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1.
Dermatol Clin ; 41(1): 101-115, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36410971

RESUMO

Merkel cell carcinoma (MCC) is a neuroendocrine carcinoma that typically presents as a rapidly enlarging violaceous papulonodule on sun-damaged skin in elderly patients. MCC has high rates of local recurrence, metastasis, and poor survival. Treatment of the primary tumor involves surgical excision with possible adjuvant radiation therapy, whereas regional nodal disease is treated with some combination of lymph node dissection and radiation therapy. Immune checkpoint inhibitors, such as avelumab and pembrolizumab, are first-line agents for metastatic MCC. Monitoring for recurrence can be aided by Merkel cell polyomavirus oncoprotein antibody titers.


Assuntos
Carcinoma de Célula de Merkel , Poliomavírus das Células de Merkel , Neoplasias Cutâneas , Humanos , Idoso , Carcinoma de Célula de Merkel/patologia , Neoplasias Cutâneas/patologia , Excisão de Linfonodo
2.
Viruses ; 14(11)2022 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-36423152

RESUMO

Since it was clearly established that HIV/AIDS predisposes to the infection, persistence or reactivation of latent viruses, the prevalence of human polyomaviruses (HPyVs) among HIV-1-infected patients and a possible correlation between HPyVs and HIV sero-status were investigated. PCR was performed to detect and quantify JCPyV, BKPyV, MCPyV, HPyV6, HPyV7 and QPyV DNA in the urine and plasma samples of 103 HIV-1-infected patients. Subsequently, NCCR, VP1 and MCPyV LT sequences were examined. In addition, for MCPyV, the expression of transcripts for the LT gene was investigated. JCPyV, BKPyV and MCPyV's presence was reported, whereas HPyV6, HPyV7 and QPyV were not detected in any sample. Co-infection patterns of JCPyV, BKPyV and MCPyV were found. Archetype-like NCCRs were observed with some point mutations in plasma samples positive for JCPyV and BKPyV. The VP1 region was found to be highly conserved among these subjects. LT did not show mutations causing stop codons, and LT transcripts were expressed in MCPyV positive samples. A significant correlation between HPyVs' detection and a low level of CD4+ was reported. In conclusion, HPyV6, HPyV7 and QPyV seem to not have a clinical relevance in HIV-1 patients, whereas further studies are warranted to define the clinical importance of JCPyV, BKPyV and MCPyV DNA detection in these subjects.


Assuntos
Líquidos Corporais , Soropositividade para HIV , HIV-1 , Poliomavírus das Células de Merkel , Polyomavirus , Humanos , HIV-1/genética , Plasma , Genômica
3.
Viruses ; 14(10)2022 10 17.
Artigo em Inglês | MEDLINE | ID: mdl-36298837

RESUMO

Our aim was to study the seroprevalence of human polyomaviruses (HPyV) linked to skin diseases. A total of 552 serum samples were analysed by the enzyme-linked immunosorbent assay to detect IgG antibodies against Merkel cell polyomavirus (MCPyV), HPyV6, HPyV7 and Trichodysplasia spinulosa-associated polyomavirus (TSPyV) using recombinant major capsid proteins of these viruses. The individuals (age 0.8-85 years, median 33) were sorted into seven age groups: <6, 6-10, 10-14, 14-21, 21-40, 40-60 and >60 years. The adulthood seroprevalence was 69.3%, 87.7%, 83.8% and 85% for MCPyV, HPyV6, HPyV7 and TSPyV, respectively. For all four polyomaviruses, there was increasing seropositivity with age until reaching the adulthood level. There was a significant increase in seroreactivity for those age groups in which the rate of already-infected individuals also showed significant differences. The adulthood seropositvity was relatively stable with ageing, except for TSPyV, for which elevated seropositivity was observed for the elderly (>60 years) age group. Since seroepidemiological data have been published with wide ranges for all the viruses studied, we performed a comprehensive analysis comparing the published age-specific seropositivities to our data. Although the cohorts, methods and even the antigens were variable among the studies, there were similar results for all studied polyomaviruses. For MCPyV, geographically distinct genotypes might exist, which might also result in the differences in the seroprevalence data. Additional studies with comparable study groups and methods are required to clarify whether there are geographical differences.


