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1.
Adv Exp Med Biol ; 1287: 123-154, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33034030

RESUMO

Since many decades, nonmelanoma skin cancer (NMSCs) is the most common malignancy worldwide. Basal cell carcinomas (BCC) and squamous cell carcinomas (SCC) are the major types of NMSCs, representing approximately 70% and 25% of these neoplasias, respectively. Because of their continuously rising incidence rates, NMSCs represent a constantly increasing global challenge for healthcare, although they are in most cases nonlethal and curable (e.g., by surgery). While at present, carcinogenesis of NMSC is still not fully understood, the relevance of genetic and molecular alterations in several pathways, including evolutionary highly conserved Notch signaling, has now been shown convincingly. The Notch pathway, which was first developed during evolution in metazoans and that was first discovered in fruit flies (Drosophila melanogaster), governs cell fate decisions and many other fundamental processes that are of high relevance not only for embryonic development, but also for initiation, promotion, and progression of cancer. Choosing NMSC as a model, we give in this review a brief overview on the interaction of Notch signaling with important oncogenic and tumor suppressor pathways and on its role for several hallmarks of carcinogenesis and cancer progression, including the regulation of cancer stem cells, tumor angiogenesis, and senescence.


Assuntos
Carcinogênese , Células-Tronco Neoplásicas/patologia , Neovascularização Patológica , Receptores Notch/metabolismo , Transdução de Sinais , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Animais , Carcinoma Basocelular/metabolismo , Carcinoma Basocelular/patologia , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Humanos , Neoplasias Cutâneas/irrigação sanguínea
2.
Nat Commun ; 11(1): 5079, 2020 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-33033234

RESUMO

Tumor heterogeneity and lack of knowledge about resistant cell states remain a barrier to targeted cancer therapies. Basal cell carcinomas (BCCs) depend on Hedgehog (Hh)/Gli signaling, but can develop mechanisms of Smoothened (SMO) inhibitor resistance. We previously identified a nuclear myocardin-related transcription factor (nMRTF) resistance pathway that amplifies noncanonical Gli1 activity, but characteristics and drivers of the nMRTF cell state remain unknown. Here, we use single cell RNA-sequencing of patient tumors to identify three prognostic surface markers (LYPD3, TACSTD2, and LY6D) which correlate with nMRTF and resistance to SMO inhibitors. The nMRTF cell state resembles transit-amplifying cells of the hair follicle matrix, with AP-1 and TGFß cooperativity driving nMRTF activation. JNK/AP-1 signaling commissions chromatin accessibility and Smad3 DNA binding leading to a transcriptional program of RhoGEFs that facilitate nMRTF activity. Importantly, small molecule AP-1 inhibitors selectively target LYPD3+/TACSTD2+/LY6D+ nMRTF human BCCs ex vivo, opening an avenue for improving combinatorial therapies.


Assuntos
Carcinoma Basocelular/metabolismo , Proteínas Hedgehog/metabolismo , Transdução de Sinais , Neoplasias Cutâneas/metabolismo , Fator de Transcrição AP-1/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Animais , Linhagem Celular Tumoral , Núcleo Celular/metabolismo , Cromatina/metabolismo , DNA de Neoplasias/metabolismo , Resistencia a Medicamentos Antineoplásicos , Matriz Extracelular/metabolismo , Ontologia Genética , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Folículo Piloso/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Células NIH 3T3 , Proteínas de Neoplasias/metabolismo , Ligação Proteica , Proteína Smad3/metabolismo , Transativadores/metabolismo , Regulação para Cima
3.
Adv Exp Med Biol ; 1268: 171-191, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32918219

RESUMO

The prevalent keratinocyte-derived neoplasms of the skin are basal cell carcinoma and squamous cell carcinoma. Both so-called non-melanoma skin cancers comprise the most common cancers in humans by far. Common risk factors for both tumor entities include sun exposure, DNA repair deficiencies leading to chromosomal instability, or immunosuppression. Yet, fundamental differences in the development of the two different entities have been and are currently unveiled. The constitutive activation of the sonic hedgehog signaling pathway by acquired mutations in the PTCH and SMO genes appears to represent the early basal cell carcinoma developmental determinant. Although other signaling pathways are also affected, small hedgehog inhibitory molecules evolve as the most promising basal cell carcinoma treatment options systemically as well as topically in current clinical trials. For squamous cell carcinoma development, mutations in the p53 gene, especially UV-induced mutations, have been identified as early events. Yet, other signaling pathways including epidermal growth factor receptor, RAS, Fyn, or p16INK4a signaling may play significant roles in squamous cell carcinoma development. The improved understanding of the molecular events leading to different tumor entities by de-differentiation of the same cell type has begun to pave the way for modulating new molecular targets therapeutically with small molecules.


