RESUMO
Merkel cell carcinoma (MCC) is a highly aggressive neuroendocrine neoplasm of the skin, which has an exceedingly poor prognosis. The AKT/mammalian target of rapamycin (mTOR) signalling pathway, which plays a pivotal role in the modulation of protein synthesis and cell survival, has been shown to be extremely important for Merkel cell carcinogenesis. In the current study, we found that AKT has important regulatory functions in MCC cells and that inhibition of AKT with the novel ATP-competitive AKT inhibitor, afuresertib, has widespread effects on proliferative pathways. In particular, we found that treatment of MCC cells with afuresertib led to deactivation of mTOR and glycogen synthase kinase 3 pathway proteins while increasing activation of proapoptotic pathways through the upregulation of p16 expression and phosphomodulation of the B-cell lymphoma-2-associated death promoter. Overall, afuresertib treatment led to significant and robust inhibition of MCC cell proliferation, thus raising intriguing questions regarding the potential efficacy of AKT inhibition for the future clinical management of MCC.
Assuntos
Antineoplásicos/uso terapêutico , Carcinoma de Célula de Merkel/tratamento farmacológico , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Pirazóis/uso terapêutico , Neoplasias Cutâneas/tratamento farmacológico , Tiofenos/uso terapêutico , Transativadores/antagonistas & inibidores , Carcinoma de Célula de Merkel/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Genes p16/efeitos dos fármacos , Quinase 3 da Glicogênio Sintase/efeitos dos fármacos , Quinase 3 da Glicogênio Sintase/metabolismo , Humanos , Fosforilação , Proteínas Proto-Oncogênicas c-bcl-2/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Transdução de Sinais , Neoplasias Cutâneas/patologia , Serina-Treonina Quinases TOR/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Regulação para CimaRESUMO
BACKGROUND: Human polyomaviruses (HPyVs) are small, nonenveloped, double-stranded DNA viruses that express tumour antigen proteins. Fourteen species of polyomaviruses have been discovered in humans, and since the 2008 discovery of the first cutaneous polyomavirus - Merkel cell polyomavirus (MCPyV) - six more species have been detected in the skin: trichodysplasia spinulosa-associated polyomavirus (TSPyV), HPyV6, HPyV7, HPyV9, HPyV10 and HPyV13. Of these cutaneous species, only MCPyV, TSPyV, HPyV6 and HPyV7 have been definitively associated with diseases of the skin, most commonly in immunocompromised individuals. MCPyV is a predominant aetiology in Merkel cell carcinomas. TSPyV is one of the aetiological factors of trichodysplasia spinulosa. HPyV6 and HPyV7 have been recently linked to pruritic skin eruptions. The roles of HPyV9, HPyV10 and HPyV13 in pathogenesis, if any, are still unknown, but their molecular features have provided some insight into their functional biology. RESULTS: In this review, we summarize the known molecular mechanisms, clinical presentation and targeted therapies of each of the eight cutaneous HPyVs. CONCLUSIONS: We hope that heightened awareness and clinical recognition of HPyVs will lead to increased reports of HPyV-associated diseases and, consequently, a more robust understanding of how to diagnose and treat these conditions.
Assuntos
Doenças Transmissíveis Emergentes/virologia , Infecções por Polyomavirus/virologia , Polyomavirus/fisiologia , Dermatopatias Virais/virologia , Infecções Tumorais por Vírus/virologia , Carcinogênese , Doenças Transmissíveis Emergentes/terapia , Humanos , Hospedeiro Imunocomprometido , Polyomavirus/genética , Infecções por Polyomavirus/terapia , Dermatopatias Virais/terapia , Infecções Tumorais por Vírus/terapiaRESUMO
Mutations in the BRAF proto-oncogene occur in the majority of cutaneous melanomas. The commonly detected valine (V) to glutamate (E) mutation (V600E) is known to drive melanomagenesis and has thus been the target of two highly selective chemotherapeutic agents: vemurafenib and dabrafenib. While BRAF inhibitor therapy has revolutionized the treatment of metastatic melanoma, unanticipated cutaneous toxicities, including the development of cutaneous squamous cell carcinomas (cSCCs), are frequently reported and hinder therapeutic durability. However, the mechanisms by which BRAF inhibitors induce cutaneous neoplasms are poorly understood, thus posing a challenge for specific therapies. In this review, we summarize the clinical and molecular profiles of BRAF inhibitor-associated cSCCs, with a focus on factors that may contribute to disease pathogenesis. In particular, we discuss the emerging evidence pointing towards viral involvement in BRAF inhibitor-induced cutaneous neoplasms and offer new perspectives on future therapeutic interventions. Continued clinical and mechanistic studies along this line will not only allow for better understanding of the pathogenic progression of BRAF inhibitor-induced cSCCs, but will also lead to development of new therapeutic and preventative options for patients receiving targeted cancer therapy.