Assuntos
Poliomavírus das Células de Merkel , Infecções por Polyomavirus , Polyomavirus , Infecções Tumorais por Vírus , Humanos , Adulto , Idoso , Pessoa de Meia-Idade , Lactente , Pré-Escolar , Criança , Adolescente , Adulto Jovem , Idoso de 80 Anos ou mais , Polyomavirus/genética , Infecções por Polyomavirus/epidemiologia , Estudos Soroepidemiológicos , Proteínas do Capsídeo/genética , Poliomavírus das Células de Merkel/genética , Imunoglobulina G , Infecções Tumorais por Vírus/epidemiologia
4.
J Immunother Cancer ; 10(9)2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-36252564

RESUMO

BACKGROUND: Merkel cell carcinoma (MCC) often responds to PD-1 pathway blockade, regardless of tumor-viral status (~80% of cases driven by the Merkel cell polyomavirus (MCPyV)). Prior studies have characterized tumor-specific T cell responses to MCPyV, which have typically been CD8, but little is known about the T cell response to UV-induced neoantigens. METHODS: A patient in her mid-50s with virus-negative (VN) MCC developed large liver metastases after a brief initial response to chemotherapy. She received anti-PD-L1 (avelumab) and had a partial response within 4 weeks. Whole exome sequencing (WES) was performed to determine potential neoantigen peptides. Characterization of peripheral blood neoantigen T cell responses was evaluated via interferon-gamma (IFNγ) ELISpot, flow cytometry and single-cell RNA sequencing. Tumor-resident T cells were characterized by multiplexed immunohistochemistry. RESULTS: WES identified 1027 tumor-specific somatic mutations, similar to the published average of 1121 for VN-MCCs. Peptide prediction with a binding cut-off of ≤100 nM resulted in 77 peptides that were synthesized for T cell assays. Although peptides were predicted based on class I HLAs, we identified circulating CD4 T cells targeting 5 of 77 neoantigens. In contrast, no neoantigen-specific CD8 T cell responses were detected. Neoantigen-specific CD4 T cells were undetectable in blood before anti-PD-L1 therapy but became readily detectible shortly after starting therapy. T cells produced robust IFNγ when stimulated by neoantigen (mutant) peptides but not by the normal (wild-type) peptides. Single cell RNAseq showed neoantigen-reactive T cells expressed the Th1-associated transcription factor (T-bet) and associated cytokines. These CD4 T cells did not significantly exhibit cytotoxicity or non-Th1 markers. Within the pretreatment tumor, resident CD4 T cells were also Th1-skewed and expressed T-bet. CONCLUSIONS: We identified and characterized tumor-specific Th1-skewed CD4 T cells targeting multiple neoantigens in a patient who experienced a profound and durable partial response to anti-PD-L1 therapy. To our knowledge, this is the first report of neoantigen-specific T cell responses in MCC. Although CD4 and CD8 T cells recognizing viral tumor antigens are often detectible in virus-positive MCC, only CD4 T cells recognizing neoantigens were detected in this patient. These findings suggest that CD4 T cells can play an important role in the response to anti-PD-(L)1 therapy.


Assuntos
Carcinoma de Célula de Merkel , Poliomavírus das Células de Merkel , Neoplasias Cutâneas , Feminino , Humanos , Antígenos Virais de Tumores , Carcinoma de Célula de Merkel/tratamento farmacológico , Carcinoma de Célula de Merkel/genética , Linfócitos T CD4-Positivos , Interferon gama , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/genética , Fatores de Transcrição
5.
Braz J Microbiol ; 53(4): 1987-1994, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36279096

RESUMO

Merkel cell polyomavirus (MCPyV) is the cause of approximately 80% of Merkel cell carcinomas (MCC). The common types of non-melanoma skin cancer (NMSC) including squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) are histologically similar to MCC. In the present study, 58 NMSC formalin-fixed paraffin-embedded tissue (FFPE) samples including 12 SCC, 46 BCC, and 58 FFPE samples of adjacent non-tumoral margins as the control were included. Determination of large tumor antigens (LTAg) copy number was performed by qReal-Time PCR as a viral copy number per cell to elucidate MCPyV carcinogenic role in non-melanoma skin cancer. Out of 58 samples, 36 (62%) cancerous and 22 (37.9%) normal tumor margins were positive for MCPyV LTAg. Median copy numbers of MCPyV LTAg among all NMSC samples and non-tumoral margins were 0.308×10-2 and 0.269×10-3 copies per cell respectively (P=0.001). In addition, although the viral load in the majority of samples was detected to be lower than one copy per cell, in 4 BCC samples, a viral load higher than one LTAg copy per cell was detected. The present study revealed that the detection of higher levels of MCPyV LTAg viral load in some BCC and SCC samples may be correlated with the role of MCPyV in some cases of BCC and SCC skin cancer.


