RESUMO
Ultraviolet (UV) radiation plays a crucial role in the development of melanoma and non-melanoma skin cancers. The types of UV radiation are differentiated by wavelength: UVA (315 to 400 nm), UVB (280 to 320 nm), and UVC (100 to 280 nm). UV radiation can cause direct DNA damage in the forms of cyclobutane pyrimidine dimers (CPDs) and 6-4 photoproducts (6-4PPs). In addition, UV radiation can also cause DNA damage indirectly through photosensitization reactions caused by reactive oxygen species (ROS), which manifest as 8-hydroxy-2'-deoxyguanine (8-OHdG). Both direct and indirect DNA damage can lead to mutations in genes that promote the development of skin cancers. The development of melanoma is largely influenced by the signaling of the melanocortin one receptor (MC1R), which plays an essential role in the synthesis of melanin in the skin. UV-induced mutations in the BRAF and NRAS genes are also significant risk factors in melanoma development. UV radiation plays a significant role in basal cell carcinoma (BCC) development by causing mutations in the Hedgehog (Hh) pathway, which dysregulates cell proliferation and survival. UV radiation can also induce the development of squamous cell carcinoma via mutations in the TP53 gene and upregulation of MMPs in the stroma layer of the skin.
RESUMO
K homology-type splicing regulatory protein (KSRP) is emerging as a key player in cancer biology, and immunology. As a single-strand nucleic acid binding protein it functions in both transcriptional and post-transcriptional regulation, while facilitating multiple stages of RNA metabolism to affect proliferation and control cell fate. However, it must interact with other proteins to determine the fate of its bound substrate. Here we provide an minireview of this important regulatory protein and describe its complex subcellular functions to affect RNA metabolism, stability, miRNA biogenesis and maturation, stress granule function, metastasis, and inflammatory processes.
Assuntos
Doenças do Sistema Imunitário , Neoplasias , Humanos , Transativadores/genética , Transativadores/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Fatores de Transcrição/metabolismo , Neoplasias/genética , RNARESUMO
Cancer patients face a significant clinical and socio-economic burden due to increased incidence, mortality, and poor survival. Factors like late diagnosis, recurrence, drug resistance, severe side effects, and poor bioavailability limit the scope of current therapies. There is a need for novel, cost-effective, and safe diagnostic methods, therapeutics to overcome recurrence and drug resistance, and drug delivery vehicles with enhanced bioavailability and less off-site toxicity. Advanced nanomaterial-based research is aiding cancer biologists by providing solutions for issues like hypoxia, tumor microenvironment, low stability, poor penetration, target non-specificity, and rapid drug clearance. Currently, nanozymes and carbon-dots are attractive due to their low cost, high catalytic activity, biocompatibility, and lower toxicity. Nanozymes and carbon-dots are increasingly used in imaging, biosensing, diagnosis, and targeted cancer therapy. Integrating these materials with advanced diagnostic tools like CT scans and MRIs can aid in clinical decision-making and enhance the effectiveness of chemotherapy, photothermal, photodynamic, and sonodynamic therapies, with minimal invasion and reduced collateral effects.
Assuntos
Nanoestruturas , Neoplasias , Humanos , Carbono , Neoplasias/diagnóstico por imagem , Neoplasias/tratamento farmacológico , Microambiente TumoralRESUMO
Extracorporeal photopheresis (ECP) is an apheresis procedure that is conventionally used as a first-line treatment for cutaneous and leukemic subtypes of T-cell lymphoma, such as Sezary's syndrome and mycosis fungoides. Over the past three decades, its immunotherapeutic properties have been tested on a variety of autoimmune conditions, including many dermatologic diseases. There is ample evidence of ECP's ability to modify leukocytes and alter cytokine production for certain dermatologic diseases that have been refractory to first-line treatments, such as atopic dermatitis. However, the evidence on the efficacy of ECP for the treatment of these dermatologic diseases is unclear and/or lacks sufficient evidence. The purpose of this paper is to review the literature on the utilization and clinical efficacy of ECP in the treatment of several [autoimmune] dermatologic diseases and discuss its applications, guidelines, recommendations, and future implementation for dermatologic diseases.
