutrition Obesity Research Center, University of Alabama at Birmingham, Birmingham, AL, 35294, USA; VA Medical Center, Birmingham, AL, 35294, USA; Department of Tumor Pathology and Pathomorphology, Oncology Centre - Prof. Franciszek Łukaszczyk Memorial Hospital, Bydgoszcz, Poland.
| | - Anna A Brożyna
- Department of Tumor Pathology and Pathomorphology, Oncology Centre - Prof. Franciszek Łukaszczyk Memorial Hospital, Bydgoszcz, Poland; Department of Tumor Pathology and Pathomorphology, Faculty of Health Sciences, Nicolaus Copernicus University Collegium Medicum in Bydgoszcz, Bydgoszcz, Poland
| | | | | | - Tae-Kang Kim
- Department of Dermatology, Birmingham, AL, 35294, USA
| | | | - Allen S Oak
- Department of Dermatology, Birmingham, AL, 35294, USA
| | - Wojciech Jozwicki
- Department of Tumor Pathology and Pathomorphology, Oncology Centre - Prof. Franciszek Łukaszczyk Memorial Hospital, Bydgoszcz, Poland; Department of Tumor Pathology and Pathomorphology, Faculty of Health Sciences, Nicolaus Copernicus University Collegium Medicum in Bydgoszcz, Bydgoszcz, Poland
| | - Anton M Jetten
- Immunity, Inflammation and Disease Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health,Research Triangle Park, NC 27709, United States
| | - Rebecca S Mason
- Bosch Institute & School of Medical Sciences, Sydney Medical School, The University of Sydney, Sydney, Australia
| | - Craig Elmets
- Department of Dermatology, Birmingham, AL, 35294, USA
| | - We Li
- Department of Pharmaceutical Sciences, University of Tennessee HSC, Memphis, TN 38163, USA
| | - Robert M Hoffman
- AntiCancer, Inc., San Diego, CA, USA; Department of Surgery, University of California, San Diego, CA, USA
| | - Robert C Tuckey
- School of Molecular Sciences, The University of Western Australia, Perth, WA 6009, Australia
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14
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Abstract
The activating BRAF mutation V600E and related mutations in this codon are most important for the activation of the RAS/RAF/MEK/ERK mitogen-activated protein kinase (MAPK) signalling pathway in melanoma. BRAF V600E mutations have been detected in ~40% of melanoma patients and BRAF V600K mutations in ~5% of melanoma patients. Activation of the MAPK pathway results in continuous stimulation of cell proliferation and inhibits programmed cell death. Vemurafenib (PLX4032) was developed as a low-molecular-weight molecule for the inhibition of the mutated serine-threonine kinase BRAF, and it selectively binds to the ATP-binding site of BRAF V600E kinase and inhibits its activity. The biochemical affinity of vemurafenib for mutated BRAF translates to potent inhibition of ERK phosphorylation and of cell proliferation exclusively in BRAF-mutant cell lines. In animal model experiments, it was demonstrated that vemurafenib achieved tumour regressions in cells harbouring the BRAF V600E mutation. The clinical trials with vemurafenib in unresectable metastatic melanoma in phases I, II and III for patients harbouring BRAF V600E mutations demonstrated all unexpected high objective response rates ranging between 50 and 80%. Median progression-free survival was prolonged from 2 months with dacarbazine to 7 months with vemurafenib, and median overall survival was, respectively, prolonged from 9 to 14 months. A major problem remains in the development of resistance to vemurafenib treatment after several months in the majority of patients, and multiple resistance mechanisms have already been described. Under vemurafenib treatment, about 25% of patients developed cutaneous squamous cell carcinomas of the keratoacanthoma type with low invasive potential and without the occurrence of metastasis. The overall tolerability of the drug was quite good, and many patients remained on treatment for long times. As other solid tumours like papillary thyroid cancer, colorectal cancer, non-small-cell lung cancer and ovarian cancer likewise harbour BRAF mutation, vemurafenib is also tested in these entities. In future, combinations of vemurafenib with other kinase inhibitors and with immunotherapies will improve its therapeutic potential.
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Affiliation(s)
- Claus Garbe
- Division of Dermatooncology, Department of Dermatology, University Medical Centre, Liebermeisterstr. 25, 72074, Tuebingen, Germany.
| | - Thomas K Eigentler
- Division of Dermatooncology, Department of Dermatology, University Medical Centre, Liebermeisterstr. 25, 72074, Tuebingen, Germany
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15
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Vitamin D signaling and melanoma: role of vitamin D and its receptors in melanoma progression and management. J Transl Med 2017; 97:706-724. [PMID: 28218743 PMCID: PMC5446295 DOI: 10.1038/labinvest.2017.3] [Citation(s) in RCA: 98] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2016] [Revised: 12/22/2016] [Accepted: 12/23/2016] [Indexed: 12/19/2022] Open
Abstract
Ultraviolet B (UVB), in addition to having carcinogenic activity, is required for the production of vitamin D3 (D3) in the skin which supplies >90% of the body's requirement. Vitamin D is activated through hydroxylation by 25-hydroxylases (CYP2R1 or CYP27A1) and 1α-hydroxylase (CYP27B1) to produce 1,25(OH)2D3, or through the action of CYP11A1 to produce mono-di- and trihydroxy-D3 products that can be further modified by CYP27B1, CYP27A1, and CYP24A1. The active forms of D3, in addition to regulating calcium metabolism, exert pleiotropic activities, which include anticarcinogenic and anti-melanoma effects in experimental models, with photoprotection against UVB-induced damage. These diverse effects are mediated through an interaction with the vitamin D receptor (VDR) and/or as most recently demonstrated through action on retinoic acid orphan receptors (ROR)α and RORγ. With respect to melanoma, low levels of 25(OH)D are associated with thicker tumors and reduced patient survival. Furthermore, single-nucleotide polymorphisms of VDR and the vitamin D-binding protein (VDP) genes affect melanomagenesis or disease outcome. Clinicopathological analyses have shown positive correlation between low or undetectable expression of VDR and/or CYP27B1 in melanoma with tumor progression and shorter overall (OS) and disease-free survival (DFS) times. Paradoxically, this correlation was reversed for CYP24A1 (inactivating 24-hydroxylase), indicating that this enzyme, while inactivating 1,25(OH)2D3, can activate other forms of D3 that are products of the non-canonical pathway initiated by CYP11A1. An inverse correlation has been found between the levels of RORα and RORγ expression and melanoma progression and disease outcome. Therefore, we propose that defects in vitamin D signaling including D3 activation/inactivation, and the expression and activity of the corresponding receptors, affect melanoma progression and the outcome of the disease. The existence of multiple bioactive forms of D3 and alternative receptors affecting the behavior of melanoma should be taken into consideration when applying vitamin D management for melanoma therapy.
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16
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Brożyna AA, Jóźwicki W, Roszkowski K, Filipiak J, Slominski AT. Melanin content in melanoma metastases affects the outcome of radiotherapy. Oncotarget 2017; 7:17844-53. [PMID: 26910282 PMCID: PMC4951254 DOI: 10.18632/oncotarget.7528] [Citation(s) in RCA: 166] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2016] [Accepted: 02/11/2016] [Indexed: 01/18/2023] Open
Abstract
Melanin possess radioprotective and scavenging properties, and its presence can affect the behavior of melanoma cells, its surrounding environment and susceptibility to the therapy, as showed in vitro experiments. To determine whether melanin presence in melanoma affects the efficiency of radiotherapy (RTH) we evaluated the survival time after RTH treatment in metastatic melanoma patients (n = 57). In another cohort of melanoma patients (n = 84), the relationship between melanin level and pT and pN status was determined. A significantly longer survival time was found in patients with amelanotic metastatic melanomas in comparison to the melanotic ones, who were treated with either RTH or chemotherapy (CHTH) and RTH. These differences were more significant in a group of melanoma patients treated only with RTH. A detailed analysis of primary melanomas revealed that melanin levels were significantly higher in melanoma cells invading reticular dermis than the papillary dermis. A significant reduction of melanin pigmentation in pT3 and pT4 melanomas in comparison to pT1 and T2 tumors was observed. However, melanin levels measured in pT3-pT4 melanomas developing metastases (pN1-3, pM1) were higher than in pN0 and pM0 cases. The presence of melanin in metastatic melanoma cells decreases the outcome of radiotherapy, and melanin synthesis is related to higher disease advancement. Based on our previous cell-based and clinical research and present research we also suggest that inhibition of melanogenesis can improve radiotherapy modalities. The mechanism of relationship between melanogenesis and efficacy of RTH requires additional studies, including larger melanoma patients population and orthotopic, imageable mouse models of metastatic melanoma.