Assuntos
Carcinoma Basocelular , Carcinoma de Célula de Merkel , Carcinoma de Células Escamosas , Poliomavírus das Células de Merkel , Neoplasias Cutâneas , Infecções Tumorais por Vírus , Humanos , Poliomavírus das Células de Merkel/genética , Carcinoma de Célula de Merkel/patologia , Carcinoma Basocelular/genética , Carcinoma Basocelular/patologia , DNA Viral/genética , DNA Viral/análise
6.
Viruses ; 14(10)2022 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-36298750

RESUMO

Merkel cell polyomavirus (MCPyV) prevalence in Merkel cell carcinoma (MCC) cases is controversial. The detection and quantification of MCPyV DNA is mainly performed by PCR techniques using formalin-fixed, paraffin-embedded (FFPE) tissues. The aim of this study is to compare the performance of two different molecular techniques, specifically the quantitative Real-Time PCR (qPCR) and digital PCR (dPCR). Samples from 31 cases of MCC excisional surgical biopsies were analyzed. DNA extraction and purification from clinical samples were performed using the QIAcube Qiagen automated nucleic acid extractor. After the extraction, MCPyV was detected by qPCR and dPCR using specially designed primers and probes. Of the 31 MCC samples under study, the MCPyV genome was detected in 11 samples (35%) by qPCR compared with 20 samples (65%) detected by dPCR. Notably, 65% of primary tumors were positive for MCPyV (15/23). The viral genome was detected in 75% of tumors located at UV-exposed sites (6/8), 55% of tumors at partially UV-protected sites (5/9), and 67% of tumors at UV-protected sites (4/6). Our results showed a better sensitivity of dPCR in detecting the MCPyV genome in MCC samples compared with traditional qPCR techniques.


Assuntos
Carcinoma de Célula de Merkel , Poliomavírus das Células de Merkel , Ácidos Nucleicos , Infecções por Polyomavirus , Polyomavirus , Neoplasias Cutâneas , Infecções Tumorais por Vírus , Humanos , Polyomavirus/genética , Reação em Cadeia da Polimerase em Tempo Real , Poliomavírus das Células de Merkel/genética , Neoplasias Cutâneas/diagnóstico , Formaldeído
7.
Viruses ; 14(10)2022 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-36298759

RESUMO

Merkel cell polyomavirus (MCPyV) is the only human polyomavirus currently known to cause human cancer. MCPyV is believed to be an etiological factor in at least 80% of cases of the rare but aggressive skin malignancy Merkel cell carcinoma (MCC). In these MCPyV+ MCC tumors, clonal integration of the viral genome results in the continued expression of two viral proteins: the viral small T antigen (ST) and a truncated form of the viral large T antigen. The oncogenic potential of MCPyV and the functional properties of the viral T antigens that contribute to neoplasia are becoming increasingly well-characterized with the recent development of model systems that recapitulate the biology of MCPyV+ MCC. In this review, we summarize our understanding of MCPyV and its role in MCC, followed by the current state of both in vitro and in vivo model systems used to study MCPyV and its contribution to carcinogenesis. We also highlight the remaining challenges within the field and the major considerations related to the ongoing development of in vitro and in vivo models of MCPyV+ MCC.


Assuntos
Carcinoma de Célula de Merkel , Poliomavírus das Células de Merkel , Infecções por Polyomavirus , Neoplasias Cutâneas , Infecções Tumorais por Vírus , Humanos , Poliomavírus das Células de Merkel/genética , Infecções Tumorais por Vírus/metabolismo , Antígenos Virais de Tumores/genética , Carcinogênese/genética , Proteínas Virais
8.
Viruses ; 14(9)2022 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-36146655

RESUMO

Merkel cell carcinoma (MCC) is a rare but aggressive form of skin cancer predominantly caused by the human Merkel cell polyomavirus (MCPyV). Treatment for MCC includes excision and radiotherapy of local disease, and chemotherapy or immunotherapy for metastatic disease. The schweinfurthin family of natural compounds previously displayed potent and selective growth inhibitory activity against the NCI-60 panel of human-derived cancer cell lines. Here, we investigated the impact of schweinfurthin on human MCC cell lines. Treatment with the schweinfurthin analog, 5'-methylschweinfurth G (MeSG also known as TTI-3114), impaired metabolic activity through induction of an apoptotic pathway. MeSG also selectively inhibited PI3K/AKT and MAPK/ERK pathways in the MCPyV-positive MCC cell line, MS-1. Interestingly, expression of the MCPyV small T (sT) oncogene selectively sensitizes mouse embryonic fibroblasts to MeSG. These results suggest that the schweinfurthin family of compounds display promising potential as a novel therapeutic option for virus-induced MCCs.