Assuntos
Carcinoma Basocelular , Carcinoma de Células Escamosas , Neoplasias Cutâneas , Carcinoma Basocelular/metabolismo , Carcinoma de Células Escamosas/metabolismo , Proteínas Hedgehog/metabolismo , Humanos , Terapia de Alvo Molecular , Transdução de Sinais , Neoplasias Cutâneas/metabolismo
4.
Adv Exp Med Biol ; 1268: 285-306, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32918224

RESUMO

Cutaneous malignancies including melanomas and keratinocyte carcinomas (KC) are the most common types of cancer, occurring at a rate of over one million per year in the United States. KC, which include both basal cell carcinomas and squamous cell carcinomas, are substantially more common than melanomas and form the subject of this chapter. Ultraviolet radiation (UVR), both UVB and UVA, as occurs with sunlight exposure is generally regarded as causal for these malignancies, but UVB is also required for vitamin D synthesis in the skin. Keratinocytes are the major cell in the epidermis. These cells not only produce vitamin D but contain the enzymatic machinery to metabolize vitamin D to its active metabolite, 1,25(OH)2D, and express the receptor for this metabolite, the vitamin D receptor (VDR). This allows the cell to respond to the 1,25(OH)2D that it produces. Based on our own data and that reported in the literature, we conclude that vitamin D signaling in the skin suppresses UVR-induced epidermal tumor formation. In this chapter we focus on four mechanisms by which vitamin D signaling suppresses tumor formation. They are inhibition of proliferation/stimulation of differentiation with discussion of the roles of hedgehog, Wnt/ß-catenin, and hyaluronan/CD44 pathways in mediating vitamin D regulation of proliferation/differentiation, regulation of the balance between oncogenic and tumor suppressor long noncoding RNAs, immune regulation, and promotion of DNA damage repair (DDR).


Assuntos
Receptores de Calcitriol/metabolismo , Pele/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Humanos , Queratinócitos/metabolismo , Pele/citologia , Neoplasias Cutâneas/metabolismo , Raios Ultravioleta/efeitos adversos , Vitamina D/metabolismo
5.
Adv Exp Med Biol ; 1268: 257-283, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32918223

RESUMO

Nonmelanoma skin cancers including basal and squamous cell carcinomas (SCC and BCC) represent a significant clinical problem due to their relatively high incidence, imposing an economic burden to healthcare systems around the world. It is accepted that ultraviolet radiation (UVR: λ = 290-400 nm) plays a crucial role in the initiation and promotion of BCC and SCC with UVB (λ = 290-320 nm) having a central role in this process. On the other hand, UVB is required for vitamin D3 (D3) production in the skin, which supplies >90% of the body's requirement for this prohormone. Prolonged exposure to UVB can also generate tachysterol and lumisterol. Vitamin D3 itself and its canonical (1,25(OH)2D3) and noncanonical (CYP11A1-intitated) D3 hydroxyderivatives show photoprotective functions in the skin. These include regulation of keratinocyte proliferation and differentiation, induction of anti-oxidative responses, inhibition of DNA damage and induction of DNA repair mechanisms, and anti-inflammatory activities. Studies in animals have demonstrated that D3 hydroxyderivatives can attenuate UVB or chemically induced epidermal cancerogenesis and inhibit growth of SCC and BCC. Genomic and non-genomic mechanisms of action have been suggested. In addition, vitamin D3 itself inhibits hedgehog signaling pathways which have been implicated in many cancers. Silencing of the vitamin D receptor leads to increased propensity to develop UVB or chemically induced epidermal cancers. Other targets for vitamin D compounds include 1,25D3-MARRS, retinoic orphan receptors α and γ, aryl hydrocarbon receptor, and Wnt signaling. Most recently, photoprotective effects of lumisterol hydroxyderivatives have been identified. Clinical trials demonstrated a beneficial role of vitamin D compounds in the treatment of actinic keratosis. In summary, recent advances in vitamin D biology and pharmacology open new exciting opportunities in chemoprevention and treatment of skin cancers.