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Affiliation(s)
- Anna A Brożyna
- Department of Tumour Pathology and Pathomorphology, Oncology Centre-Prof. Franciszek Łukaszczyk Memorial Hospital, Bydgoszcz, Poland.,Department of Tumour Pathology and Pathomorphology, Faculty of Health Sciences, Nicolaus Copernicus University Collegium Medicum in Bydgoszcz, Bydgoszcz, Poland
| | - Wojciech Jóźwicki
- Department of Tumour Pathology and Pathomorphology, Oncology Centre-Prof. Franciszek Łukaszczyk Memorial Hospital, Bydgoszcz, Poland.,Department of Tumour Pathology and Pathomorphology, Faculty of Health Sciences, Nicolaus Copernicus University Collegium Medicum in Bydgoszcz, Bydgoszcz, Poland
| | - Krzysztof Roszkowski
- Department of Oncology, Radiotherapy and Gynecologic Oncology, Faculty of Health Sciences, Nicolaus Copernicus University Collegium Medicum in Bydgoszcz, Bydgoszcz, Poland
| | - Jan Filipiak
- Department of Chemotherapy, Oncology Centre-Prof. Franciszek Łukaszczyk Memorial Hospital, Bydgoszcz, Poland
| | - Andrzej T Slominski
- Departments of Dermatology and Pathology, University of Alabama at Birmingham, Birmingham, AL, USA.,Laboratory Service of The VA Medical Center at Birmingham, Birmingham, AL, USA
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17
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De Souza LM, Robertson BM, Robertson GP. Future of circulating tumor cells in the melanoma clinical and research laboratory settings. Cancer Lett 2017; 392:60-70. [PMID: 28163189 DOI: 10.1016/j.canlet.2017.01.023] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2016] [Revised: 01/12/2017] [Accepted: 01/13/2017] [Indexed: 12/24/2022]
Abstract
Circulating tumor cells (CTC) have become a field of interest for oncologists based on the premise that they constitute the underpinning for metastatic dissemination. The lethal nature of cancer is no longer attributed to solid tumor formation, but rather to the process of metastasis; shifting the focus of current studies towards the isolation and identification of metastatic progenitors, such as CTCs. CTCs originate from primary tumor masses that undergo morphologic and genetic alterations, which involve the release of mesenchymal-like cancer cells into the bloodstream, capable of invading nearby tissues for secondary tumor development. Cancerous cells contained in the primary tumor mass acquire the motile mesenchymal phenotype as a result of the Epithelial-to-Mesenchymal Transition, where substantial variations in protein expression and signaling pathways take place. CTCs that migrate from the primary tumor, intravasate into the systemic vasculature, are transported through the bloodstream, and invade tissues and organs suitable for secondary tumor development. While only a limited number of CTCs are viable in the bloodstream, their ability to elude the immune system, evade apoptosis and successfully metastasize at secondary tumor sites, makes CTCs promising candidates for unraveling the triggers that initiates the metastatic process. In this article, these subjects are explored in greater depth to elucidate the potential use of CTCs in the detection, disease staging and management of metastatic melanoma.
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Affiliation(s)
- Luisa M De Souza
- The Pennsylvania State University College of Medicine, Departments of Pharmacology, 500 University Drive, Hershey, PA 17033, USA.
| | - Bailey M Robertson
- The Pennsylvania State University College of Medicine, Departments of Pharmacology, 500 University Drive, Hershey, PA 17033, USA
| | - Gavin P Robertson
- The Pennsylvania State University College of Medicine, Departments of Pharmacology, 500 University Drive, Hershey, PA 17033, USA; Pathology, 500 University Drive, Hershey, PA 17033, USA; Dermatology, 500 University Drive, Hershey, PA 17033, USA; Surgery, 500 University Drive, Hershey, PA 17033, USA; The Melanoma and Skin Cancer Center, 500 University Drive, Hershey, PA 17033, USA; The Melanoma Therapeutics Program, 500 University Drive, Hershey, PA 17033, USA.
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18
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Next-Generation Sequencing Reveals Pathway Activations and New Routes to Targeted Therapies in Cutaneous Metastatic Melanoma. Am J Dermatopathol 2017; 39:1-13. [PMID: 28045747 DOI: 10.1097/dad.0000000000000729] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Comprehensive genomic profiling of clinical samples by next-generation sequencing (NGS) can identify one or more therapy targets for the treatment of metastatic melanoma (MM) with a single diagnostic test. METHODS NGS was performed on hybridization-captured, adaptor ligation-based libraries using DNA extracted from 4 formalin-fixed paraffin-embedded sections cut at 10 microns from 30 MM cases. The exons of 182 cancer-related genes were fully sequenced using the Illumina HiSeq 2000 at an average sequencing depth of 1098X and evaluated for genomic alterations (GAs) including point mutations, insertions, deletions, copy number alterations, and select gene fusions/rearrangements. Clinically relevant GAs (CRGAs) were defined as those identifying commercially available targeted therapeutics or therapies in registered clinical trials. RESULTS The 30 American Joint Committee on Cancer Stage IV MM included 17 (57%) male and 13 (43%) female patients with a mean age of 59.5 years (range 41-83 years). All MM samples had at least 1 GA, and an average of 2.7 GA/sample (range 1-7) was identified. The mean number of GA did not differ based on age or sex; however, on average, significantly more GAs were identified in amelanotic and poorly differentiated MM. GAs were most commonly identified in BRAF (12 cases, 40%), CDKN2A (6 cases, 20%), NF1 (8 cases, 26.7%), and NRAS (6 cases, 20%). CRGAs were identified in all patients, and represented 77% of the GA (64/83) detected. The median and mean CRGAs per tumor were 2 and 2.1, respectively (range 1-7). CONCLUSION Comprehensive genomic profiling of MM, using a single diagnostic test, uncovers an unexpectedly high number of CRGA that would not be identified by standard of care testing. Moreover, NGS has the potential to influence therapy selection and can direct patients to enter relevant clinical trials evaluating promising targeted therapies.