Assuntos
Remoção de Componentes Sanguíneos , Micose Fungoide , Fotoferese , Síndrome de Sézary , Neoplasias Cutâneas , Humanos , Fotoferese/métodos , Neoplasias Cutâneas/patologia , Micose Fungoide/patologia , Remoção de Componentes Sanguíneos/métodos , Síndrome de Sézary/terapiaRESUMO
Skin cancer represents a major public health issue with a tremendous cost to healthcare systems in the United States and worldwide [...].
Assuntos
Neoplasias Cutâneas , Humanos , Estados Unidos , Imunomodulação , Saúde Pública , Atenção à Saúde , PeleRESUMO
Type I interferons (IFNs) are important enhancers of immune responses which are downregulated in human cancers, including skin cancer. Solar ultraviolet (UV) B radiation is a proven environmental carcinogen, and its exposure contributes to the high prevalence of skin cancer. The carcinogenic effects of UV light can be attributed to the formation of cyclobutane pyrimidine dimers (CPD) and errors in the repair and replication of DNA. Treatment with a single dose of UVB (100 mJ/cm2) upregulated IFNα and IFNß in the skin of C57BL/6 mice. IFNα and IFNß were predominantly produced by CD11b+ cells. In mice lacking the type I IFN receptor 1 (IFNAR1), the repair of CPD following cutaneous exposure to a single dose of UVB (100 mJ/cm2) was decreased. UVB induced the expression of the DNA repair gene xeroderma pigmentosum A (XPA) in wild-type (WT) mice. In contrast, such treatment in IFNAR1 (IFNAR1-/-) mice downregulated XPA. A local UVB regimen consisting of UVB radiation (150 mJ/cm2) for 4 days followed by sensitization with hapten 2,4, dinitrofluorobenzene (DNFB) resulted in significant suppression of immune responses in both WT and IFNAR1-/- mice. However, there were significantly higher CD4+CD25+Foxp3+ regulatory T-cells in the draining lymph nodes of IFNAR1-/- mice in comparison to WT mice. Overall, our studies reveal a previously unknown action of type I IFNs in the repair of photodamage and the prevention of UVB-induced immune suppression.
Assuntos
Interferon Tipo I , Neoplasias Cutâneas , Xeroderma Pigmentoso , Animais , Dano ao DNA , Reparo do DNA , Interferon Tipo I/genética , Interferon Tipo I/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Dímeros de Pirimidina/metabolismo , Pele/metabolismo , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/metabolismo , Raios Ultravioleta/efeitos adversos , Xeroderma Pigmentoso/metabolismoRESUMO
Ultraviolet (UV) B irradiation of the skin induces acute inflammation, as characterized by erythema, edema, and immunosuppression, and is subsequently linked to the progression of skin cancer. Toll-like receptor 4 (TLR4), a component of innate immunity, has been shown to play an important role in cancer. To elucidate the role of TLR4 in UVB-induced tumor development, TLR4-proficient (C3H/HeN) and TLR4-deficient (C3H/HeJ) mice were exposed to multiple doses of UVB radiation (200 mJ/cm2 ) for 40 weeks. Photocarcinogenesis was retarded in terms of tumor incidence, and tumor latency, in mice deficient in TLR4 compared with TLR4-proficient mice, whereas significantly greater numbers of tumors occurred in TLR4-proficient mice. There was significant upregulation of inflammatory markers like COX-2, PGE2 , S100A8, and S100A9 in the skin of TLR4-proficient mice than the skin of TLR4-deficient mice. Furthermore, we found that TLR4-proficient mice had a significantly higher number of Gr1+CD11b+ myeloid cells CD4+CD25+ regulatory T-cells than TLR4-deficient mice. Furthermore, the levels of interferon (IFN)-γ cytokine was increased and the levels of interleukin (IL)-4, IL-10, and IL-17 cytokines were decreased in serum, skin, and tumor lysates of TLR4-deficient mice in comparison with samples from TLR4-proficient mice. Together, our data indicate that TLR4-mediated inflammation may cause suppression of antitumor responses and trigger the development of UVB-induced skin cancers. Thus, strategies to inhibit TLR4-mediated immune suppression may allow us to develop preventive and therapeutic approaches for the management of UVB-induced cutaneous tumors.