Assuntos
Carcinoma de Célula de Merkel , Poliomavírus das Células de Merkel , Infecções por Polyomavirus , Neoplasias Cutâneas , Infecções Tumorais por Vírus , Animais , Carcinoma de Célula de Merkel/patologia , Fibroblastos/metabolismo , Guanosina/análogos & derivados , Humanos , Poliomavírus das Células de Merkel/genética , Camundongos , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologia , Estilbenos , Tionucleosídeos
9.
Int J STD AIDS ; 33(12): 1084-1086, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36112903

RESUMO

Merkel cell carcinoma (MCC) of the skin is a rare, aggressive and often fatal neuroendocrine skin cancer. The incidence of MCC has significantly increased in the last decades. Factors that have been associated with the development of MCC include infection with Merkel Cell polyomavirus (MCPyV), ultraviolet exposure, hematologic malignancies and immunosuppression.We present three cases of patients living with HIV who were diagnosed with MCC. HIV cases associated with MCC have been rarely reported and to our knowledge, not yet before in the UK.


Assuntos
Carcinoma de Célula de Merkel , Infecções por HIV , Poliomavírus das Células de Merkel , Neoplasias Cutâneas , Humanos , Carcinoma de Célula de Merkel/diagnóstico , Carcinoma de Célula de Merkel/patologia , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/patologia , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Reino Unido
10.
Oncotarget ; 13: 960-967, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35937502

RESUMO

INTRODUCTION: Merkel cell carcinoma (MCC) is an aggressive skin cancer, related to the Merkel Cell Polyomavirus (MCPyV) in 80% of cases. Immune checkpoint inhibitors provide sustained benefit in about 50% of MCC patients with advanced disease. Glypican-3 (GPC3) is an oncofetal tumor antigen that is an attractive target for chimeric antigen receptor T cell therapy due to its highly restricted expression on normal tissue and high prevalence in several solid tumors. GPC3 is known to be expressed in MCC but its association with tumor characteristics or prognosis has not been reported. We investigated MCC GPC3 expression by immunohistochemistry (IHC) and its association with tumor characteristics, MCPyV status, and patient outcome. METHODS: The GC33 antibody clone was validated for GPC3 IHC staining of tumor specimens in comparison to an established GPC3 IHC antibody. An MCC tissue microarray was stained for GPC3 by IHC using GC33 antibody. Association of GPC3+ IHC with baseline characteristics, MCPyV status (qPCR) and outcome (death from MCC/recurrence) were assessed. RESULTS: Forty-two of 62 samples (67.7%) were GPC3+. GPC3 expression was more frequently observed in females (p = 0.048) and MCPyV-negative tumors (p = 0.021). By multivariate analysis, GPC3 expression was associated with increased death from disease (CSS) (hazard ratio [HR] 4.05, 95% CI 1.06-15.43), together with advanced age (HR 4.85, 95% CI 1.39-16.9) and male gender (HR 4.64, 95% CI 1.31-16.41). CONCLUSIONS: GPC3 expression is frequent in MCC tumors, especially MCPyV-negative cases, and is associated with increased risk of death. High prevalence of surface GPC3 makes it a putative drug target.


Assuntos
Carcinoma de Célula de Merkel , Poliomavírus das Células de Merkel , Infecções por Polyomavirus , Receptores de Antígenos Quiméricos , Neoplasias Cutâneas , Infecções Tumorais por Vírus , Antígenos de Neoplasias , Carcinoma de Célula de Merkel/patologia , Feminino , Glipicanas , Humanos , Inibidores de Checkpoint Imunológico , Masculino , Infecções por Polyomavirus/complicações , Neoplasias Cutâneas/patologia , Infecções Tumorais por Vírus/complicações
11.
J Clin Invest ; 132(13)2022 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-35775490