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19
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Brożyna AA, Guo H, Yang S, Cornelius L, Linette G, Murphy M, Sheehan C, Ross J, Slominski A, Carlson JA. TRPM1
(melastatin) expression is an independent predictor of overall survival in clinical
AJCC
stage I and
II
melanoma patients. J Cutan Pathol 2017; 44:328-337. [DOI: 10.1111/cup.12872] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2016] [Revised: 11/11/2016] [Accepted: 12/13/2016] [Indexed: 11/29/2022]
Affiliation(s)
- Anna A. Brożyna
- Department of Tumor Pathology and Pathomorphology, Oncology Centre—Prof. Franciszek Łukaszczyk Memorial Hospital, Department of Tumor Pathology and Pathomorphology, Faculty of Health SciencesNicolaus Copernicus University Collegium Medicum in Bydgoszcz Bydgoszcz Poland
| | - Huazhang Guo
- Department of PathologyUniversity of Pittsburgh Medical Center, UPMC Cancer Pavilion Pittsburgh Pennsylvania
| | - Sun‐Eun Yang
- Department of PathologyAlbany Medical College MC‐81 Albany New York
| | - Lynn Cornelius
- Division of Dermatology, Washington University School of Medicine St. Louis Missouri
| | - Gerald Linette
- Division of Oncology, Washington University School of Medicine St. Louis Missouri
| | - Michael Murphy
- Department of Dermatology, MC‐6230University of Connecticut Health Center Farmington Connecticut
| | | | - Jeffrey Ross
- Department of PathologyAlbany Medical College MC‐81 Albany New York
| | - Andrzej Slominski
- Department of DermatologyUniversity of Alabama at Birmingham Birmingham Alabama
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20
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Yao Z, Allen T, Oakley M, Samons C, Garrison D, Jansen B. Analytical Characteristics of a Noninvasive Gene Expression Assay for Pigmented Skin Lesions. Assay Drug Dev Technol 2016; 14:355-63. [PMID: 27505074 DOI: 10.1089/adt.2016.724] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
We previously reported clinical performance of a novel noninvasive and quantitative PCR (qPCR)-based molecular diagnostic assay (the pigmented lesion assay; PLA) that differentiates primary cutaneous melanoma from benign pigmented skin lesions through two target gene signatures, LINC00518 (LINC) and preferentially expressed antigen in melanoma (PRAME). This study focuses on analytical characterization of this PLA, including qPCR specificity and sensitivity, optimization of RNA input in qPCR to achieve a desired diagnostic sensitivity and specificity, and analytical performance (repeatability and reproducibility) of this two-gene PLA. All target qPCRs demonstrated a good specificity (100%) and sensitivity (with a limit of detection of 1-2 copies), which allows reliable detection of gene expression changes of LINC and PRAME between melanomas and nonmelanomas. Through normalizing RNA input in qPCR, we converted the traditional gene expression analyses to a binomial detection of gene transcripts (i.e., detected or not detected). By combining the binomial qPCR results of the two genes, an improved diagnostic sensitivity (raised from 52%- 65% to 71% at 1 pg of total RNA input, and to 91% at 3 pg of total RNA input) was achieved. This two-gene PLA demonstrates a high repeatability and reproducibility (coefficient of variation <3%) and all required analytical performance characteristics for the commercial processing of clinical samples.
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Affiliation(s)
- Zuxu Yao
- DermTech, Inc. , La Jolla, California
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21
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Bin BH, Bhin J, Yang SH, Shin M, Nam YJ, Choi DH, Shin DW, Lee AY, Hwang D, Cho EG, Lee TR. Membrane-Associated Transporter Protein (MATP) Regulates Melanosomal pH and Influences Tyrosinase Activity. PLoS One 2015. [PMID: 26057890 DOI: 10.1371/journal.pone.0129273.] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
The SLC45A2 gene encodes a Membrane-Associated Transporter Protein (MATP). Mutations of this gene cause oculocutaneous albinism type 4 (OCA4). However, the molecular mechanism of its action in melanogenesis has not been elucidated. Here, we discuss the role of MATP in melanin production. The SLC45A2 gene is highly enriched in human melanocytes and melanoma cell lines, and its protein, MATP, is located in melanosomes. The knockdown of MATP using siRNAs reduced melanin content and tyrosinase activity without any morphological change in melanosomes or the expression of melanogenesis-related proteins. Interestingly, the knockdown of MATP significantly lowered the melanosomal pH, as verified through DAMP analysis, suggesting that MATP regulates melanosomal pH and therefore affects tyrosinase activity. Finally, we found that the reduction of tyrosinase activity associated with the knockdown of MATP was readily recovered by copper treatment in the in vitro L-DOPA oxidase activity assay of tyrosinase. Considering that copper is an important element for tyrosinase activity and that its binding to tyrosinase depends on melanosomal pH, MATP may play an important role in regulating tyrosinase activity via controlling melanosomal pH.
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Affiliation(s)
- Bum-Ho Bin
- Bioscience Research Institute, Amorepacific Corporation R&D Center, Yongin, Republic of Korea
| | - Jinhyuk Bhin
- Department of Chemical Engineering, POSTECH, Pohang, Republic of Korea
| | - Seung Ha Yang
- Bioscience Research Institute, Amorepacific Corporation R&D Center, Yongin, Republic of Korea
| | - Misun Shin
- Bioscience Research Institute, Amorepacific Corporation R&D Center, Yongin, Republic of Korea
| | - Yeon-Ju Nam
- Gyeonggi Bio Center, Gyeonggi Institute of Science & Technology Promotion, Suwon, Republic of Korea
| | - Dong-Hwa Choi
- Gyeonggi Bio Center, Gyeonggi Institute of Science & Technology Promotion, Suwon, Republic of Korea
| | - Dong Wook Shin
- Bioscience Research Institute, Amorepacific Corporation R&D Center, Yongin, Republic of Korea
| | - Ai-Young Lee
- Department of Dermatology, Dongguk University Ilsan Hospital, Goyang, Republic of Korea
| | - Daehee Hwang
- Department of Chemical Engineering, POSTECH, Pohang, Republic of Korea
| | - Eun-Gyung Cho
- Bioscience Research Institute, Amorepacific Corporation R&D Center, Yongin, Republic of Korea
| | - Tae Ryong Lee
- Bioscience Research Institute, Amorepacific Corporation R&D Center, Yongin, Republic of Korea
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22
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Bin BH, Bhin J, Yang SH, Shin M, Nam YJ, Choi DH, Shin DW, Lee AY, Hwang D, Cho EG, Lee TR. Membrane-Associated Transporter Protein (MATP) Regulates Melanosomal pH and Influences Tyrosinase Activity. PLoS One 2015; 10:e0129273. [PMID: 26057890 PMCID: PMC4461305 DOI: 10.1371/journal.pone.0129273] [Citation(s) in RCA: 64] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2014] [Accepted: 05/06/2015] [Indexed: 11/17/2022] Open
Abstract
The SLC45A2 gene encodes a Membrane-Associated Transporter Protein (MATP). Mutations of this gene cause oculocutaneous albinism type 4 (OCA4). However, the molecular mechanism of its action in melanogenesis has not been elucidated. Here, we discuss the role of MATP in melanin production. The SLC45A2 gene is highly enriched in human melanocytes and melanoma cell lines, and its protein, MATP, is located in melanosomes. The knockdown of MATP using siRNAs reduced melanin content and tyrosinase activity without any morphological change in melanosomes or the expression of melanogenesis-related proteins. Interestingly, the knockdown of MATP significantly lowered the melanosomal pH, as verified through DAMP analysis, suggesting that MATP regulates melanosomal pH and therefore affects tyrosinase activity. Finally, we found that the reduction of tyrosinase activity associated with the knockdown of MATP was readily recovered by copper treatment in the in vitro L-DOPA oxidase activity assay of tyrosinase. Considering that copper is an important element for tyrosinase activity and that its binding to tyrosinase depends on melanosomal pH, MATP may play an important role in regulating tyrosinase activity via controlling melanosomal pH.