Assuntos
Neoplasias Cutâneas/etiologia , Neoplasias Cutâneas/prevenção & controle , Vitamina D/química , Animais , Progressão da Doença , Humanos , Receptores de Calcitriol/metabolismo , Pele/efeitos dos fármacos , Pele/metabolismo , Pele/efeitos da radiação , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Raios Ultravioleta/efeitos adversos , Vitamina D/metabolismo , Vitamina D/farmacologia , Vitaminas/química , Vitaminas/metabolismo , Vitaminas/farmacologia
6.
PLoS Pathog ; 16(8): e1008792, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32813746

RESUMO

Tumor suppressors can exert pro-proliferation functions in specific contexts. In the beta human papillomavirus type 38 (HPV38) experimental model, the viral proteins E6 and E7 promote accumulation of a wild-type (WT) p53 form in human keratinocytes (HKs), promoting cellular proliferation. Inactivation of p53 by different means strongly decreases the proliferation of HPV38 E6/E7 HKs. This p53 form is phosphorylated at S392 by the double-stranded RNA-dependent protein kinase PKR, which is highly activated by HPV38. PKR-mediated S392 p53 phosphorylation promotes the formation of a p53/DNMT1 complex, which inhibits expression of integrin alpha 1 (ITGA1), a repressor of epidermal growth factor receptor (EGFR) signaling. Ectopic expression of ITGA1 in HPV38 E6/E7 HKs promotes EGFR degradation, inhibition of cellular proliferation, and cellular death. Itga1 expression was also inhibited in the skin of HPV38 transgenic mice that have an elevated susceptibility to UV-induced skin carcinogenesis. In summary, these findings reveal the existence of a specific WT p53 form that displays pro-proliferation properties.


Assuntos
Proteínas de Transporte/antagonistas & inibidores , Proliferação de Células , Queratinócitos/patologia , Proteínas de Membrana/antagonistas & inibidores , Proteínas Oncogênicas Virais/metabolismo , Proteínas E7 de Papillomavirus/metabolismo , Infecções por Papillomavirus/complicações , Proteínas Repressoras/metabolismo , Neoplasias Cutâneas/etiologia , Proteína Supressora de Tumor p53/metabolismo , Animais , Células Cultivadas , Regulação para Baixo , Humanos , Queratinócitos/imunologia , Queratinócitos/virologia , Camundongos , Camundongos Transgênicos , Proteínas Oncogênicas Virais/genética , Papillomaviridae/isolamento & purificação , Proteínas E7 de Papillomavirus/genética , Infecções por Papillomavirus/virologia , Proteínas Repressoras/genética , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Proteína Supressora de Tumor p53/genética
7.
Anticancer Res ; 40(7): 3723-3732, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32620611

RESUMO

BACKGROUND/AIM: Skin melanoma belongs to the most invasive malignancies with no cure for a progressing disease. Personalized therapy would allow for the selection of patients that will benefit from treatment. For this purpose, proper predictive biomarkers must be defined. MATERIALS AND METHODS: Allogeneic whole-cell gene-modified therapeutic melanoma vaccine (AGI-101H) was applied in advanced melanoma patients. Humoral responses were analyzed using SEREX, and in silico gene expression analysis in TCGA melanoma patients was performed. RESULTS: A specific antibody response was raised against an antigen identified as BNIP3L, which correlated with a good prognosis. Moreover, AGI-101H directs an immune response against autophagy, as BNIP3L is a marker of this process. Medium and high expression of BNIP3L was also linked with longer overall survival. CONCLUSION: BNIP3L is a candidate prognostic marker of clinical outcome of melanoma patients treated with AGI-101H, and may be considered as a prediction marker for patient survival.


Assuntos
Autofagia/fisiologia , Biomarcadores Tumorais/metabolismo , Melanoma/metabolismo , Melanoma/patologia , Proteínas de Membrana/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Proteínas Supressoras de Tumor/metabolismo , Proteínas Reguladoras de Apoptose/metabolismo , Vacinas Anticâncer/imunologia , Feminino , Humanos , Masculino , Melanoma/imunologia , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Neoplasias Cutâneas/imunologia
8.
Yonsei Med J ; 61(7): 562-571, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32608199

RESUMO

Melanoma, originating from epidermal melanocytes, is a heterogeneous disease that has the highest mortality rate among all types of skin cancers. Numerous studies have revealed the cause of this cancer as related to various somatic driver mutations, including alterations in KIT-a proto-oncogene encoding for a transmembrane receptor tyrosine kinase. Although accounting for only 3% of all melanomas, mutations in c-KIT are mostly derived from acral, mucosal, and chronically sun-damaged melanomas. As an important factor for cell differentiation, proliferation, and survival, inhibition of c-KIT has been exploited for clinical trials in advanced melanoma. Here, apart from the molecular background of c-KIT and its cellular functions, we will review the wide distribution of alterations in KIT with a catalogue of more than 40 mutations reported in various articles and case studies. Additionally, we will summarize the association of KIT mutations with clinicopathologic features (age, sex, melanoma subtypes, anatomic location, etc.), and the differences of mutation rate among subgroups. Finally, several therapeutic trials of c-KIT inhibitors, including imatinib, dasatinib, nilotinib, and sunitinib, will be analyzed for their success rates and limitations in advanced melanoma treatment. These not only emphasize c-KIT as an attractive target for personalized melanoma therapy but also propose the requirement for additional investigational studies to develop novel therapeutic trials co-targeting c-KIT and other cytokines such as members of signaling pathways and immune systems.