RESUMO

Cancers avoid immune surveillance through an array of mechanisms, including perturbation of HLA class I antigen presentation. Merkel cell carcinoma (MCC) is an aggressive, HLA-I-low, neuroendocrine carcinoma of the skin often caused by the Merkel cell polyomavirus (MCPyV). Through the characterization of 11 newly generated MCC patient-derived cell lines, we identified transcriptional suppression of several class I antigen presentation genes. To systematically identify regulators of HLA-I loss in MCC, we performed parallel, genome-scale, gain- and loss-of-function screens in a patient-derived MCPyV-positive cell line and identified MYCL and the non-canonical Polycomb repressive complex 1.1 (PRC1.1) as HLA-I repressors. We observed physical interaction of MYCL with the MCPyV small T viral antigen, supporting a mechanism of virally mediated HLA-I suppression. We further identify the PRC1.1 component USP7 as a pharmacologic target to restore HLA-I expression in MCC.


Assuntos
Carcinoma de Célula de Merkel , Poliomavírus das Células de Merkel , Infecções por Polyomavirus , Neoplasias Cutâneas , Antígenos Virais de Tumores/genética , Antígenos Virais de Tumores/metabolismo , Carcinoma de Célula de Merkel/genética , Carcinoma de Célula de Merkel/patologia , Epigênese Genética , Humanos , Poliomavírus das Células de Merkel/genética , Poliomavírus das Células de Merkel/metabolismo , Infecções por Polyomavirus/genética , Neoplasias Cutâneas/patologia , Peptidase 7 Específica de Ubiquitina/metabolismo
12.
JCI Insight ; 7(13)2022 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-35801592

RESUMO

Merkel cell carcinoma (MCC) is an aggressive neuroendocrine carcinoma of the skin with 2 etiologies. Merkel cell polyomavirus (MCPyV) integration is present in about 80% of all MCC. Virus-positive MCC (MCCP) tumors have few somatic mutations and usually express WT p53 (TP53). By contrast, virus-negative MCC (MCCN) tumors present with a high tumor mutational burden and predominantly UV mutational signature. MCCN tumors typically contain mutated TP53. MCCP tumors express 2 viral proteins: MCPyV small T antigen and a truncated form of large T antigen. MCPyV ST specifically activates expression of MDM2, an E3 ubiquitin ligase of p53, to inhibit p53-mediated tumor suppression. In this study, we assessed the efficacy of milademetan, a potent, selective, and orally available MDM2 inhibitor in several MCC models. Milademetan reduced cell viability of WT p53 MCC cell lines and triggered a rapid and sustained p53 response. Milademetan showed a dose-dependent inhibition of tumor growth in MKL-1 xenograft and patient-derived xenograft models. Here, along with preclinical data for the efficacy of milademetan in WT p53 MCC tumors, we report several in vitro and in vivo models useful for future MCC studies.


Assuntos
Carcinoma de Célula de Merkel , Infecções por Polyomavirus , Proteínas Proto-Oncogênicas c-mdm2 , Neoplasias Cutâneas , Infecções Tumorais por Vírus , Animais , Antígenos Virais de Tumores/metabolismo , Carcinoma de Célula de Merkel/tratamento farmacológico , Carcinoma de Célula de Merkel/genética , Humanos , Indóis/farmacologia , Poliomavírus das Células de Merkel , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-mdm2/genética , Piridinas/farmacologia , Pirrolidinas/farmacologia , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/genética , Proteína Supressora de Tumor p53/genética
13.
Oncogene ; 41(27): 3511-3523, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35688945

RESUMO

Merkel cell carcinoma (MCC) is an aggressive malignancy with neuroendocrine (NE) features, limited treatment options, and a lack of druggable targets. There is no reported involvement of the MUC1-C oncogenic protein in MCC progression. We show here that MUC1-C is broadly expressed in MCCs and at higher levels in Merkel cell polyomavirus (MCPyV)-positive (MCCP) relative to MCPyV-negative (MCCN) tumors. Our results further demonstrate that MUC1-C is expressed in MCCP, as well as MCCN, cell lines and regulates common sets of signaling pathways related to RNA synthesis, processing, and transport in both subtypes. Mechanistically, MUC1-C (i) interacts with MYCL, which drives MCC progression, (ii) is necessary for expression of the OCT4, SOX2, KLF4, MYC, and NANOG pluripotency factors, and (iii) induces the NEUROD1, BRN2 and ATOH1 NE lineage dictating transcription factors. We show that MUC1-C is also necessary for MCCP and MCCN cell survival by suppressing DNA replication stress, the p53 pathway, and apoptosis. In concert with these results, targeting MUC1-C genetically and pharmacologically inhibits MCC self-renewal capacity and tumorigenicity. These findings demonstrate that MCCP and MCCN cells are addicted to MUC1-C and identify MUC1-C as a potential target for MCC treatment.