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Affiliation(s)
- Bum-Ho Bin
- Bioscience Research Institute, Amorepacific Corporation R&D Center, Yongin, Republic of Korea
| | - Jinhyuk Bhin
- Department of Chemical Engineering, POSTECH, Pohang, Republic of Korea
| | - Seung Ha Yang
- Bioscience Research Institute, Amorepacific Corporation R&D Center, Yongin, Republic of Korea
| | - Misun Shin
- Bioscience Research Institute, Amorepacific Corporation R&D Center, Yongin, Republic of Korea
| | - Yeon-Ju Nam
- Gyeonggi Bio Center, Gyeonggi Institute of Science & Technology Promotion, Suwon, Republic of Korea
| | - Dong-Hwa Choi
- Gyeonggi Bio Center, Gyeonggi Institute of Science & Technology Promotion, Suwon, Republic of Korea
| | - Dong Wook Shin
- Bioscience Research Institute, Amorepacific Corporation R&D Center, Yongin, Republic of Korea
| | - Ai-Young Lee
- Department of Dermatology, Dongguk University Ilsan Hospital, Goyang, Republic of Korea
| | - Daehee Hwang
- Department of Chemical Engineering, POSTECH, Pohang, Republic of Korea
| | - Eun-Gyung Cho
- Bioscience Research Institute, Amorepacific Corporation R&D Center, Yongin, Republic of Korea
| | - Tae Ryong Lee
- Bioscience Research Institute, Amorepacific Corporation R&D Center, Yongin, Republic of Korea
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Schneider FM, Mohr F, Behrendt M, Oberwinkler J. Properties and functions of TRPM1 channels in the dendritic tips of retinal ON-bipolar cells. Eur J Cell Biol 2015; 94:420-7. [PMID: 26111660 DOI: 10.1016/j.ejcb.2015.06.005] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022] Open
Abstract
An increase in light intensity induces a depolarization in retinal ON-bipolar cells via a reduced glutamate release from presynaptic photoreceptor cells. The underlying transduction cascade in the dendritic tips of ON-bipolar cells involves mGluR6 glutamate receptors signaling to TRPM1 proteins that are an indispensable part of the transduction channel. Several other proteins are recognized to participate in the transduction machinery. Deficiency in many of these leads to congenital stationary night blindness, because rod bipolar cells, a subgroup of ON-bipolar cells, constitute the main route for sensory information under scotopic conditions. Here, we review the current knowledge about TRPM1 ion channels and how their activity is regulated within the postsynaptic compartment of ON-bipolar cells. The functional properties of TRPM1 channels in the dendritic compartment are not well understood as they differ substantially from those of recombinant TRPM1 channels. Critical evaluation of possible explanations of these discrepancies indicates that some key components of this transduction pathway might still not be known. The continued exploration of this pathway will yield further clinically useful insights.
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Affiliation(s)
- Franziska M Schneider
- Institut für Physiologie und Pathophysiologie, Philipps-Universität Marburg, Deutschhausstr. 1-2, D-35037 Marburg, Germany
| | - Florian Mohr
- Institut für Physiologie und Pathophysiologie, Philipps-Universität Marburg, Deutschhausstr. 1-2, D-35037 Marburg, Germany
| | - Marc Behrendt
- Institut für Physiologie und Pathophysiologie, Philipps-Universität Marburg, Deutschhausstr. 1-2, D-35037 Marburg, Germany
| | - Johannes Oberwinkler
- Institut für Physiologie und Pathophysiologie, Philipps-Universität Marburg, Deutschhausstr. 1-2, D-35037 Marburg, Germany.
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Bacolod MD, Das SK, Sokhi UK, Bradley S, Fenstermacher DA, Pellecchia M, Emdad L, Sarkar D, Fisher PB. Examination of Epigenetic and other Molecular Factors Associated with mda-9/Syntenin Dysregulation in Cancer Through Integrated Analyses of Public Genomic Datasets. Adv Cancer Res 2015; 127:49-121. [PMID: 26093898 DOI: 10.1016/bs.acr.2015.04.006] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
mda-9/Syntenin (melanoma differentiation-associated gene 9) is a PDZ domain containing, cancer invasion-related protein. In this study, we employed multiple integrated bioinformatic approaches to identify the probable epigenetic factors, molecular pathways, and functionalities associated with mda-9 dysregulation during cancer progression. Analyses of publicly available genomic data (e.g., expression, copy number, methylation) from TCGA, GEO, ENCODE, and Human Protein Atlas projects led to the following observations: (a) mda-9 expression correlates with both copy number and methylation level of an intronic CpG site (cg1719774) located downstream of the CpG island, (b) cg1719774 methylation is a likely prognostic marker in glioma, (c) among 22 cancer types, melanoma exhibits the highest mda-9 level, and lowest level of methylation at cg1719774, (d) cg1719774 hypomethylation is also associated with histone modifications (at the mda-9 locus) indicative of more active transcription, (e) using Gene Set Enrichment Analysis (GSEA), and the Virtual Gene Overexpression or Repression (VIGOR) analytical scheme, we were able to predict mda-9's association with extracellular matrix organization (e.g., MMPs, collagen, integrins), IGFBP2 and NF-κB signaling pathways, phospholipid metabolism, cytokines (e.g., interleukins), CTLA-4, and components of complement cascade pathways. Indeed, previous publications have shown that many of the aforementioned genes and pathways are associated with mda-9's functionality.
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Affiliation(s)
- Manny D Bacolod
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA; VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA
| | - Swadesh K Das
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA; VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA; VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA
| | - Upneet K Sokhi
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA
| | - Steven Bradley
- VCU Bioinformatics Program, School of Medicine, Virginia Commonwealth University, Richmond, Virginia, USA
| | - David A Fenstermacher
- VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA; Department of Biostatistics, School of Medicine, Virginia Commonwealth University, Richmond, Virginia, USA
| | | | - Luni Emdad
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA; VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA; VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA
| | - Devanand Sarkar
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA; VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA; VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA
| | - Paul B Fisher
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA; VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA; VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA.
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Giorgini E, Tosi G, Conti C, Staibano S, Ilardi G, Sabbatini S. FTIR microspectroscopic characterization of Spitz nevi. SPECTROCHIMICA ACTA. PART A, MOLECULAR AND BIOMOLECULAR SPECTROSCOPY 2015; 141:99-103. [PMID: 25666330 DOI: 10.1016/j.saa.2015.01.052] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/21/2014] [Revised: 07/23/2014] [Accepted: 01/22/2015] [Indexed: 06/04/2023]
Abstract
In the last 10 years, few efforts have been carried out to apply vibrational spectroscopy in the study of dermal pathologies in order to characterize the most relevant spectral markers for distinguishing benign from cancerous lesions. Spitz nevi are a special group of benign melanocytic lesions, characterized by spindled and/or epithelioid nevomelanocytes, with peculiar clinical, dermoscopic and histopathological features. The "atypical forms" of Spitz nevi are among the commonest problems of differential diagnosis with the so-called "spitzoid melanomas". The clinical and histological criteria for discriminating these two entities are very subtle and often still quite subjective, and, in a significant percentage of cases, can lead to diagnostic pitfalls and inadequate therapies. Therefore, it is noteworthy to outline that the diagnosis of melanocytic lesions still represents a challenging problem and a continue matter of discussion. We exploited FTIR microspectroscopy to study the different kinds of spitzoid melanocytes, in order to define the most relevant spectral markers of each specimen and to achieve objective information on "borderline" histologically atypical lesions. In particular, the spectroscopic investigation was carried out on melanocytes deriving from normal skin (as a normal control), malignant melanoma and Spitz nevi. The presence of the characteristic bands of melanin was investigated, too.
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Affiliation(s)
- Elisabetta Giorgini
- Dipartimento di Scienze della Vita e dell'Ambiente, Università Politecnica delle Marche, via Brecce Bianche, 60131 Ancona, Italy
| | - Giorgio Tosi
- Dipartimento di Scienze della Vita e dell'Ambiente, Università Politecnica delle Marche, via Brecce Bianche, 60131 Ancona, Italy
| | - Carla Conti
- Dipartimento di Scienze e Ingegneria della Materia, dell'Ambiente ed Urbanistica, Università Politecnica delle Marche, via Brecce Bianche, 60131 Ancona, Italy
| | - Stefania Staibano
- Dipartimento di Scienze Biomorfologiche e Funzionali, Università Federico II, via Panzini 5, 80131 Napoli, Italy
| | - Gennaro Ilardi
- Dipartimento di Scienze Biomorfologiche e Funzionali, Università Federico II, via Panzini 5, 80131 Napoli, Italy
| | - Simona Sabbatini
- Dipartimento di Scienze e Ingegneria della Materia, dell'Ambiente ed Urbanistica, Università Politecnica delle Marche, via Brecce Bianche, 60131 Ancona, Italy.