Assuntos
Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Melanoma/tratamento farmacológico , Melanoma/metabolismo , Proteínas Proto-Oncogênicas c-kit/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/metabolismo , Feminino , Humanos , Masculino , Melanoma/genética , Membrana Mucosa/metabolismo , Mutação , Proteínas Proto-Oncogênicas c-kit/genética , Proteínas Proto-Oncogênicas c-kit/metabolismo , Receptores Proteína Tirosina Quinases/genética , Neoplasias Cutâneas/genética
9.
Am J Med Sci ; 359(6): 339-346, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32498941

RESUMO

BACKGROUND: There is a growing interest in using programmed death ligand-1 (PD-L1) as a prognostic marker for melanoma. We conducted this meta-analysis to explore the prognostic and clinicopathological value of PD-L1 in melanoma. MATERIALS AND METHODS: The electronic databases PubMed, Web of Science and the Cochrane Library were searched for relevant studies. The major investigated parameters were PD-L1 expression levels in relation to patient gender, tumor-infiltrating lymphocytes (TILs), tumor stage, lymph node (LN) metastasis, histological type, progression-free survival (PFS) and overall survival (OS). Odds ratios (ORs) and hazard ratios (HRs) were computed using the fixed-effect or random-effects model according to data heterogeneity. RESULTS: Positive PD-L1 expression was significantly associated with high levels of TILs (OR = 7.56, 95% CI 2.04-28.02), metastatic melanoma (OR = 0.45, 95% CI 0.30-0.67) and LN-positive melanoma (OR = 2.56, 95% CI 1.31-4.99) but not gender or histological type. In addition, the pooled HRs showed no relation between PD-L1 expression and PFS (HR = 1.18, 95% CI 0.83-1.69) or OS (HR = 0.77, 95% CI 0.47-1.25). When restricted to metastatic melanoma, positive PD-L1 expression was significantly related to prolonged OS (HR = 0.57, 95% CI 0.46-0.70). CONCLUSIONS: Positive PD-L1 expression may be an important prognostic factor for longer OS in patients with metastatic melanoma.


Assuntos
Antígeno B7-H1/metabolismo , Melanoma/diagnóstico , Melanoma/metabolismo , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/metabolismo , Biomarcadores Tumorais/metabolismo , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Metástase Linfática , Linfócitos do Interstício Tumoral/citologia , Masculino , Metástase Neoplásica , Razão de Chances , Prognóstico , Modelos de Riscos Proporcionais , Resultado do Tratamento
10.
Toxicol Appl Pharmacol ; 401: 115110, 2020 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-32533954

RESUMO

Melanoma is characterized by high malignancy and early onset of metastasis. Epithelial-to-mesenchymal transition (EMT) is an early event during tumor metastasis. Tumor cells that develop EMT can escape apoptosis, but they are vulnerable to ferroptosis inducers. Gambogenic acid (GNA), a xanthone found in Gamboge, has cytotoxic effects in highly invasive melanoma cells. This study investigated the anti-melanoma effect and mechanism of action of GNA in TGF-ß1-induced EMT melanoma cells. We found that GNA significantly inhibited the invasion, migration and EMT in melanoma cells, and these cells exhibited small mitochondrial wrinkling (an important feature of ferroptosis). An iron chelator, but not an apoptosis inhibitor or a necrosis inhibitor, abolished the inhibitory effects of GNA on proliferation, invasion and migration of TGF-ß1-stimulated melanoma cells. GNA upregulated the expression of p53, solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4) in the model cells, contributing to the mechanisms underlying GNA-induced ferroptosis. Collectively, our findings suggest that GNA induces ferroptosis in TGF-ß1-stimulated melanoma cells via the p53/SLC7A11/GPX4 signaling pathway.