Assuntos
Antineoplásicos/efeitos adversos , Carcinoma de Células Escamosas/induzido quimicamente , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Neoplasias Cutâneas/induzido quimicamente , Idoso , Carcinoma de Células Escamosas/prevenção & controle , Humanos , Pessoa de Meia-Idade , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Terapia de Alvo Molecular , Infecções por Papillomavirus/fisiopatologia , Infecções por Polyomavirus/fisiopatologia , Proto-Oncogene Mas , Dermatopatias Infecciosas/fisiopatologia , Neoplasias Cutâneas/prevenção & controle , Infecções Tumorais por Vírus/fisiopatologiaRESUMO
BACKGROUND: Trichodysplasia spinulosa (TS) is a disfiguring folliculocentric cutaneous disease caused by infection with the trichodysplasia spinulosa polyomavirus (TSPyV). The TSPyV genome contains splice variants encoding the middle tumour (mT) antigen, although the potential role for TSPyV mT antigen in disease development remains unknown. OBJECTIVE: The current study was designed to investigate the mechanistic properties of TSPyV mT antigen, which may further our understanding of TS pathogenesis and provide insight into potential therapies. METHODS: A lentiviral packaging system was used to create an inducible cell line expressing TSPyV mT antigen. Proteins were extracted, separated by SDS-PAGE and subjected to Western blot analysis. Co-immunoprecipitation experiments and mutational analyses were also performed to evaluate protein-protein interactions of mT antigen. RESULTS: We describe a novel mechanism of action for mT antigen that involves hyperactivation of MEK, ERK and MNK1. Our findings suggest that dysregulation of these key signalling molecules depends upon TSPyV mT antigen interaction with protein phosphatase 2A (PP2A) via intact Zn binding motifs. CONCLUSION: Given that PP2A interaction and MEK/ERK/MNK1 phosphorylation are associated with high levels of cell proliferation and inflammation, our findings provide new evidence that TSPyV mT antigen may contribute to the pro-proliferative conditions that lead to TS development.
Assuntos
Antígenos Virais de Tumores/imunologia , Doenças do Cabelo/virologia , Sistema de Sinalização das MAP Quinases , Infecções por Polyomavirus/virologia , Polyomavirus/imunologia , Dermatopatias Virais/virologia , Western Blotting , Eletroforese em Gel de Poliacrilamida , Humanos , Transdução de SinaisAssuntos
Carcinoma in Situ , Infecções por Papillomavirus , Lesões Intraepiteliais Escamosas , Neoplasias Vulvares , Acetamidas , Carcinoma in Situ/patologia , Feminino , Papillomavirus Humano 16 , Humanos , Morfolinas , Pomadas , Papillomaviridae , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/tratamento farmacológico , Infecções por Papillomavirus/patologia , Piridinas , Neoplasias Vulvares/patologiaRESUMO
BACKGROUND: Epidermodysplasia verruciformis (EV) is a genodermatosis leading to infections with cutaneous HPV, persistent plane warts and a high rate of non-melanoma skin cancer (NMSC). Biallelic loss-of-function mutations in TMC6 and TMC8 are known to be causative. OBJECTIVE: The aim of this study was to report EV-causing mutations in four patients with EV and to give an overview of all described patients with EV. PATIENTS AND METHODS: We investigated four patients with classical features of EV from two families. All patients were affected by plane warts with typical EV histology since early childhood, and ß-HPVs were detected on their skin. One patient had recurring cutaneous squamous cell carcinomas (cSCC) and carcinomas in situ (Bowen type). We sequenced both TMC6/8 for disease-causing mutations and quantified levels of gene expression. We also performed a systematic literature review to discuss these patients in the context of previously reported cases, mutations already identified, as well as HPV types. RESULTS: Three patients of one family carried a homozygous splice site mutation in TMC8 resulting in aberrantly spliced transcripts that were not degraded. By contrast, no TMC6/8 mutation was detected in the patient from the other family. A systematic literature review revealed 501 described patients with EV. Around 40% of patients with EV analysed for genetic alterations carried no mutation in TMC6/8. While ß-HPVs were identified in the majority of cases, α-HPVs were detected in several individuals. CONCLUSION: The relatively high proportion of EV patients without mutation in TMC6/8 indicates the existence of EV-causing mutations in additional, presently unknown gene(s). However, a homozygous TMC8 splice site mutation in our patients resulted in aberrant transcripts which cannot retain the healthy phenotype. The literature review revealed that HPV-5 is the most commonly identified HPV in patients with EV, but HPV-3, HPV-14 and HPV-20 were unexpectedly identified more frequently than HPV-8.