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Mumford BS, Robertson GP. Circulating melanoma cells in the diagnosis and monitoring of melanoma: an appraisal of clinical potential. Mol Diagn Ther 2014; 18:175-83. [PMID: 24297151 DOI: 10.1007/s40291-013-0071-2] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Circulating melanoma cells (CMCs) are thought to be the foundation for metastatic disease, which makes this cancer especially lethal. Cancer cells contained in the primary tumor undergo genotypic and phenotypic changes leading to an epithelial-to-mesenchymal transition, during which numerous changes occur in signaling pathways and proteins in the cells. CMCs are then shed off or migrate from the primary tumor and intravasate the vasculature system. A few CMCs are able to survive in the circulation through expression of a variety of genes and also by evading immune system recognition to establish metastases at distant sites after extravasating from the vessels. The presence of CMCs in the blood of a melanoma patient can be used for disease staging, predicting metastasis development, and evaluating the efficacy of therapeutic agents. Overall survival and disease-free duration can also be correlated with the presence of CMCs. Finally, analysis of CMCs for druggable therapeutic gene targets could lead to the development of personalized treatment regimens to prevent metastasis. Thus, the study of CMCs shows promise for the detection, staging, and monitoring of disease treatment, as well as for determination of prognosis and predicting overall disease-free survival. These are the areas reviewed in this article.
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Affiliation(s)
- Brigid S Mumford
- Department of Pharmacology, Penn State College of Medicine, Penn State Milton S. Hershey Medical Center, Hershey, PA, USA
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Kleemann B, Loos B, Scriba TJ, Lang D, Davids LM. St John's Wort (Hypericum perforatum L.) photomedicine: hypericin-photodynamic therapy induces metastatic melanoma cell death. PLoS One 2014; 9:e103762. [PMID: 25076130 PMCID: PMC4116257 DOI: 10.1371/journal.pone.0103762] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2014] [Accepted: 07/01/2014] [Indexed: 12/24/2022] Open
Abstract
Hypericin, an extract from St John's Wort (Hypericum perforatum L.), is a promising photosensitizer in the context of clinical photodynamic therapy due to its excellent photosensitizing properties and tumoritropic characteristics. Hypericin-PDT induced cytotoxicity elicits tumor cell death by various mechanisms including apoptosis, necrosis and autophagy-related cell death. However, limited reports on the efficacy of this photomedicine for the treatment of melanoma have been published. Melanoma is a highly aggressive tumor due to its metastasizing potential and resistance to conventional cancer therapies. The aim of this study was to investigate the response mechanisms of melanoma cells to hypericin-PDT in an in vitro tissue culture model. Hypericin was taken up by all melanoma cells and partially co-localized to the endoplasmic reticulum, mitochondria, lysosomes and melanosomes, but not the nucleus. Light activation of hypericin induced a rapid, extensive modification of the tubular mitochondrial network into a beaded appearance, loss of structural details of the endoplasmic reticulum and concomitant loss of hypericin co-localization. Surprisingly the opposite was found for lysosomal-related organelles, suggesting that the melanoma cells may be using these intracellular organelles for hypericin-PDT resistance. In line with this speculation we found an increase in cellular granularity, suggesting an increase in pigmentation levels in response to hypericin-PDT. Pigmentation in melanoma is related to a melanocyte-specific organelle, the melanosome, which has recently been implicated in drug trapping, chemotherapy and hypericin-PDT resistance. However, hypericin-PDT was effective in killing both unpigmented (A375 and 501mel) and pigmented (UCT Mel-1) melanoma cells by specific mechanisms involving the externalization of phosphatidylserines, cell shrinkage and loss of cell membrane integrity. In addition, this treatment resulted in extrinsic (A375) and intrinsic (UCT Mel-1) caspase-dependent apoptotic modes of cell death, as well as a caspase-independent apoptotic mode that did not involve apoptosis-inducing factor (501 mel). Further research is needed to shed more light on these mechanisms.
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Affiliation(s)
- Britta Kleemann
- Redox Laboratory and Confocal and Light Microscope Imaging Facility, Department of Human Biology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
| | - Benjamin Loos
- Department of Physiological Sciences, Stellenbosch University, Stellenbosch, South Africa
| | - Thomas J. Scriba
- South African TB Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine and School of Child and Adolescent Health, University of Cape Town, Cape Town, South Africa
| | - Dirk Lang
- Redox Laboratory and Confocal and Light Microscope Imaging Facility, Department of Human Biology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
| | - Lester M. Davids
- Redox Laboratory and Confocal and Light Microscope Imaging Facility, Department of Human Biology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
- * E-mail:
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Ribeiro-Pereira C, Moraes JA, Souza MDJ, Laurindo FR, Arruda MA, Barja-Fidalgo C. Redox modulation of FAK controls melanoma survival--role of NOX4. PLoS One 2014; 9:e99481. [PMID: 24911159 PMCID: PMC4050056 DOI: 10.1371/journal.pone.0099481] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2013] [Accepted: 05/15/2014] [Indexed: 01/08/2023] Open
Abstract
Studies have demonstrated that reactive oxygen species (ROS) generated by NADPH oxidase are essential for melanoma proliferation and survival. However, the mechanisms by which NADPH oxidase regulates these effects are still unclear. In this work, we investigate the role of NADPH oxidase-derived ROS in the signaling events that coordinate melanoma cell survival. Using the highly metastatic human melanoma cell line MV3, we observed that pharmacological NADPH oxidase inhibition reduced melanoma viability and induced dramatic cellular shape changes. These effects were accompanied by actin cytoskeleton rearrangement, diminished FAKY397 phosphorylation, and decrease of FAK-actin and FAK-cSrc association, indicating disassembly of focal adhesion processes, a phenomenon that often results in anoikis. Accordingly, NADPH oxidase inhibition also enhanced hypodiploid DNA content, and caspase-3 activation, suggesting activation of the apoptotic machinery. NOX4 is likely to be involved in these effects, since silencing of NOX4 significantly inhibited basal ROS production, reduced FAKY397 phosphorylation and decreased tumor cell viability. Altogether, the results suggest that intracellular ROS generated by the NADPH oxidase, most likely NOX4, transmits cell survival signals on melanoma cells through the FAK pathway, maintaining adhesion contacts and cell viability.
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Affiliation(s)
- Cristiane Ribeiro-Pereira
- Laboratory of Cellular and Molecular Pharmacology, Department of Cell Biology, IBRAG, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, RJ, Brazil
| | - João Alfredo Moraes
- Laboratory of Cellular and Molecular Pharmacology, Department of Cell Biology, IBRAG, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, RJ, Brazil
| | - Mariele de Jesus Souza
- Laboratory of Cellular and Molecular Pharmacology, Department of Cell Biology, IBRAG, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, RJ, Brazil
| | - Francisco R. Laurindo
- Laboratory of Vascular Biology, Instituto do Coração, Universidade de São Paulo, São Paulo, SP, Brazil
| | - Maria Augusta Arruda
- Laboratory of Cellular and Molecular Pharmacology, Department of Cell Biology, IBRAG, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, RJ, Brazil
- Vice-Diretoria de Ensino, Pesquisa e Inovação, Farmanguinhos, Fiocruz, Rio de Janeiro, RJ, Brazil
| | - Christina Barja-Fidalgo
- Laboratory of Cellular and Molecular Pharmacology, Department of Cell Biology, IBRAG, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, RJ, Brazil
- * E-mail:
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Femtosecond laser induced photodynamic therapy on 5-ALA treated SKMEL-30 cells: An efficient theranostic strategy to combat melanoma. Biomed Pharmacother 2014; 68:657-62. [DOI: 10.1016/j.biopha.2014.04.001] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2014] [Accepted: 04/16/2014] [Indexed: 01/07/2023] Open
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Abbas O, Miller DD, Bhawan J. Cutaneous malignant melanoma: update on diagnostic and prognostic biomarkers. Am J Dermatopathol 2014; 36:363-79. [PMID: 24803061 DOI: 10.1097/dad.0b013e31828a2ec5] [Citation(s) in RCA: 105] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
The incidence of cutaneous malignant melanoma has rapidly increased in recent years in all parts of the world, and melanoma is a leading cause of cancer death. As even relatively small melanomas may have metastatic potential, accurate assessment of progression is critical. Although diagnosis of cutaneous malignant melanoma is usually based on histopathologic criteria, these criteria may at times be inadequate in differentiating melanoma from certain types of benign nevi. As for prognosis, tumor (Breslow) thickness, mitotic rate, and ulceration have been considered the most important prognostic indicators among histopathologic criteria. However, there are cases of thin primary melanomas that have ultimately developed metastases despite complete excision. Given this, an accurate assessment of melanoma progression is critical, and development of molecular biomarkers that identify high-risk melanoma in its early phase is urgently needed. Large-scale genomic profiling has identified considerable heterogeneity in melanoma and suggests subgrouping of tumors by patterns of gene expression and mutation will ultimately be essential to accurate staging. This subgrouping in turn may allow for more targeted therapy. In this review, we aim to provide an update on the most promising new biomarkers that may help in the identification and prognostication of melanoma.