Assuntos
Medicamentos de Ervas Chinesas/toxicidade , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Ferroptose/efeitos dos fármacos , Melanoma/metabolismo , Neoplasias Cutâneas/metabolismo , Xantenos/toxicidade , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Medicamentos de Ervas Chinesas/uso terapêutico , Transição Epitelial-Mesenquimal/fisiologia , Ferroptose/fisiologia , Humanos , Melanoma/tratamento farmacológico , Melanoma/patologia , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologia , Xantenos/uso terapêutico
11.
Mol Cell ; 79(3): 472-487.e10, 2020 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-32531202

RESUMO

It is widely assumed that decreasing transcription factor DNA-binding affinity reduces transcription initiation by diminishing occupancy of sequence-specific regulatory elements. However, in vivo transcription factors find their binding sites while confronted with a large excess of low-affinity degenerate motifs. Here, using the melanoma lineage survival oncogene MITF as a model, we show that low-affinity binding sites act as a competitive reservoir in vivo from which transcription factors are released by mitogen-activated protein kinase (MAPK)-stimulated acetylation to promote increased occupancy of their regulatory elements. Consequently, a low-DNA-binding-affinity acetylation-mimetic MITF mutation supports melanocyte development and drives tumorigenesis, whereas a high-affinity non-acetylatable mutant does not. The results reveal a paradoxical acetylation-mediated molecular clutch that tunes transcription factor availability via genome-wide redistribution and couples BRAF to tumorigenesis. Our results further suggest that p300/CREB-binding protein-mediated transcription factor acetylation may represent a common mechanism to control transcription factor availability.


Assuntos
Regulação Neoplásica da Expressão Gênica , Genoma , Melanoma/genética , Fator de Transcrição Associado à Microftalmia/genética , Processamento de Proteína Pós-Traducional , Neoplasias Cutâneas/genética , Acetilação , Sequência de Aminoácidos , Animais , Sítios de Ligação , Linhagem Celular Tumoral , Sequência Conservada , Elementos Facilitadores Genéticos , Feminino , Xenoenxertos , Humanos , Masculino , Melanócitos/metabolismo , Melanócitos/patologia , Melanoma/metabolismo , Melanoma/patologia , Camundongos , Camundongos Nus , Fator de Transcrição Associado à Microftalmia/química , Fator de Transcrição Associado à Microftalmia/metabolismo , Motivos de Nucleotídeos , Regiões Promotoras Genéticas , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Peixe-Zebra
12.
Nat Commun ; 11(1): 2749, 2020 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-32488012

RESUMO

The tumour microenvironment (TME) forms a major obstacle in effective cancer treatment and for clinical success of immunotherapy. Conventional co-cultures have shed light onto multiple aspects of cancer immunobiology, but they are limited by the lack of physiological complexity. We develop a human organotypic skin melanoma culture (OMC) that allows real-time study of host-malignant cell interactions within a multicellular tissue architecture. By co-culturing decellularized dermis with keratinocytes, fibroblasts and immune cells in the presence of melanoma cells, we generate a reconstructed TME that closely resembles tumour growth as observed in human lesions and supports cell survival and function. We demonstrate that the OMC is suitable and outperforms conventional 2D co-cultures for the study of TME-imprinting mechanisms. Within the OMC, we observe the tumour-driven conversion of cDC2s into CD14+ DCs, characterized by an immunosuppressive phenotype. The OMC provides a valuable approach to study how a TME affects the immune system.


Assuntos
Plasticidade Celular/fisiologia , Células Dendríticas/metabolismo , Melanoma/metabolismo , Microambiente Tumoral/fisiologia , Comunicação Celular , Sobrevivência Celular , Técnicas de Cocultura , Fibroblastos/patologia , Humanos , Queratinócitos/patologia , Melanoma/imunologia , Melanoma/patologia , Pele/patologia , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Microambiente Tumoral/imunologia
13.
Cutis ; 105(3): 138-142;E5, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32352432

RESUMO

Nonmelanoma skin cancer (NMSC) is the most common malignancy worldwide, and the incidence continues to increase. Originally, treatment options for NMSCs largely relied on destructive and surgical methods. Basal cell carcinomas (BCCs) and squamous cell carcinomas (SCCs) commonly are treated with cryosurgery, electrodesiccation and curettage, or more definitive surgical options. Over time, topical agents such as 5-fluorouracil, imiquimod, ingenol mebutate, and various forms of aminolevulinic acid (ALA) for photodynamic therapy (PDT) were included for superficial lesions as well as field treatment. The development of oral hedgehog (Hh) inhibitors such as vismodegib offered a promising alternative to patients with advanced disease. Each treatment has its own specific indications and side effects, thus there is always room for novel therapeutic approaches. We review new and potential treatments for NMSCs since 2018 including topical sonidegib, cemiplimab, taladegib, posaconazole, radiation therapy (RT), combination RT with vismodegib, PDT, and laser therapies.