Assuntos
Epidermodisplasia Verruciforme/genética , Proteínas de Membrana/genética , Mutação , Infecções por Papillomavirus/complicações , Splicing de RNA , Adolescente , Criança , Epidermodisplasia Verruciforme/complicações , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Trichodysplasia spinulosa (TS) is a disfiguring skin disease that occurs most frequently in patients receiving immunosuppressive therapies, and is thus frequently associated with organ transplantation. TS is characterized clinically by folliculocentric papular eruption, keratin spine formation and development of leonine face; and histologically by expansion of the inner root sheath epithelium and high expression of the proliferative marker Ki-67. Recent discovery of the TS-associated polyomavirus (TSPyV) and emerging studies demonstrating the role of TSPyV tumour antigens in cell proliferation pathways have opened a new corridor for research on TS. In this brief review, we summarize the clinical and histological features of TS and evaluate the current options for therapy. Furthermore, we address the viral aetiology of the disease and explore the mechanisms by which TSPyV may influence TS development and progression. As reports of TS continue to rise, clinician recognition of TS, as well as accompanying research on its underlying pathogenesis and therapeutic options, is becoming increasingly important. It is our hope that heightened clinical suspicion for TS will increase rates of diagnosis and will galvanize both molecular and clinical interest in this disease.
Assuntos
Dermatoses Faciais/virologia , Imunossupressores/efeitos adversos , Infecções Oportunistas/diagnóstico , Infecções por Polyomavirus/diagnóstico , Dermatopatias Virais/diagnóstico , Adulto , Antígenos de Neoplasias/metabolismo , Proliferação de Células/fisiologia , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/metabolismo , Infecções Oportunistas/complicações , Transplante de Órgãos/efeitos adversos , Infecções por Polyomavirus/complicações , Dermatopatias Virais/complicaçõesAssuntos
Carcinoma de Célula de Merkel , Poliomavírus das Células de Merkel , Infecções por Polyomavirus , Neoplasias Cutâneas , Infecções Tumorais por Vírus , Antígenos Virais de Tumores , Carcinoma de Célula de Merkel/tratamento farmacológico , Humanos , Hidrazinas , Infecções por Polyomavirus/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , TriazóisRESUMO
Generalized verrucosis is a characteristic of several genetic and immunodeficiency disorders including epidermodysplasia verruciformis; warts, hypogammaglobulinaemia, infections and myelokathexis (WHIM) syndrome; warts, immunodeficiency, lymphoedema and anogenital dysplasia (WILD) syndrome; severe combined immune deficiency and HIV, among others. In recent years, it has been consistently recognized in patients with GATA2 deficiency, a novel immunodeficiency syndrome characterized by monocytopenia, B-cell and natural killer-cell lymphopenia, and a tendency to develop myeloid leukaemias and disseminated mycobacterial, human papillomavirus (HPV) and opportunistic fungal infections. Mutations in GATA2 cause haploinsufficiency and track in families as an autosomal dominant immunodeficiency. GATA2 is a transcription factor involved in early haematopoietic differentiation and lymphatic and vascular development. We describe a case of generalized verrucosis with HPV type 57 presenting in a young man with GATA2 deficiency. GATA2 deficiency is a novel dominant immunodeficiency that is often recognized later in life and should be considered in the differential diagnosis of patients with generalized verrucosis.