Assuntos
Neoplasias Cutâneas/etiologia , Neoplasias Cutâneas/genética , Receptor 4 Toll-Like/genética , Raios Ultravioleta/efeitos adversos , Animais , Carcinogênese/genética , Carcinogênese/imunologia , Carcinogênese/efeitos da radiação , Deleção de Genes , Imunidade , Inflamação/etiologia , Inflamação/genética , Inflamação/imunologia , Camundongos , Neoplasias Cutâneas/imunologia , Receptor 4 Toll-Like/imunologiaRESUMO
The tumor microenvironment (TME), which assists in the development, progression, and metastasis of malignant cells, is instrumental in virtually every step of tumor development. While a healthy TME can protect against malignancy, in an unhealthy state, it can result in aberrant cellular behavior and augment tumor progression. Cytokines are one component of the TME, therefore, understanding the composition of the cytokine milieu in the tumor microenvironment is critical to understand the biology of malignant transformation. One cytokine, interleukin (IL)-23, has received particular scrutiny in cancer research because of its ability to manipulate host immune responses, its role in modulating the cells in TME, and its capacity to directly affect a variety of premalignant and malignant tumors. IL-23 belongs to the IL-12 cytokine family, which is produced by activated dendritic cells (DC) and macrophages. IL-23 acts by binding to its receptor consisting of two distinct subunits, IL-12Rß1 and IL-23R. This, in turn, leads to janus kinase (JAK) activation and signal transducer and activator of transcription (STAT) 3/4 phosphorylation. There have been contradictory reports of pro- and antitumor effects of IL-23, which likely depend on the genetic background, the type of tumor, the causative agent, and the critical balance of STAT3 signaling in both the tumor itself and the TME. Clinical trials of IL-12/23 inhibitors that are used to treat patients with psoriasis, have been scrutinized for reports of malignancy, the most common being nonmelanoma skin cancers (NMSCs). Continued investigation into the relationship of IL-23 and its downstream pathways holds promise in identifying novel targets for the management of cancer and other diseases.
Assuntos
Interleucina-23 , Microambiente Tumoral , Humanos , Interleucina-12 , Janus Quinases/metabolismo , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Transdução de SinaisRESUMO
BACKGROUND: Studies have begun to investigate the complex relationship between host and microorganisms in non-infectious pathologies such as acne, atopic dermatitis and psoriasis. Though the skin is exposed to environmental stressors such as ultraviolet radiation (UVR), no studies exist examining the effects of both UVA and UVB on the skin microbiome. OBJECTIVE: To test the effect of UVA and UVB on human skin microbiome. METHODS: To test whether UV will alter the cutaneous microbiome, participants were exposed to doses of UVA (22-47 J/cm2 ) or UVB (100-350 mJ/cm2 ) and samples were collected. DNA was isolated and sequenced to identify the microbial composition of each sample. RESULTS: There was vast intra- and inter-subject variation at all time points, and phylum and species-level differences were identified. These included an increase in the phylum Cyanobacteria and a decrease in the family Lactobacillaceae and Pseudomonadaceae. The sensitivity of microbes to UVR and their re-colonization potential following exposure differed in UVA vs UVB samples. LIMITATIONS: The sample size was small, and the study was limited to males. CONCLUSION: The results demonstrate that UVR has profound qualitative and quantitative influences on the composition of the skin microbiome, possibly effecting skin pathology in which UVR is a factor.
Assuntos
Microbiota/efeitos da radiação , Pele/microbiologia , Pele/efeitos da radiação , Raios Ultravioleta , Acne Vulgar/microbiologia , Adulto , DNA/efeitos da radiação , Dermatite Atópica/microbiologia , Humanos , Inflamação/microbiologia , Masculino , Psoríase/microbiologia , Adulto JovemRESUMO
Non-melanoma skin cancer is one of the major ailments in the United States. Effective drugs that can cure skin cancers are limited. Moreover, the available drugs have toxic side effects. Therefore, skin cancer drugs with less toxic side effects are urgently needed. To achieve this goal, we focused our work on identifying potent lead compounds from marine natural products. Five lead compounds identified from a class of pyrroloiminoquinone natural products were evaluated for their ability to selectively kill squamous cell carcinoma (SCC13) skin cancer cells using an MTT assay. The toxicity of these compounds was also evaluated against the normal human keratinocyte HaCaT cell line. The most potent compound identified from these studies, C278 was further evaluated for its ability to inhibit cancer cell migration and invasion using a wound-healing assay and a trans-well migration assay, respectively. To investigate the molecular mechanism of cell death, the expression of apoptotic and autophagy proteins was studied in C278 treated cells compared to untreated cells using western blot. Our results showed that all five compounds effectively killed the SCC13 cells, with compound C278 being the most effective. Compound C278 was more effective in killing the SCC13 cells compared to HaCaT cells with a two-fold selectivity. The migration and the invasion of the SCC13 cells were also inhibited upon treatment with compound C278. The expression of pro-apoptotic and autophagy proteins with concomitant downregulation in the expression of survival proteins were observed in C278 treated cells. In summary, the marine natural product analog compound C278 showed promising anticancer activity against human skin cancer cells and holds potential to be developed as an effective anticancer agent to combat skin cancer.