Assuntos
Antineoplásicos/administração & dosagem , Carcinoma Basocelular/terapia , Carcinoma de Células Escamosas/terapia , Neoplasias Cutâneas/terapia , Carcinoma Basocelular/metabolismo , Carcinoma de Células Escamosas/metabolismo , Humanos , Terapia a Laser , Fotoquimioterapia , Radioterapia , Neoplasias Cutâneas/metabolismo
14.
Am J Surg Pathol ; 44(6): 776-781, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32412717

RESUMO

Unlike systemic anaplastic large cell lymphoma, the vast majority of primary cutaneous anaplastic large cell lymphomas (C-ALCL) do not carry translocations involving the ALK gene and do not express ALK. Expression of ALK protein therefore strongly suggests secondary cutaneous involvement of a systemic anaplastic large cell lymphoma. Recent studies described a small subgroup of ALK-positive C-ALCL, but information on frequency, prognosis, and translocation partners is virtually lacking. A total of 6/309 (2%) C-ALCL patients included in the Dutch registry for cutaneous lymphomas between 1993 and 2019 showed immunohistochemical ALK expression. Clinical and histopathologic characteristics, immunophenotype and disease course were evaluated. Underlying ALK translocations were analyzed with anchored multiplex polymerase chain reaction-based targeted next-generation sequencing. Median age at diagnosis was 39 years (range: 16 to 53 y). All patients presented with a solitary lesion. Treatment with radiotherapy (n=5) or anthracycline-based chemotherapy (n=1) resulted in complete responses in all 6 patients. Three patients developed a relapse, of whom 2 extracutaneous. After a median follow-up of 41 months, 5 patients were alive without disease and 1 patient died of lymphoma. Immunohistochemically, 3 cases (50%) showed combined nuclear and cytoplasmic ALK expression with underlying NPM1-ALK fusions, while 3 cases (50%) showed solely cytoplasmic ALK expression with variant ALK fusion partners (TRAF1, ATIC, TPM3). ALK-positive C-ALCL is extremely uncommon, has a comparable favorable prognosis to ALK-negative C-ALCL, and should be treated in the same way with radiotherapy as first-line treatment.


Assuntos
Quinase do Linfoma Anaplásico/genética , Linfoma Anaplásico Cutâneo Primário de Células Grandes/genética , Linfoma Anaplásico Cutâneo Primário de Células Grandes/patologia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Adolescente , Adulto , Quinase do Linfoma Anaplásico/metabolismo , Feminino , Humanos , Linfoma Anaplásico Cutâneo Primário de Células Grandes/metabolismo , Masculino , Pessoa de Meia-Idade , Neoplasias Cutâneas/metabolismo , Adulto Jovem
15.
Anticancer Res ; 40(4): 2157-2163, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32234909

RESUMO

BACKGROUND/AIM: There is a lack of quality biomarkers of survival for patients with metastatic melanoma treated with immunotherapy. Although the baseline level of S100 has prognostic value, its role during/after therapy in survival is unclear. PATIENTS AND METHODS: We evaluated patients with metastatic melanoma treated with pembrolizumab with the goal of analysing the relationship between a relative change in S100 level at 12 weeks of immunotherapy and survival. RESULTS: Patients with a relative change in S100 level >145% at 12 weeks of immunotherapy had significantly shorter progression-free (5.1 vs. 18.5 months, p≤0.0001) and overall survival (5.7 vs. 26.3 months, p<0.0001), further confirmed on multivariate analysis with hazard ratio of 32.25 (95% confidence interval=4.78-217.6, p=0.0004) for overall survival. CONCLUSION: A relative change in S100 level might be useful as a more precise biomarker of survival for patients with metastatic melanoma treated with pembrolizumab.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Biomarcadores Tumorais/análise , Melanoma/tratamento farmacológico , Proteínas S100/análise , Neoplasias Cutâneas/tratamento farmacológico , Idoso , Antineoplásicos Imunológicos/uso terapêutico , Intervalo Livre de Doença , Feminino , Humanos , Neoplasias Pulmonares/secundário , Metástase Linfática , Masculino , Melanoma/metabolismo , Melanoma/patologia , Pessoa de Meia-Idade , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia
16.
Biochim Biophys Acta Proteins Proteom ; 1868(7): 140423, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32247787

RESUMO

The human genome encodes for 11 papain-like endolysosomal cysteine peptidases, collectively known as the cysteine cathepsins. Based on their biochemical properties and with the help of experiments in cell culture, the cysteine cathepsins have acquired a reputation as promotors of progression and metastasis of various cancer entities. However, tumors are known to be complex tissues in which non-cancerous cells are also critical for tumorigenesis. Here we discuss the results of the intense investigation of cathepsins in mouse models of human cancers. We focus on models in immunocompetent mice, because only such models allow for analysis of cathepsins in a fully functional tumor microenvironment. An important outcome of those studies was the identification of cancer-promoting cathepsins in tumor-associated macrophages. Another interesting outcome of these animal studies was the identification of a homeostatic tumor-suppressive role for cathepsin L in skin and intestinal cancers. Taken together, these in vivo findings provide a basis for the use of cysteine cathepsins as therapeutic targets, prodrug activators, or as proteases for imaging tumors.