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Affiliation(s)
- Ossama Abbas
- *Associate Professor of Clinical Dermatology, Dermatology Department, American University of Beirut-Medical Center, Beirut, Lebanon; and †Assistant Professor of Dermatology (D.D.M.), Professor of Dermatology and Pathology (J.B.), Dermatopathology Section, Department of Dermatology, Boston University School of Medicine, Boston, MA
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Kiszner G, Wichmann B, Nemeth IB, Varga E, Meggyeshazi N, Teleki I, Balla P, Maros ME, Penksza K, Krenacs T. Cell cycle analysis can differentiate thin melanomas from dysplastic nevi and reveals accelerated replication in thick melanomas. Virchows Arch 2014; 464:603-12. [PMID: 24682564 DOI: 10.1007/s00428-014-1570-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2013] [Accepted: 03/11/2014] [Indexed: 12/13/2022]
Abstract
Cell replication integrates aberrations of cell cycle regulation and diverse upstream pathways which all can contribute to melanoma development and progression. In this study, cell cycle regulatory proteins were detected in situ in benign and malignant melanocytic tumors to allow correlation of major cell cycle fractions (G1, S-G2, and G2-M) with melanoma evolution. Dysplastic nevi expressed early cell cycle markers (cyclin D1 and cyclin-dependent kinase 2; Cdk2) significantly more (p < 0.05) than common nevi. Post-G1 phase markers such as cyclin A, geminin, topoisomerase IIα (peaking at S-G2) and aurora kinase B (peaking at G2-M) were expressed in thin (≤1 mm) melanomas but not in dysplastic nevi, suggesting that dysplastic melanocytes engaged in the cell cycle do not complete replication and remain arrested in G1 phase. In malignant melanomas, the expression of general and post-G1 phase markers correlated well with each other implying negligible cell cycle arrest. Post-G1 phase markers and Ki67 but none of the early markers cyclin D1, Cdk2 or minichromosome maintenance protein 6 (Mcm6) were expressed significantly more often in thick (>1 mm) than in thin melanomas. Marker expression did not differ between metastatic melanomas and thick melanomas, with the exception of aurora kinase A of which the expression was higher in metastatic melanomas. Combined detection of cyclin A (post-G1 phase) with Mcm6 (replication licensing) and Ki67 correctly classified thin melanomas and dysplastic nevi in 95.9 % of the original samples and in 93.2 % of cross-validated grouped cases at 89.5 % sensitivity and 92.6 % specificity. Therefore, cell cycle phase marker detection can indicate malignancy in early melanocytic lesions and accelerated cell cycle progression during vertical melanoma growth.
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Affiliation(s)
- Gergo Kiszner
- 1st Department of Pathology and Experimental Cancer Research and MTA-SE Tumor Progression Research Group, Semmelweis University, Ulloi ut 26, Budapest, 1085, Hungary
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Boyle GM. Therapy for metastatic melanoma: an overview and update. Expert Rev Anticancer Ther 2014; 11:725-37. [DOI: 10.1586/era.11.25] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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Jiang H, Wortsman J, Matsuoka L, Granese J, Carlson JA, Mihm M, Slominski A. Molecular spectrum of pigmented skin lesions: from nevus to melanoma. ACTA ACUST UNITED AC 2014. [DOI: 10.1586/17469872.1.5.679] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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Zbytek B, Carlson JA, Granese J, Ross J, Mihm MC, Slominski A. Current concepts of metastasis in melanoma. ACTA ACUST UNITED AC 2014; 3:569-585. [PMID: 19649148 DOI: 10.1586/17469872.3.5.569] [Citation(s) in RCA: 168] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
The main cause of death in melanoma patients is widespread metastases. Staging of melanoma is based on the primary tumor thickness, ulceration, lymph node and distant metastases. Metastases develop in regional lymph nodes, as satellite or in-transit lesions, or in distant organs. Lymph flow and chemotaxis is responsible for the homing of melanoma cells to different sites. Standard pathologic evaluation of sentinel lymph nodes fails to find occult melanoma in a significant proportion of cases. Detection of small numbers of malignant melanoma cells in these and other sites, such as adjacent to the primary site, bone marrow or the systemic circulation, may be enhanced by immunohistochemistry, reverse transcription PCR, evaluation of lymphatic vessel invasion and proteomics. In the organs to which melanoma cells metastasize, extravasation of melanoma cells is regulated by adhesion molecules, matrix metalloproteases, chemokines and growth factors. Melanoma cells may travel along external vessel lattices. After settling in the metastatic sites, melanoma cells develop mechanisms that protect them against the attack of the immune system. It is thought that one of the reasons why melanoma cells are especially resistant to killing is the fact that melanocytes (cells from which melanoma cells derive) are resistant to such noxious factors as ultraviolet light and reactive oxygen species. Targeted melanoma therapies are, so far, largely unsuccessful, and new ones, such as adjuvant inhibition of melanogenesis, are under development.
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Affiliation(s)
- Blazej Zbytek
- Department of Pathology and Laboratory Medicine, University of Tennessee Health Science Center, 930 Madison Avenue, Memphis, TN 38163, USA, Tel.: +1 901 448 6300, ,
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Abstract
The activating BRAF mutation V600E and related mutations in this codon are most important for the activation of the RAS/RAF/MEK/ERK mitogen-activated protein kinase (MAPK) signalling pathway in melanoma. BRAF V600E mutations have been detected in ~40% of melanoma patients and BRAF V600K mutations in ~5% of melanoma patients. Activation of the MAPK pathway results in continuous stimulation of cell proliferation and inhibits programmed cell death. Vemurafenib (PLX4032) was developed as a low molecular weight molecule for the inhibition of the mutated serine threonine kinase BRAF, and it selectively binds to the ATP-binding site of BRAF-V600E kinase and inhibits its activity. The biochemical affinity of vemurafenib for mutated BRAF translates to potent inhibition of ERK phosphorylation and of cell proliferation exclusively in BRAF-mutant cell lines. In animal model experiments, it was demonstrated that vemurafenib achieved tumour regressions in cells harbouring the BRAF V600E mutation. The clinical trials with vemurafenib in unresectable metastatic melanoma in phase I, II, and III for patients harbouring BRAF V600E mutations demonstrated all unexpected high objective response rates ranging between 50 and 80%. Median progression-free survival was prolonged from two months with dacarbazine to seven months with vemurafenib, and median overall survival was respectively prolonged from 9 to 14 months. A major problem that remains is the development of resistance to vemurafenib treatment after several months in the majority of patients, and multiple resistance mechanisms have already been described. Under vemurafenib treatment, about 25% of patients developed cutaneous squamous cell carcinomas of the keratoacanthoma type with low invasive potential and without occurrence of metastasis. The overall tolerability of the drug was quite good, and a number of patients remained on treatment for long times. As other solid tumours like papillary thyroid cancer, colorectal cancer, non-small-cell lung cancer, and ovarian cancer likewise harbour BRAF mutation, vemurafenib is also tested in these entities. In future, combinations of vemurafenib with other kinase inhibitors and with immunotherapies will improve its therapeutic potential.