Assuntos
Carcinoma de Célula de Merkel , Poliomavírus das Células de Merkel , Mucina-1 , Neoplasias Cutâneas , Carcinoma de Célula de Merkel/tratamento farmacológico , Carcinoma de Célula de Merkel/genética , Carcinoma de Célula de Merkel/virologia , Humanos , Mucina-1/metabolismo , Transdução de Sinais , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/virologia
14.
Rinsho Ketsueki ; 63(5): 383-392, 2022.
Artigo em Japonês | MEDLINE | ID: mdl-35662161

RESUMO

Histiocytosis is classified based on proliferating histiocyte-like cells. Langerhans cell histiocytosis (LCH) has several subtypes with various outcomes, from spontaneous to fatal regression, and these subtypes had been managed as different diseases. However, these different names of disease were unified to one disease named histiocytosis X since they are pathologically identical. Presently, LCH has been used as a unified name because proliferating cells have the characteristics of Langerhans cells. Since then, clonality and BRAF mutations have been reported, and their neoplastic characteristics has become clear; however, explaining its various subtypes is difficult with only the neoplastic character. Various relationships/correlations are also known between inflammatory factors and LCH subtypes. We have pointed out that the Merkel cell polyomavirus may be involved in LCH development and LCH is a disease with both neoplastic and reactive characters, that is, "a disease in which abnormal Langerhans-like cells with neoplastic character overreact to some triggers."


Assuntos
Histiocitose de Células de Langerhans , Poliomavírus das Células de Merkel , Histiocitose de Células de Langerhans/genética , Humanos , Células de Langerhans , Mutação , Proteínas Proto-Oncogênicas B-raf/genética
15.
J Virol ; 96(14): e0206121, 2022 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-35770990

RESUMO

Several studies reported the presence of a recently discovered polyomavirus (PyV), Lyon IARC PyV (LIPyV), in human and domestic animal specimens. LIPyV has some structural similarities to well-established animal and human oncogenic PyVs, such as raccoon PyV and Merkel cell PyV (MCPyV), respectively. In this study, we demonstrate that LIPyV early proteins immortalize human foreskin keratinocytes. LIPyV LT binds pRb, accordingly cell cycle checkpoints are altered in primary human fibroblasts and keratinocytes expressing LIPyV early genes. Mutation of the pRb binding site in LT strongly affected the ability of LIPyV ER to induced HFK immortalization. LIPyV LT also binds p53 and alters p53 functions activated by cellular stresses. Finally, LIPyV early proteins activate telomerase reverse transcriptase (hTERT) gene expression, via accumulation of the Sp1 transcription factor. Sp1 recruitment to the hTERT promoter is controlled by its phosphorylation, which is mediated by ERK1 and CDK2. Together, these data highlight the transforming properties of LIPyV in in vitro experimental models, supporting its possible oncogenic nature. IMPORTANCE Lyon IARC PyV is a recently discovered polyomavirus that shows some structural similarities to well-established animal and human oncogenic PyVs, such as raccoon PyV and Merkel cell PyV, respectively. Here, we show the capability of LIPyV to efficiently promote cellular transformation of primary human cells, suggesting a possible oncogenic role of this virus in domestic animals and/or humans. Our study identified a novel virus-mediated mechanism of activation of telomerase reverse transcriptase gene expression, via accumulation of the Sp1 transcription factor. In addition, because the persistence of infection is a key event in virus-mediated carcinogenesis, it will be important to determine whether LIPyV can deregulate immune-related pathways, similarly to the well-established oncogenic viruses.