Assuntos
Catepsinas/metabolismo , Cisteína/metabolismo , Neoplasias/metabolismo , Microambiente Tumoral/fisiologia , Aloenxertos , Animais , Neoplasias da Mama/metabolismo , Carcinogênese , Catepsina B/genética , Catepsina B/metabolismo , Catepsina L , Catepsinas/genética , Modelos Animais de Doenças , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Intestinais/metabolismo , Camundongos , Neoplasias/genética , Neoplasias Pancreáticas/metabolismo , Neoplasias Cutâneas/metabolismo , Microambiente Tumoral/genética
17.
Mol Carcinog ; 59(6): 640-650, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32232919

RESUMO

A few single-nucleotide polymorphisms (SNPs) have been identified to be associated with cutaneous melanoma (CM) survival through genome-wide association studies, but stringent multiple testing corrections required for the hypothesis-free testing may have masked some true associations. Using a hypothesis-driven analysis approach, we sought to evaluate associations between SNPs in ketone body metabolic pathway genes and CM survival. We comprehensively assessed associations between 4196 (538 genotyped and 3658 imputed) common SNPs in 44 ketone body metabolic pathway genes and CM survival, using a dataset of 858 patients of a case-control study from The University of Texas M.D. Anderson Cancer Center as the discovery set and another dataset of 409 patients from the Nurses' Health Study and the Health Professionals Follow-up Study as the replication set. There were 95/858 (11.1%) and 48/409 (11.7%) patients who died of CM, respectively. We identified two independent SNPs (ie, PDSS1 rs12254548 G>C and SLC16A6 rs71387392 G>A) that were associated with CM survival, with allelic hazards ratios of 0.58 (95% confidence interval [CI] = 0.44-0.76, P = 9.00 × 10-5 ) and 1.98 (95% CI = 1.34-2.94, P = 6.30 × 10-4 ), respectively. Additionally, associations between genotypes of the SNPs and messenger RNA expression levels of their corresponding genes support the biologic plausibility of a role for these two variants in CM tumor progression and survival. Once validated by other larger studies, PDSS1 rs12254548 and SLC16A6 rs71387392 may be valuable biomarkers for CM survival.


Assuntos
Alquil e Aril Transferases/genética , Biomarcadores Tumorais/genética , Cetonas/metabolismo , Melanoma/mortalidade , Transportadores de Ácidos Monocarboxílicos/genética , Polimorfismo de Nucleotídeo Único , Neoplasias Cutâneas/mortalidade , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Melanoma/genética , Melanoma/metabolismo , Melanoma/patologia , Redes e Vias Metabólicas , Pessoa de Meia-Idade , Prognóstico , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Taxa de Sobrevida , Adulto Jovem
18.
Life Sci ; 253: 117600, 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32234492

RESUMO

BACKGROUND: Skin cutaneous melanoma (SKCM) is the most common subtype of skin malignancy, with ever-increasing incidence, mortality, and disease burden. Dysregulation of JAK-STATs signaling pathway is involved in the pathogenesis and progression of cancers, thus affecting the prognosis of cancer patients. The function of JAKs in SKCM is still not clarified. METHODS: A total of five online portal (GEPIA, TIMER, GeneMANIA, LinkedOmics, and GSCALite) is used to mine the expression and gene regulation network JAK2 in SKCM. RESULTS: JAK2 expression was downregulated in SKCM and significantly associated with pathological stage and the prognosis of patients. The functions of JAK2 and associated genes were primarily involved in the DNA recombination, cell cycle checkpoint, metabolic process, NOD-like receptor signaling pathways, p53 signaling pathway and apoptosis. JAK2 level was significantly correlated with the abundance of immune cells and the level of immune biomarkers. Low expression of JAK2 were resistant to QL-VIII-58, TL-1-85, Ruxolitinib, TG101348 and Sunitinib. CONCLUSIONS: Our results reveal the expression and gene regulation network of JAK2 in skin cutaneous melanoma, providing more evidences about the role of JAK2 in carcinogenesis.