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Photodynamic therapy in treatment of cutaneous and choroidal melanoma. Photodiagnosis Photodyn Ther 2013; 10:503-9. [DOI: 10.1016/j.pdpdt.2013.05.006] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2013] [Revised: 05/15/2013] [Accepted: 05/19/2013] [Indexed: 01/10/2023]
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38
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Carlson JA. On the cusp of a revolution: melanoma molecular diagnostics. J Am Acad Dermatol 2013; 69:646-7. [PMID: 24034371 DOI: 10.1016/j.jaad.2012.09.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2012] [Accepted: 09/05/2012] [Indexed: 10/26/2022]
Affiliation(s)
- John Andrew Carlson
- Divisions of Dermatology and Dermatopathology, Albany Medical College, Albany, New York.
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Abstract
Transient receptor potential (TRP) cation channel superfamily plays important roles in variety cellular processes including polymodal cellular sensing, cell adhesion, cell polarity, proliferation, differentiation and apoptosis. One of its subfamilies are TRPM channels. mRNA expression of its founding member, TRPM1 (melastatin), correlates with terminal melanocytic differentiation and loss of its expression has been identified as an important diagnostic and prognostic marker for primary cutaneous melanoma. Because TRPM1 gene codes two transcripts: TRPM1 channel protein in its exons and miR-211 in one of its introns, we propose a dual role for TRPM1 gene where the loss of TRPM1 channel protein is an excellent marker of melanoma aggressiveness, while the expression of miR-211 is linked to the tumor suppressor function of TRPM1. In addition, three other members of this subfamily, TRPM 2, 7 and 8 are implicated in the regulation of melanocytic behaviour. TRPM2 is capable of inducing melanoma apoptosis and necrosis. TRPM7 can be a protector and detoxifier in both melanocytes and melanoma cells. TRPM8 can mediate agonist-induced melanoma cell death. Therefore, we propose that TRPM1, TRPM2, TRPM7 and TRPM8 play crucial roles in melanocyte physiology and melanoma oncology and are excellent diagnostic markers and theraputic targets.
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Affiliation(s)
- Huazhang Guo
- Department of Pathology, Westchester Medical Center, New York Medical College, Valhalla, NY, USA
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40
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Mathieu V, Pirker C, Schmidt WM, Spiegl-Kreinecker S, Lötsch D, Heffeter P, Hegedus B, Grusch M, Kiss R, Berger W. Aggressiveness of human melanoma xenograft models is promoted by aneuploidy-driven gene expression deregulation. Oncotarget 2012; 3:399-413. [PMID: 22535842 PMCID: PMC3380575 DOI: 10.18632/oncotarget.473] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
Melanoma is a devastating skin cancer characterized by distinct biological subtypes. Besides frequent mutations in growth- and survival-promoting genes like BRAF and NRAS, melanomas additionally harbor complex non-random genomic alterations. Using an integrative approach, we have analysed genomic and gene expression changes in human melanoma cell lines (N=32) derived from primary tumors and various metastatic sites and investigated the relation to local growth aggressiveness as xenografts in immuno-compromised mice (N=22). Although the vast majority >90% of melanoma models harbored mutations in either BRAF or NRAS, significant differences in subcutaneous growth aggressiveness became obvious. Unsupervised clustering revealed that genomic alterations rather than gene expression data reflected this aggressive phenotype, while no association with histology, stage or metastatic site of the original melanoma was found. Genomic clustering allowed separation of melanoma models into two subgroups with differing local growth aggressiveness in vivo. Regarding genes expressed at significantly altered levels between these subgroups, a surprising correlation with the respective gene doses (>85% accordance) was found. Genes deregulated at the DNA and mRNA level included well-known cancer genes partly already linked to melanoma (RAS genes, PTEN, AURKA, MAPK inhibitors Sprouty/Spred), but also novel candidates like SIPA1 (a Rap1GAP). Pathway mining further supported deregulation of Rap1 signaling in the aggressive subgroup e.g. by additional repression of two Rap1GEFs. Accordingly, siRNA-mediated down-regulation of SIPA1 exerted significant effects on clonogenicity, adherence and migration in aggressive melanoma models. Together our data suggest that an aneuploidy-driven gene expression deregulation drives local aggressiveness in human melanoma.
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Affiliation(s)
- Véronique Mathieu
- Laboratory of Toxicology, Faculty of Pharmacy, Université Libre de Bruxelles, Brussels, Belgium
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41
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HOX Gene Aberrant Expression in Skin Melanoma: A Review. J Skin Cancer 2012; 2012:707260. [PMID: 23091727 PMCID: PMC3468127 DOI: 10.1155/2012/707260] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2012] [Revised: 09/04/2012] [Accepted: 09/04/2012] [Indexed: 12/17/2022] Open
Abstract
The homeobox family and its subset of HOX gene products represent a family of transcription factors directing DNA-protein and protein-protein interactions. In the embryo, they are central regulators in cell differentiation during morphogenesis. A series of genes of the four HOX gene clusters A, B, C, and D were reported to show aberrant expressions in oncogenesis, particularly in cutaneous malignant melanoma (CMM). They are involved in cell proliferation and progression in the CMM metastatic path. We present relevant peer-reviewed literature findings about the aberrant expression of HOX genes in CMM. The number of CMM cell nuclei exhibiting aberrant HOX protein expression appears correlated with tumour progression.
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42
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Krenacs T, Kiszner G, Stelkovics E, Balla P, Teleki I, Nemeth I, Varga E, Korom I, Barbai T, Plotar V, Timar J, Raso E. Collagen XVII is expressed in malignant but not in benign melanocytic tumors and it can mediate antibody induced melanoma apoptosis. Histochem Cell Biol 2012; 138:653-67. [PMID: 22688676 DOI: 10.1007/s00418-012-0981-9] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/26/2012] [Indexed: 10/28/2022]
Abstract
The 180 kDa transmembrane collagen XVII is known to anchor undifferentiated keratinocytes to the basement membrane in hemidesmosomes while constitutively shedding a 120 kDa ectodomain. Inherited mutations or auto-antibodies targeting collagen XVII cause blistering skin disease. Collagen XVII is down-regulated in mature keratinocytes but re-expressed in skin cancer. By recently detecting collagen XVII in melanocyte hyperplasia, here we tested its expression in benign and malignant melanocytic tumors using endodomain and ectodomain selective antibodies. We found the full-length collagen XVII protein in proliferating tissue melanocytes, basal keratinocytes and squamous cell carcinoma whereas resting melanocytes were negative. Furthermore, the cell-residual 60 kDa endodomain was exclusively detected in 62/79 primary and 15/18 metastatic melanomas, 8/9 melanoma cell lines, HT199 metastatic melanoma xenografts and atypical nests in 8/63 dysplastic nevi. The rest of 19 nevi including common, blue and Spitz subtypes were also negative. In line with the defective ectodomain, sequencing of COL17A1 gene revealed aberrations in the ectodomain coding region including point mutations. Collagen XVII immunoreaction-stained spindle cell melanomas, showed partly overlapping profiles with those of S100B, Melan A and HMB45. It was concentrated at vertical melanoma fronts and statistically associated with invasive phenotype. Antibody targeting the extracellular aa507-529 terminus of collagen XVII endodomain promoted apoptosis and cell adhesion, while inhibiting proliferation in HT199 cells. These results suggest that the accumulation of collagen XVII endodomain in melanocytic tumors is associated with malignant transformation to be a potential marker of malignancy and a target for antibody-induced melanoma apoptosis.
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Affiliation(s)
- T Krenacs
- 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Ulloi ut 26, Budapest 1085, Hungary.