Assuntos
Organismos Aquáticos/química , Produtos Biológicos/farmacologia , Pirroliminoquinonas/farmacologia , Neoplasias Cutâneas/tratamento farmacológico , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Carcinoma de Células Escamosas/tratamento farmacológico , Linhagem Celular , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Chalconas/farmacologia , Regulação para Baixo/efeitos dos fármacos , Humanos , Queratinócitos/efeitos dos fármacos , Pele/diagnóstico por imagemRESUMO
Doxorubicin (DOX) is a widely used drug for cancer treatment as a chemotherapeutic agent. However, the cellular and integrative mechanism of DOX-induced immunometabolism is unclear. Two-month-old male C57BL/6J mice were divided into high- and low-dose DOX-treated groups with a maintained saline control group. The first group was injected with a high dose of DOX (H-DOX; 15 mg·kg-1·wk-1), and the second group was injected with 7.5 mg·kg-1·wk-1 as a latent low dose of DOX (LL-DOX). H-DOX treatment led to complete mortality in 2 wk and 70% survival in the LL-DOX group compared with the saline control group. Therefore, an additional group of mice was injected with an acute high dose of DOX (AH-DOX) and euthanized at 24 h to compare with LL-DOX and saline control groups. The LL-DOX and AH-DOX groups showed obvious apoptosis and dysfunctional and structural changes in cardiac tissue. Splenic contraction was evident in AH-DOX- and LL-DOX-treated mice, indicating the systems-wide impact of DOX on integrative organs of the spleen, which is essential for cardiac homeostasis and repair. DOX dysregulated splenic-enriched immune-sensitive lipoxygenase and cyclooxygenase in the spleen and left ventricle compared with the saline control group. As a result, lipoxygenase-dependent D- and E-series resolvin precursors, such as 16HDoHE, 4HDoHE, and 12-HEPE, as well as cyclooxygenase-mediated PG species (PGD2, PGE2, and 6-keto-PG2α) were decreased in the left ventricle, suggestive of defective immunometabolism. Both AH-DOX and LL-DOX induced splenic contraction and expansion of red pulp with decreased CD169+ metallophilic macrophages. AH-DOX intoxicated macrophages in the spleen by depleting CD169+ cells in the acute setting and sustained the splenic macrophage loss in the chronic phase in the LL-DOX group. Thus, DOX triggers a vicious cycle of splenocardiac cachexia to facilitate defective immunometabolism and irreversible macrophage toxicity and thereby impaired the inflammation-resolution program. NEW & NOTEWORTHY Doxorubicin (DOX) triggered splenic mass loss and decreased CD169 with germinal center contraction in acute and chronic exposure. Cardiac toxicity of DOX is marked with dysregulation of immunometabolism and thereby impaired resolution of inflammation. DOX suppressed physiological levels of cytokines and chemokines with signs of splenocardiac cachexia.