Assuntos
Infecções por Polyomavirus , Polyomavirus , Animais , Carcinogênese , Fibroblastos/virologia , Humanos , Queratinócitos/virologia , Poliomavírus das Células de Merkel/genética , Polyomavirus/genética , Polyomavirus/metabolismo , Infecções por Polyomavirus/virologia , Fator de Transcrição Sp1/metabolismo , Telomerase/genética , Proteína Supressora de Tumor p53/metabolismo
16.
Microb Pathog ; 169: 105644, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35752381

RESUMO

Merkel cell polyomavirus (MCPyV) has been detected in respiratory specimens including those from Cystic Fibrosis (CF) patients, raising questions about its immunological and clinical relevance in the respiratory tract. MCPyV might promote an inappropriate antiviral response contributing to a chronic inflammatory response and resulting in detrimental effects in CF. Respiratory samples (n = 1138) were randomly collected from respiratory tract of CF patients (n = 539) during July 2018-October 2019. MCPyV-DNA detection was performed by real time PCR and positive samples were characterized by sequencing of the NCCR genomic region. The transcript levels of Toll-like receptor 9 (TLR9) and type I interferon (IFN-I) genes (IFNα, IFNß and IFNε) were examined by real-time RT-PCR assays. MCPyV-DNA was detected in 268 out of 1138 respiratory specimens (23.5%) without any difference in the prevalence of MCPyV-DNA according to age, gender or bacteriological status of CF individuals. Thirteen out of 137 CF patients remained positive for MCPyV-DNA over the time (a median follow-up period of 8.8 months). Detection of MCPyV-DNA in respiratory specimens was not associated with the occurrence of exacerbation events. Both MCPyV positive adolescents (11-24 years) and adults (≥25 years) had lower mRNA levels of TLR9, IFNß, IFNε and IFNα than the negative patients of the same age group, while MCPyV positive children produced increased levels of TLR9 and IFN-I genes (p < 0.05 for TLR9, IFNß, IFNε) with respect to the negative ones. There were significant differences in TLR9 levels (p < 0.01), but not in those of IFNs, between MCPyV-DNA positive and negative patients with S. aureus, P. aeruginosa or both. Overall, these results indicate that MCPyV-DNA is frequently detected in the respiratory samples of CF patients and might influence the expression levels of IFN-related genes in an age dependent manner. The concomitant detection of MCPyV together with S. aureus and/or P. aeruginosa correlated with alterations in TLR9 levels suggesting that virus-bacteria coinfections might contribute to affect antiviral immunity in CF patients.


Assuntos
Fibrose Cística , Poliomavírus das Células de Merkel , Infecções por Polyomavirus , Adolescente , Adulto , Antivirais , Criança , Fibrose Cística/complicações , DNA Viral/análise , DNA Viral/genética , Humanos , Poliomavírus das Células de Merkel/genética , Infecções por Polyomavirus/epidemiologia , Prevalência , Pseudomonas aeruginosa/genética , Staphylococcus aureus/genética , Receptor Toll-Like 9/genética
17.
J Immunother Cancer ; 10(6)2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35701070

RESUMO

Merkel cell carcinoma (MCC) is a rare and highly aggressive cutaneous neuroendocrine carcinoma. The MCC incidence rate has rapidly grown over the last years, with Italy showing the highest increase among European countries. This malignancy has been the focus of active scientific research over the last years, focusing mainly on pathogenesis, new therapeutic trials and diagnosis. A national expert board developed 28 consensus statements that delineated the evolution of disease management and highlighted the paradigm shift towards the use of immunological strategies, which were then presented to a national MCC specialists panel for review. Sixty-five panelists answered both rounds of the questionnaire. The statements were divided into five areas: a high level of agreement was reached in the area of guidelines and multidisciplinary management, even if in real life the multidisciplinary team was not always represented by all the specialists. In the diagnostic pathway area, imaging played a crucial role in diagnosis and initial staging, planning for surgery or radiation therapy, assessment of treatment response and surveillance of recurrence and metastases. Concerning diagnosis, the usefulness of Merkel cell polyomavirus is recognized, but the agreement and consensus regarding the need for cytokeratin evaluation appears greater. Regarding the areas of clinical management and follow-up, patients with MCC require customized treatment. There was a wide dispersion of results and the suggestion to increase awareness about the adjuvant radiation therapy. The panelists unanimously agreed that the information concerning avelumab provided by the JAVELIN Merkel 200 study is adequate and reliable and that the expanded access program data could have concrete clinical implications. An immunocompromised patient with advanced MCC can be treated with immunotherapy after multidisciplinary risk/benefit assessment, as evidenced by real-world analysis and highlighted in the guidelines. A very high consensus regarding the addition of radiotherapy to treat the ongoing focal progression of immunotherapy was observed. This paper emphasizes the importance of collaboration and communication among the interprofessional team members and encourages managing patients with MCC within dedicated multidisciplinary teams. New insights in the treatment of this challenging cancer needs the contribution of many and different experts.