Assuntos
Antineoplásicos/farmacologia , Janus Quinases/metabolismo , Melanoma/metabolismo , Pirazóis/farmacologia , Neoplasias Cutâneas/tratamento farmacológico , Sunitinibe/farmacologia , Antineoplásicos/metabolismo , Bases de Dados de Ácidos Nucleicos , Bases de Dados de Proteínas , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes/efeitos dos fármacos , Humanos , Janus Quinases/genética , MicroRNAs/metabolismo , Modelos Biológicos , Prognóstico , Pirazóis/metabolismo , Transdução de Sinais , Neoplasias Cutâneas/metabolismo , Sunitinibe/metabolismo
19.
Res Vet Sci ; 131: 7-14, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32278962

RESUMO

Melanoma progression is associated with the epithelial-mesenchymal transition (EMT) when tumor cells reduce E-cadherin and increase N-cadherin expression resulting in an escape from the microenvironment via loss of cellular adhesion and gain of motility. Transcription factor proteins Snail and ZEB trigger EMT by repression of epithelial markers and activation of mesenchymal properties. This study evaluated E-cadherin, N-cadherin, Snail, ZEB1 and ZEB2 expression by IHC and investigated their relationship with morphological characteristics in cutaneous and oral canine melanoma. Results from melanoma cases demonstrated E-cadherin expression in 45% (9/20) of oral and 58% (22/38) of cutaneous tumors, while N-cadherin expression was observed in 95% (18/19) of oral and 92% (34/37) of cutaneous melanoma. Cytoplasmic and nuclear N-cadherin expression was positively correlated with ZEB1 expression, while the cell membrane N-cadherin expression was positively correlated with ZEB2. In addition, an increase in nuclear N-cadherin expression was associated with reduced Snail expression in cutaneous melanoma and an increase in Snail expression in oral melanoma, indicating that the correlation between N-cadherin and Snail expression is coincident with tumor location. Our data suggest that ZEB family protein is associated with N-cadherin translocation from cell membrane to the cytoplasm and nuclei, and may act as important transcription factors of EMT regulation in canine melanoma.


Assuntos
Doenças do Cão/metabolismo , Transição Epitelial-Mesenquimal/fisiologia , Melanoma/veterinária , Neoplasias Cutâneas/veterinária , Fatores de Transcrição da Família Snail/metabolismo , Homeobox 1 de Ligação a E-box em Dedo de Zinco/metabolismo , Animais , Caderinas/metabolismo , Adesão Celular , Movimento Celular , Doenças do Cão/genética , Cães , Regulação Neoplásica da Expressão Gênica , Humanos , Melanoma/metabolismo , Neoplasias Bucais/metabolismo , Neoplasias Bucais/patologia , Neoplasias Bucais/veterinária , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Fatores de Transcrição da Família Snail/genética , Fatores de Transcrição/metabolismo , Microambiente Tumoral , Homeobox 1 de Ligação a E-box em Dedo de Zinco/genética
20.
Am J Surg Pathol ; 44(7): 862-872, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32271188

RESUMO

Primary cutaneous CD4 small/medium T-cell lymphoproliferative disorder (PCSMLPD) is a recently recognized entity in the 2017 World Health Organization (WHO) classification. It belongs to the T-follicular helper (TFH) lymphoproliferations. The clinical, pathologic, and molecular features of this localized disease are underresearched. We conducted a retrospective multicentric study of 60 patients with a PCSMLPD that presented as a single cutaneous lesion. Clinical, pathologic, and targeted molecular analyses were performed. PCSMLPD presented mostly as a nodule (45%), located on the head and neck area (50%) in adults (mean age: 59 y [43.3 to 75.2]). All patients had an indolent disease course, either at initial staging or during follow-up (mean: 16.6 mo [1.3 to 31.9]). Spontaneous regression was reported in 31.9% of cases. The infiltrates were most often nodular and/or diffuse, expanding in the whole dermis (78%, Pattern 1), rather than subepidermal band-like in the superficial dermis (22%, Pattern 2). Epidermotropism, folliculotropism, and capillary hyperplasia were common. The expression of TFH lineage markers was more extensive in lesions with Pattern 2, but a substantial B-cell infiltrate was seen in both types of lesions. A clonal rearrangement of the TCR genes was identified in 68% of cases. One sample of the 13 tested revealed a mutation in the DNMT3A gene among the 9 genes studied (TET2, DNMT3A, IDH2, RHOA, SETD2, PLCG1, STAT3, STAT5B, and CD28). PCSMLPD follows a benign clinical course and can spontaneously regress after biopsy. Although PCSMLPD expresses TFH lineage markers, mutations usually found in angioimmunoblastic T-cell lymphomas are uncommon.


Assuntos
Linfoma Cutâneo de Células T/diagnóstico , Neoplasias Cutâneas/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Feminino , Seguimentos , França , Humanos , Imuno-Histoquímica , Linfoma Cutâneo de Células T/genética , Linfoma Cutâneo de Células T/metabolismo , Linfoma Cutâneo de Células T/patologia , Masculino , Pessoa de Meia-Idade , Mutação , Fenótipo , Remissão Espontânea , Estudos Retrospectivos , Análise de Sequência de DNA , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia
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