Assuntos
Antibióticos Antineoplásicos/toxicidade , Caquexia/induzido quimicamente , Doxorrubicina/toxicidade , Cardiopatias/induzido quimicamente , Ventrículos do Coração/efeitos dos fármacos , Lipoxigenase/metabolismo , Macrófagos/efeitos dos fármacos , Prostaglandina-Endoperóxido Sintases/metabolismo , Baço/efeitos dos fármacos , Esplenopatias/induzido quimicamente , Animais , Apoptose/efeitos dos fármacos , Caquexia/enzimologia , Caquexia/imunologia , Caquexia/patologia , Cardiotoxicidade , Citocinas/genética , Citocinas/metabolismo , Relação Dose-Resposta a Droga , Fibrose , Regulação Enzimológica da Expressão Gênica , Cardiopatias/enzimologia , Cardiopatias/imunologia , Cardiopatias/patologia , Ventrículos do Coração/enzimologia , Ventrículos do Coração/imunologia , Ventrículos do Coração/patologia , Lipoxigenase/genética , Macrófagos/enzimologia , Macrófagos/imunologia , Macrófagos/patologia , Masculino , Camundongos Endogâmicos C57BL , Miocárdio/enzimologia , Miocárdio/imunologia , Miocárdio/patologia , Tamanho do Órgão , Prostaglandina-Endoperóxido Sintases/genética , Transdução de Sinais/efeitos dos fármacos , Baço/enzimologia , Baço/imunologia , Baço/patologia , Esplenopatias/enzimologia , Esplenopatias/imunologia , Esplenopatias/patologia , Fatores de Tempo , Função Ventricular Esquerda/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacosRESUMO
Immune cells and cytokines play an important role in the pathogenesis of psoriasis. Interleukin-12 (IL-12) and IL-23 promote cellular responses mediated by T cells, which contribute to an inflammatory loop responsible for the induction and maintenance of psoriatic plaques. Antibodies that inhibit IL-12/23 or IL-23 are key treatment options for patients with psoriasis. IL-12 and IL-23 also play a key role in immune responses to infections and tumors. A growing body of information from clinical trials, cohort studies, postmarketing reports, genetic studies and animal models provides insights into the potential biological relationships between IL-12/23 inhibition and malignancies. We summarize this information in tables and provide some context for the interpretation of these data with the goal of informing dermatologists who are using IL-12/23 or IL-23 inhibitors to treat patients with psoriasis.
Assuntos
Interleucina-12/antagonistas & inibidores , Interleucina-23/antagonistas & inibidores , Neoplasias/etiologia , Psoríase/imunologia , Psoríase/terapia , Animais , Ensaios Clínicos como Assunto , Fármacos Dermatológicos/efeitos adversos , Fármacos Dermatológicos/uso terapêutico , Modelos Animais de Doenças , Humanos , Imunidade Celular , Interleucina-12/química , Interleucina-12/imunologia , Interleucina-23/química , Interleucina-23/imunologia , Camundongos , Modelos Imunológicos , Vigilância de Produtos Comercializados , Psoríase/complicações , Receptores de Interleucina/deficiência , Receptores de Interleucina/genética , Receptores de Interleucina-12/deficiência , Receptores de Interleucina-12/genética , Linfócitos T/imunologia , Ustekinumab/efeitos adversos , Ustekinumab/uso terapêuticoRESUMO
Conjugation of bioactive targeting molecules to nano- or micrometer-sized drug carriers is a pivotal strategy to improve their therapeutic efficiency. Herein, we developed pH- and redox-sensitive hydrogel particles with a surface-conjugated cancer cell targeting ligand for specific tumor-targeting and controlled release of the anticancer drug doxorubicin. The poly(methacrylic acid) (PMAA) hydrogel cubes of 700 nm and 2 µm with a hepsin-targeting (IPLVVPL) surface peptide are produced through multilayer polymer assembly on sacrificial cubical mesoporous cores. Direct peptide conjugation to the disulfide-stabilized hydrogels through a thiol-amine reaction does not compromise the structural integrity, hydrophilicity, stability in serum, or pH/redox sensitivity but does affect internalization by cancer cells. The cell uptake kinetics and the ultimate extent of internalization are controlled by the cell type and hydrogel size. The peptide modification significantly promotes the uptake of the 700 nm hydrogels by hepsin-positive MCF-7 cells due to ligand-receptor recognition but has a negligible effect on the uptake of 2 µm PMAA hydrogels. The selectivity of 700 nm IPLVVPL-PMAA hydrogel cubes to hepsin-overexpressing tumor cells is further confirmed by a 3-10-fold higher particle internalization by hepsin-positive MCF-7 and SK-OV-3 compared to that of hepsin-negative PC-3 cells. This work provides a facile method to fabricate enhanced tumor-targeting carriers of submicrometer size and improves the general understanding of particle design parameters for targeted drug delivery.