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43
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44
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Clawson GA, Kimchi E, Patrick SD, Xin P, Harouaka R, Zheng S, Berg A, Schell T, Staveley-O'Carroll KF, Neves RI, Mosca PJ, Thiboutot D. Circulating tumor cells in melanoma patients. PLoS One 2012; 7:e41052. [PMID: 22829910 PMCID: PMC3400630 DOI: 10.1371/journal.pone.0041052] [Citation(s) in RCA: 73] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2012] [Accepted: 06/20/2012] [Indexed: 12/24/2022] Open
Abstract
Circulating tumor cells (CTCs) are of recognized importance for diagnosis and prognosis of cancer patients. With melanoma, most studies do not show any clear relationship between CTC levels and stage of disease. Here, CTCs were enriched (∼400X) from blood of melanoma patients using a simple centrifugation device (OncoQuick), and 4 melanocyte target RNAs (TYR, MLANA, MITF, and MIF) were quantified using QPCR. Approximately one-third of melanoma patients had elevated MIF and MLANA transcripts (p<0.0001 and p<0.001, respectively) compared with healthy controls. In contrast, healthy controls had uniformly higher levels of TYR and MITF than melanoma patients (p<0.0001). There was a marked shift of leukocytes into the CTC-enriched fractions (a 430% increase in RNA recovery, p<0.001), and no relationship between CTC levels and stage of disease was found. CTCs were captured on microfabricated filters and cultured. Captured melanoma CTCs were large cells, and consisted of 2 subpopulations, based on immunoreactivity. One subpopulation (∼50%) stained for both pan-cytokeratin (KRT) markers and the common leukocyte marker CD-45, whereas the second subpopulation stained for only KRT. Since similar cells are described in many cancers, we also examined blood from colorectal and pancreatic cancer patients. We observed analogous results, with most captured CTCs staining for both CD-45/KRT markers (and for the monocyte differentiation marker CD-14). Our results suggest that immature melanocyte-related cells (expressing TYR and MITF RNA) may circulate in healthy controls, although they are not readily detectable without considerable enrichment. Further, as early-stage melanomas develop, immature melanocyte migration into the blood is somehow curtailed, whereas a significant proportion of patients develop elevated CTC levels (based on MIF and MLANA RNAs). The nature of the captured CTCs is consistent with literature describing leukocyte/macrophage-tumor cell fusion hybrids, and their role in metastatic progression.
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Affiliation(s)
- Gary A Clawson
- Gittlen Cancer Research Foundation and Department of Pathology, Hershey Medical Center, Pennsylvania State University, Hershey, Pennsylvania, USA.
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45
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46
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Photodynamic therapy-induced killing is enhanced in depigmented metastatic melanoma cells. Cell Biol Int 2012; 35:939-44. [PMID: 21542806 DOI: 10.1042/cbi20110103] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
The resistance of pigmented human melanomas over their unpigmented counterparts to a number of therapies has suggested that the presence of intracellular melanin plays a role in rendering these cells less susceptible to cell death, probably through the ability of this pigment to act as an intracellular antioxidant, thus neutralizing chemotherapeutic-induced ROS (reactive oxygen species). PDT (photodynamic therapy) was recently suggested as an attractive, adjunctive therapy owing to its cellular specificity and limited side effects. In the present study, we propose that first depigmenting melanomas with a reversible TYR (tyrosinase) inhibitor such as PTU (phenylthiourea) increases their susceptibility to HYP-PDT (hypericin-mediated PDT). Pigmented [UCT Mel-1 (University of Cape Town melanoma cell line 1)] and unpigmented (A375) melanomas were first characterized with respect to their TYR activities and melanin quantities and then treated with a TYR inhibitor for 48 h. Cell viability assays after treatment with 3 μM HYP-PDT showed a significant increase in cell death in depigmented melanomas compared with untreated melanomas that returned to the level of untreated melanoma cells on removing the TYR inhibitor. The present study supports the hypothesis that combining the inhibition of melanogenesis with PDT should be explored as a valid therapeutic target for the management of advanced melanoma.
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47
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Piérard GE. Cell proliferation in cutaneous malignant melanoma: relationship with neoplastic progression. ISRN DERMATOLOGY 2012; 2012:828146. [PMID: 22363864 PMCID: PMC3265211 DOI: 10.5402/2012/828146] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 11/04/2011] [Accepted: 11/30/2011] [Indexed: 12/12/2022]
Abstract
The establishment of the diagnosis of cutaneous malignant melanoma (CMM) always calls for histopathological confirmation. Further to the recognition of the CMM aspects, immunohistochemistry is helpful, in particular, in determining the size of the replicative compartment and the activity in each of the cell cycle phases (G(1), S, G(2), M). The involvement of cancer stem cells and transient amplifier cells in CMM genesis is beyond doubt. The proliferation activity is indicative of the neoplastic progression and is often related to the clinical growth rate of the neoplasm. It allows to distinguish high-risk CMM commonly showing a high growth rate, from those CMMs of lower malignancy associated with a more limited growth rate. The recruitment and progression of CMM cells in the cell cycle of proliferation depend on mitogen-activated protein kinase (MAPK) pathway and result from a loss of control normally involving a series of key regulatory cyclins. In addition, the apoptotic pathways potentially counteracting any excess in proliferative activity are out of the dependency of specific regulatory molecular mechanisms. Key molecular components involved in the deregulation of the growth fraction, the cell cycle phases of proliferation, and apoptosis are presently described in CMM.
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Affiliation(s)
- G. E. Piérard
- Department of Dermatopathology, University Hospital of Liège, 4000 Liège, Belgium
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48
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Differential expression of microRNAs during melanoma progression: miR-200c, miR-205 and miR-211 are downregulated in melanoma and act as tumour suppressors. Br J Cancer 2012; 106:553-61. [PMID: 22223089 PMCID: PMC3273359 DOI: 10.1038/bjc.2011.568] [Citation(s) in RCA: 163] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
BACKGROUND The incidence of malignant melanoma is increasing faster than that for any other cancer. Histological examination of skin excision biopsies remains the standard method for melanoma diagnosis and prognosis. Significant morphological overlap between benign and malignant lesions complicates diagnosis, and tumour thickness is not always an accurate predictor of prognosis. METHODS To identify improved molecular markers to support histological examination, we used microarray analysis of formalin-fixed and paraffin-embedded samples from different stages of melanomagenesis to identify differentially expressed microRNAs (miRNAs). Differential expression was validated by qRT-PCR, and functional studies were carried out after transfection of miRNA precursors or inhibitors into melanoma cells to modulate miRNA expression. RESULTS In all, 20 miRNAs showed highly significant differential expression between benign naevi and either primary or metastatic melanomas, the majority being downregulated in melanoma, whereas only 2 miRNAs, namely miR-203 and miR-205, were differentially expressed between primary and metastatic melanomas. In functional in vitro assays, overexpression of miR-200c and miR-205 inhibited anchorage-independent colony formation and overexpression of miR-211 inhibited both anchorage-independent colony formation and invasion. CONCLUSION We have identified a series of differentially expressed miRNAs that could be useful as diagnostic or prognostic markers for melanoma and have shown that three miRNAs (namely miR-200c, miR-205 and miR-211) act as tumour suppressors.
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de la Fouchardière A. [Melanoma and search for therapeutic targets]. Ann Pathol 2011; 31:S123-4. [PMID: 22054449 DOI: 10.1016/j.annpat.2011.09.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2011] [Accepted: 09/05/2011] [Indexed: 11/28/2022]
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50
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Manganoni AM, Rossi MT, Sala R, Venturini M, Sereni E, Ungari M, Marocolo D, Lonardi S, Calzavara-Pinton P. Dermoscopic, histological and immunohistochemical evaluation of cancerous features in acquired melanocytic nevi that have been repeatedly exposed to UVA or UVB. Exp Dermatol 2011; 21:86-90. [DOI: 10.1111/j.1600-0625.2011.01397.x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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