Assuntos
Fator de Transcrição GATA2/deficiência , Síndromes de Imunodeficiência/genética , Mutação/genética , Neoplasias Cutâneas/genética , Verrugas/genética , Fator de Transcrição GATA2/genética , Humanos , Masculino , Linhagem , Adulto JovemAssuntos
Alopecia/virologia , Hospedeiro Imunocomprometido , Infecções por Polyomavirus , Dermatoses do Couro Cabeludo/virologia , Folículo Piloso/virologia , Humanos , Transplante de Pulmão/efeitos adversos , Poliomavírus das Células de Merkel , Mieloma Múltiplo/complicações , Complicações Pós-Operatórias/virologiaRESUMO
BACKGROUND: Epidermodysplasia verruciformis (EV) is a rare autosomal-recessive disorder characterized by widespread and persistent infection with human papilloma virus (HPV) and a risk of malignant degeneration. Most cases of EV are caused by mutations in the two EV genes, EVER1/TMC6 and EVER2/TMC8. The clinical presentation of EV takes two different forms, which coexist in most cases. Over a period of years, patients develop plane warts and pityriasis versicolor-like lesions. Sixteen cases of EV in HIV-positive patients have been clinically investigated and reported in the literature. However, different inherited susceptibilities towards HPV infection in immunodeficient patients, like HIV-positive patients, have only rarely been addressed. OBSERVATION: We describe a 22-year-old female patient with a congenital HIV infection, who presented with slowly progressing and confluent erythematous papules on her hands and hypopigmented macules on her extremities. The histopathology was typical for EV, and HPV5 was detected by PCR and reverse hybridization. The 44-year-old HIV-positive mother has no typical EV lesions. The patient is homozygous for an A to T single nucleotide polymorphism (SNP) at position 917 of the TMC8/EVER2 gene. The mother of the patient is heterozygous for this SNP. CONCLUSION: These results support the hypothesis that the combination of immunodeficiency and a susceptibility allele may contribute to the differences in occurrence of EV in HIV-positive patients.
Assuntos
Infecções Oportunistas Relacionadas com a AIDS/genética , Epidermodisplasia Verruciforme/genética , Infecções por HIV/genética , Hospedeiro Imunocomprometido , Proteínas de Membrana/genética , Polimorfismo de Nucleotídeo Único , Infecções Oportunistas Relacionadas com a AIDS/complicações , Infecções Oportunistas Relacionadas com a AIDS/patologia , Adulto , Alanina , Epidermodisplasia Verruciforme/patologia , Epidermodisplasia Verruciforme/virologia , Feminino , Infecções por HIV/congênito , Infecções por HIV/patologia , Homozigoto , Humanos , Mutação , Papillomaviridae/isolamento & purificação , TreoninaRESUMO
Genomic DNA from 14 basal cell carcinoma biopsies was screened for the presence of mutations in the p53 gene, using the polymerase chain reaction followed by direct DNA sequencing. Heterozygous mutations were detected in 7 of 14 (50%) samples investigated. All mutations were G:C-A:T transitions, and five (71%) of these mutations were transitions at hot spots with CpG sites, three at codon 248 and two at codon 273. The striking similarity of the type of mutations detected in this study and with the UV mutagenesis studies reported in literature suggest the hypothesis that UV may act on the p53 gene in a carcinogenic-specific fashion.