Assuntos
Carcinoma de Célula de Merkel , Poliomavírus das Células de Merkel , Neoplasias Cutâneas , Carcinoma de Célula de Merkel/diagnóstico , Carcinoma de Célula de Merkel/patologia , Carcinoma de Célula de Merkel/terapia , Humanos , Imunoterapia/métodos , Itália , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/terapia
18.
PLoS Pathog ; 18(5): e1010551, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35560034

RESUMO

Clear evidence supports a causal link between Merkel cell polyomavirus (MCPyV) and the highly aggressive human skin cancer called Merkel cell carcinoma (MCC). Integration of viral DNA into the human genome facilitates continued expression of the MCPyV small tumor (ST) and large tumor (LT) antigens in virus-positive MCCs. In MCC tumors, MCPyV LT is truncated in a manner that renders the virus unable to replicate yet preserves the LXCXE motif that facilitates its binding to and inactivation of the retinoblastoma tumor suppressor protein (pRb). We previously developed a MCPyV transgenic mouse model in which MCC tumor-derived ST and truncated LT expression were targeted to the stratified epithelium of the skin, causing epithelial hyperplasia, increased proliferation, and spontaneous tumorigenesis. We sought to determine if any of these phenotypes required the association between the truncated MCPyV LT and pRb. Mice were generated in which K14-driven MCPyV ST/LT were expressed in the context of a homozygous RbΔLXCXE knock-in allele that attenuates LT-pRb interactions through LT's LXCXE motif. We found that many of the phenotypes including tumorigenesis that develop in the K14-driven MCPyV transgenic mice were dependent upon LT's LXCXE-dependent interaction with pRb. These findings highlight the importance of the MCPyV LT-pRb interaction in an in vivo model for MCPyV-induced tumorigenesis.


Assuntos
Carcinoma de Célula de Merkel , Poliomavírus das Células de Merkel , Infecções por Polyomavirus , Neoplasias Cutâneas , Infecções Tumorais por Vírus , Animais , Antígenos Transformantes de Poliomavirus/genética , Antígenos Transformantes de Poliomavirus/metabolismo , Antígenos Virais de Tumores/genética , Antígenos Virais de Tumores/metabolismo , Transformação Celular Neoplásica , Hiperplasia/patologia , Células de Merkel/metabolismo , Células de Merkel/patologia , Poliomavírus das Células de Merkel/genética , Camundongos , Neoplasias Cutâneas/patologia
19.
Endocr Pathol ; 33(2): 289-303, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35551625

RESUMO

Merkel cell carcinoma is a rare and aggressive primary neuroendocrine carcinoma of the skin, whose pathogenesis can be traced back to UV radiation damage or Merkel cell polyomavirus (MCPyV) infection. Despite some improvements on the characterization of the disease partly due to its increased incidence, crucial pathogenetic and prognostic factors still need to be refined. A consecutive series of 228 MCC from three hospitals in Turin was collected with the aim of both analyzing the apparent increase in MCC incidence in our area and investigating the distribution and prognostic role of clinical-pathological parameters, with a focus on MCPyV status, ALK tumor expression and tumor infiltrating lymphocytes (TILs). Review of morphology and conventional immunohistochemical staining was possible in 191 cases. In 50 cases, the expression of the novel neuroendocrine marker INSM1 was additionally assessed. Fourteen cases of MCC of unknown primary skin lesion were identified and separately analyzed. While confirming an exponential trend in MCC incidence in the last decades and providing a description of histological and cytological features of a large series of MCC, the present study concludes that 1) INSM1 is a highly sensitive marker in both skin and lymph node primary MCC; 2) positive MCPyV status, brisk TILs and lower tumor size and thickness are independent positive prognostic parameters, and the combination of the former two may provide a novel tool for prognostic stratification; 3) ALK is expressed 87% of MCC and associated with positive viral status, and could represent a prognostic biomarker, if validated in larger series.


Assuntos
Carcinoma de Célula de Merkel , Poliomavírus das Células de Merkel , Infecções por Polyomavirus , Neoplasias Cutâneas , Carcinoma de Célula de Merkel/patologia , Humanos , Linfócitos do Interstício Tumoral , Prognóstico , Receptores Proteína Tirosina Quinases , Proteínas Repressoras , Neoplasias Cutâneas/patologia
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