Assuntos
Doxorrubicina/química , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Hidrogéis/química , Neoplasias/tratamento farmacológico , Fragmentos de Peptídeos/química , Ácidos Polimetacrílicos/química , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/química , Sobrevivência Celular , Doxorrubicina/administração & dosagem , Humanos , Neoplasias/patologia , Fragmentos de Peptídeos/metabolismo , Polímeros/química , Serina Endopeptidases/química , Serina Endopeptidases/metabolismo , Células Tumorais CultivadasRESUMO
There has been increasing interest in understanding the role of the human microbiome in skin diseases. Microbiome studies are being utilized in skin cancer research in numerous ways. Commensal bacteria are being studied as a potential tool to judge the biggest environmental risk of skin cancer, ultraviolet (UV) radiation. Owing to the recognized link of skin microbes in the process of inflammation, there have been theories linking commensal bacteria to skin cancer. Viral metagenomics has also provided insight into virus linked forms of skin cancers. Speculations can be drawn for skin microbiome that in a manner similar to gut microbiome, they can be involved in chemoprevention of skin cancer. Nonetheless, there are definitely huge gaps in our knowledge of the relationship of microbiome and skin cancers, especially in relation to chemoprevention. The utilization of microbiome in skin cancer research seems to be a promising field and may help yield novel skin cancer prevention and treatment options. This review focuses on recent utilization of the microbiome in skin cancer research, and it explores the potential of utilizing the microbiome in prevention, earlier diagnosis, and treatment of skin cancers.
Assuntos
Microbiota , Neoplasias Cutâneas/microbiologia , Neoplasias Cutâneas/prevenção & controle , Pele/imunologia , Pele/microbiologia , Animais , Microbioma Gastrointestinal , Humanos , Microbiota/efeitos da radiação , Prebióticos , Probióticos/farmacologia , Neoplasias Cutâneas/imunologia , Raios Ultravioleta , Viroses/complicações , Vitamina D/análogos & derivados , Vitamina D/metabolismoRESUMO
The CDKN2A locus encodes for tumor suppressor genes p16INK4a and p14Arf which are frequently inactivated in human skin tumors. The purpose of this study was to determine the relationship between loss of INK4a/Arf activity and inflammation in the development of ultraviolet (UV) radiation-induced skin tumors. Panels of INK4a/Arf-/- mice and wild-type (WT) mice were treated with a single dose of UVB (200 mJ/cm2 ). For long-term studies, these mice were irradiated with UVB (200 mJ/cm2 ) three times weekly for 30 weeks. At the end of the experiment, tissues were harvested from mice and assayed for inflammatory biomarkers and cytokines. A single dose of UVB resulted in a significant increase in reactive oxygen species (ROS) and 8-dihydroxyguanosine (8-oxo-dG) lesions in INK4a/Arf-/- mice compared to WT mice. When subjected to chronic UVB, we found that 100% of INK4a/Arf-/- mice had tumors, whereas there were no tumors in WT controls after 24 weeks of UVB exposure. The increase in tumor development correlated with a significant increase in nuclear factor (NF)-κB, cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2 ) and its receptors both in UVB-exposed skin and in the tumors. A significant increase was seen in inflammatory cytokines in skin samples of INK4a/Arf-/- mice following treatment with chronic UVB radiation. Furthermore, significantly more CD11b+ Gr1+ myeloid cells were present in UVB-exposed INK4a/Arf-/- mice compared to WT mice. Our data indicate that by targeting UVB-induced inflammation, it may be possible to prevent UVB-induced skin tumors in individuals that carry CDKN2A mutation.