Assuntos
Carcinoma Basocelular/genética , Genes p53 , Mutação , Sequência de Bases , Humanos , Dados de Sequência Molecular , Raios UltravioletaRESUMO
The potential role of oncogenic viruses mediating development of proliferative skin lesions in patients treated with RAF inhibitors is poorly understood. The objective of this study was to investigate human papilloma virus (HPV) and Merkel cell polyomavirus (MCPyV) in skin lesions among patients treated with RAF inhibitors with the help of a case series describing prevalence of HPV, MCPyV, and RAS mutations in skin biopsies obtained from patients receiving RAF inhibitors and developing cutaneous lesions. HPV-DNA was amplified by PCR utilizing multiple nested primer systems designed for detection of a broad range of HPV types. MCPyV copy number determination with real time PCR technology was performed by a "Quantification of MCPyV, small t region" kit. Thirty-six patients were tested (squamous cell carcinoma (SCC) = 14; verruca vulgaris = 15; other = 11). Nine of 12 SCCs (75 %) and eight of 13 verruca vulgaris lesions (62 %) tested positive for MCPyV whereas none of the normal skin biopsies obtained from nine of these patients tested positive for MCPyV (p = 0.0007). HPV incidence in cutaneous SCCs was not different compared to normal skin (50 vs. 56 %, p = 0.86). The association between MCPyV and proliferative skin lesions after RAF inhibitor therapy merits further investigation.
Assuntos
Carcinoma de Células Escamosas/virologia , Imidazóis/efeitos adversos , Melanoma/tratamento farmacológico , Poliomavírus das Células de Merkel/isolamento & purificação , Oximas/efeitos adversos , Papillomaviridae/isolamento & purificação , Inibidores de Proteínas Quinases/efeitos adversos , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Neoplasias Cutâneas/virologia , Verrugas/virologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia , Carcinoma de Células Escamosas/induzido quimicamente , Carcinoma de Células Escamosas/patologia , Feminino , Humanos , Imidazóis/uso terapêutico , Masculino , Melanoma/genética , Pessoa de Meia-Idade , Mutação , Oximas/uso terapêutico , Estudos Prospectivos , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/genética , Estudos Retrospectivos , Pele/patologia , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologia , Verrugas/induzido quimicamente , Verrugas/patologiaRESUMO
Kaposi's sarcoma (KS) is a malignancy suspected of having an infectious etiology. Unique viral DNA sequences were recognized in KS lesions, using a novel technique that identifies small differences between two complex genomes. The virus had homology with the herpesvirus family, especially Epstein Barr virus (EBV), yet it was distinct from the known herpesviridae, and was appropriately named human herpesvirus 8 (HHV-8) or Kaposi's sarcoma-associated herpesvirus (KSHV). HHV-8 DNA sequences were present in AIDS-associated KS, classic KS, African endemic KS, Mediterranean KS, iatrogenic KS, and KS in homosexual men without HIV infection. HHV-8 DNA sequences were also present in peripheral blood mononuclear cells (PBMC) of KS+ patients; body-cavity-based lymphomas in HIV positive patients without KS; and in tissue from a number of malignant and non-malignant lesions in patients without HIV infection. The role of HHV-8 in KS and other malignancies is not known. Viruses are notoriously trophic for lesional tissue. Therefore, in order to determine the role of HHV-8 in KS pathogenesis, HHV-8 needs to be isolated and shown to induce immortalization in a suitable system. Regardless of its role in KS, another human herpesvirus has been discovered, and the extent of its pathogenicity needs to be uncovered.
Assuntos
DNA Viral/genética , Herpesviridae/genética , Sarcoma de Kaposi/virologia , Soropositividade para HIV/patologia , Soropositividade para HIV/virologia , Herpesviridae/isolamento & purificação , Humanos , Sarcoma de Kaposi/patologiaRESUMO
Some of the effects that high-dose anabolic steroid abuse have and could have on the interactions between the immune and neuroendocrine systems are reviewed. Considering the past demonstrations on the actions of normal steroids on endocrine and immune responses, it is apparent that pharmacologically high doses of both normal and derivatized androgens (anabolic steroids) could have a significant effect. Indeed, some of the pathologies attributed to anabolic steroid abuse point to disturbances in the intimate connection between neuroendocrine and immune function and interaction. We attempt to review both the direct and indirect effects of this abuse, not only on this interaction but also on certain immune functions in particular.