Assuntos
Inibidor p16 de Quinase Dependente de Ciclina/genética , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Radiodermite/etiologia , Neoplasias Cutâneas/etiologia , Raios Ultravioleta/efeitos adversos , 8-Hidroxi-2'-Desoxiguanosina , Animais , Antígenos Ly/metabolismo , Núcleo Celular/metabolismo , Ciclo-Oxigenase 2/metabolismo , Citoplasma/metabolismo , Desoxiguanosina/análogos & derivados , Desoxiguanosina/metabolismo , Dinoprostona/metabolismo , Feminino , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Camundongos , Camundongos Knockout , Células Mieloides/metabolismo , Células Mieloides/patologia , Inibidor de NF-kappaB alfa/metabolismo , Radiodermite/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptores de Prostaglandina E/metabolismo , Neoplasias Cutâneas/metabolismo , Fator de Transcrição RelA/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Heat shock proteins (HSPs) are constitutively expressed in murine skin. HSP27 is present in the epidermis, and HSP70 can be found in both the epidermis and dermis. The purpose of this study was to investigate the role of these proteins in cutaneous chemical carcinogenesis and to determine whether their effects on cell-mediated immune function were a contributing factor. In vivo inhibition of HSP27 and HSP70 produced a reduction in the T cell-mediated immune response to 7,12-dimethylbenz(a)anthracene (DMBA) and benzo(a)pyrene in C3H/HeN mice and resulted in a state of Ag-specific tolerance. When mice were pretreated with anti-HSP27 and anti-HSP70 Abs in vivo prior to subjecting them to a standard two-stage DMBA/12-O-tetradecanoylphorbol-13-acetate cutaneous carcinogenesis protocol, the percentage of mice with tumors was much greater (p < 0.05) in anti-HSP27- and HSP70-pretreated animals compared with mice pretreated with control Ab. Similar results were obtained when the data were evaluated as the cumulative number of tumors per group. Mice pretreated with HSP27 and HSP70 Abs developed more H-ras mutations and fewer DMBA-specific cytotoxic T lymphocytes. These findings indicate that in mice HSP27 and HSP70 play a key role in the induction of cell-mediated immunity to carcinogenic polyaromatic hydrocarbons. Bolstering the immune response to carcinogenic polyaromatic hydrocarbons may be an effective method for prevention of the tumors that they produce.
Assuntos
Carcinogênese/imunologia , Proteínas de Choque Térmico HSP27/imunologia , Proteínas de Choque Térmico HSP70/imunologia , Tolerância Imunológica/imunologia , Neoplasias Cutâneas/imunologia , 9,10-Dimetil-1,2-benzantraceno/imunologia , 9,10-Dimetil-1,2-benzantraceno/toxicidade , Animais , Carcinógenos/toxicidade , Modelos Animais de Doenças , Feminino , Camundongos , Camundongos Endogâmicos C3H , Neoplasias Cutâneas/induzido quimicamente , Neoplasias Cutâneas/metabolismoRESUMO
Acquired melanocytic nevi are commonly found in sun exposed and unexposed human skin, but the potential for their transformation into invasive melanoma is not clear. Therefore, a mouse model of nevus initiation and progression was developed in C3H/HeN mice using a modified chemical carcinogenesis protocol. Nevi develop due to DNA damage initiated by dimethylbenz(a) anthracene (DMBA) followed by chronic promotion with 12-O-tetradecanoyl-phorbol-13-acetate (TPA). Dysplastic pigmented skin lesions appeared in 7-9 wk with 100% penetrance. Nests of melanocytic cells appeared in a subset of skin draining lymph nodes (dLN) by 25 wk, but not in age matched controls. Immunohistochemistry, real-time PCR, and flow cytometric analyses confirmed their melanocytic origin. Transformed cells were present in a subset of nevi and dLNs, which exhibited anchorage-independent growth, tumor development, and metastasis in nude mice. Approximately 50% of the cell lines contained H-Ras mutations and lost tumor suppressor p16(Ink4a) expression. While most studies of melanoma focus on tumor progression in transgenic mouse models where the mutations are present from birth, our model permits investigation of acquired mutations at the earliest stages of nevus initiation and promotion of nevus cell transformation. This robust nevus/melanoma model may prove useful for identifying genetic loci associated with nevus formation, novel oncogenic pathways, tumor targets for immune-prevention, screening therapeutics, and elucidating mechanisms of immune surveillance and immune evasion.