Assuntos
Anabolizantes/efeitos adversos , Anabolizantes/imunologia , Neuroimunomodulação/efeitos dos fármacos , Sistemas Neurossecretores/efeitos dos fármacos , Transtornos Relacionados ao Uso de Substâncias/imunologia , HumanosRESUMO
BACKGROUND: Patients undergoing chronic steroid therapy for organ transplantation are at increased risk for development of human herpes virus 8(HHV-8)-associated Kaposi's sarcoma (KS). It has also been reported that following steroid withdrawal, KS lesions often undergo partial or complete regression. METHODS: We have examined the effect of corticosteroid treatment on HHV-8 replication, gene expression, and lytic protein expression in BCBL-1 cells in vitro. BCBL-1 cells were collected after culture for 24-72 hr with hydrocortisone (HC) 1-5 microM, phorbol ester 20 ng/ml (positive control), and culture medium only (negative control). HHV-8 genomic conformation was examined by Gardella gel analysis. mRNA expression of viral cyclin (v-Cyc), viral Bcl-2 (v-Bcl-2), viral macrophage inflammatory protein-I (v-MIP-I), viral interferon regulatory factor-1(v-IRF-1), and viral tegument protein (TP) was examined by RT-PCR Southern blot. Viral protein expression within the cells was examined by indirect immunofluorescence using 5 different HHV-8 positive antisera from 4 renal transplant recipients and 1 patient with classic KS. RESULTS: Gardella gel analysis revealed that HC induced an accumulation of the linear replicative genomic form of the virus in a time-dependent fashion. Southern blot analysis of the RT-PCR products revealed that HC induced increased expression of v-IRF-1, v-Bcl-2, and TP mRNA, with little discernible effect on v-Cyc, and v-MIP-I. Immunofluorescence revealed that HC induced increased numbers of cells expressing lytic antigens. CONCLUSIONS: These data indicate that hydrocortisone acts directly on BCBL-1 cells to activate the lytic cycle of HHV-8 and provide further support for the hypothesis that HHV-8 is activated in corticosteroid-treated immunocompromised patients.
Assuntos
Replicação do DNA/efeitos dos fármacos , DNA Viral/biossíntese , Regulação Viral da Expressão Gênica/efeitos dos fármacos , Herpesvirus Humano 8/genética , Hidrocortisona/farmacologia , Eletroforese em Gel de Poliacrilamida , Humanos , Receptores de Glucocorticoides/genética , Células Tumorais CultivadasRESUMO
Even though the "low-risk" human papillomavirus (HPV) diseases, such as condyloma acuminatum, rarely progress to malignancy, their high incidence evidences the need for a better understanding of molecular interactions between these viruses and the epithelium. Our study examined the contribution of altered expression of certain cytokines and antioncogenes to the hyperproliferative properties of HPV-related skin lesions. The "low-risk" human papillomavirus types (HPV 6 or 11) were determined by in situ hybridization and PCR amplification followed by direct sequencing using consensus primers from the highly conserved L1 region in six different condylomas. mRNA levels of certain cytokines (e.g., TGF-beta 1, IFN-beta), tumor suppressor genes (RB, p53), c-myc, epidermal growth factor receptor, and cdc2 kinase were measured by RT/PCR. A characteristic change in mRNA levels of those genes was found in condylomas compared to that of the expression levels of uninfected skin. Western blot experiments demonstrated a higher proportion of the hyperphosphorylated form of RB protein and a higher level of cdc2 kinase and c-myc, but low p53 and TGF-beta 1 levels in condylomas. These data reflect a higher proliferative state of those condylomas compared to the normal skin, suggesting a direct or indirect involvement of "low-risk" HPVs in interaction with the cellular cytokine/antioncogene system providing growth advantage to those infected cells.