Assuntos
Modelos Animais de Doenças , Melanoma/genética , Nevo Pigmentado/induzido quimicamente , Nevo Pigmentado/genética , Neoplasias Cutâneas/induzido quimicamente , Neoplasias Cutâneas/genética , 9,10-Dimetil-1,2-benzantraceno , Animais , Linhagem Celular Tumoral , Separação Celular , Inibidor p16 de Quinase Dependente de Ciclina , Progressão da Doença , Melanoma/patologia , Camundongos , Camundongos Nus , Mutação , Proteínas de Neoplasias/genética , Nevo Pigmentado/patologia , Neoplasias Cutâneas/patologia , Acetato de Tetradecanoilforbol , Proteínas ras/genéticaRESUMO
IFN-λ is a type III interferon (IFN) with pleiotropic functions in modulating immune responses. To address its function in autoimmune neuroinflammation, we evaluated the development and progression of experimental autoimmune encephalitis (EAE) in IFNLR1KO (Ifnlr1-/-) and C57Bl/6 (WT) mice following immunization with MOG35-55 peptide. The results show that Ifnlr1-/-mice developed significantly more severe EAE than WT littermates with a similar day of onset, suggesting the potential of IFN-λ in reducing disease severity. We next interrogated whether IFN-λ differentially modulates EAE induced by encephalitogenic Th1 cells or Th17 cells. Encephalitogenic Th1 or Th17 generated from WT donors were transferred into WT or Ifnlr1-/-recipient mice. Whereas encephalitogenic Th1 cells induced more severe EAE in Ifnlr1-/- than WT recipients, the disease severity induced by encephalitogenic Th17 cells was similar. Additionally, in vitro experiments showed that Ifnlr1-/-macrophages promoted the expansion of myelin peptide-reactive Th17 cells but not Th1 cells. Early in the disease, the spinal cords of EAE mice displayed a significantly greater proportion of Ly6C-Ly6G+ cells with CXCR2+CD62Llo phenotype, indicating activated neutrophils. These findings suggest that IFN-λ signaling restrains activation and migration of neutrophils to the CNS, potentially attenuating neutrophil-mediated disease progression in autoimmune neuroinflammation. Recombinant IFN-λ can be used as a potential therapeutic target for treatment of patients with multiple sclerosis as it has fewer side effects due to the restricted expression of its receptor.
RESUMO
The inflammasome is a multi-protein complex which when activated regulates caspase-1 activation and IL-1ß and IL-18 secretion. The NLRP3 (NACHT, LRR, and pyrin domain-containing protein 3) inflammasome is constitutively assembled and activated in human melanoma cells. We have examined the inhibitory effect of thymoquinone (2-isopropyl-5-methylbenzo-1,4-quinone), a major ingredient of black seed obtained from the plant Nigella sativa on metastatic human (A375) and mouse (B16F10) melanoma cell lines. We have assessed whether thymoquinone inhibits metastasis of melanoma cells by targeting NLRP3 subunit of inflammasomes. Using an in vitro cell migration assay, we found that thymoquinone inhibited the migration of both human and mouse melanoma cells. The inhibitory effect of thymoquinone on metastasis was also observed in vivo in B16F10 mouse melanoma model. The inhibition of migration of melanoma cells by thymoquinone was accompanied by a decrease in expression of NLRP3 inflammasome resulting in decrease in proteolytic cleavage of caspase-1. Inactivation of caspase-1 by thymoquinone resulted in inhibition of IL-1ß and IL-18. Treatment of mouse melanoma cells with thymoquinone also inhibited NF-κB activity. Furthermore, inhibition of reactive oxygen species (ROS) by thymoquinone resulted in partial inactivation of NLRP3 inflammasome. Thus, thymoquinone exerts its inhibitory effect on migration of human and mouse melanoma cells by inhibition of NLRP3 inflammasome. Thus, our results indicate that thymoquinone can be a potential immunotherapeutic agent not only as an adjuvant therapy for melanoma, but also, in the control and prevention of metastatic melanoma.
Assuntos
Benzoquinonas/uso terapêutico , Proteínas de Transporte/antagonistas & inibidores , Inflamassomos/antagonistas & inibidores , Melanoma Experimental/tratamento farmacológico , Animais , Benzoquinonas/farmacologia , Proteínas de Transporte/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/fisiologia , Feminino , Humanos , Inflamassomos/metabolismo , Melanoma Experimental/metabolismo , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos C57BL , Proteína 3 que Contém Domínio de Pirina da Família NLRRESUMO
ABSTRACT: Novel immunotherapeutics for advanced melanoma have drastically changed survival rates and management strategies in recent years. Immune checkpoint inhibitors have emerged as efficacious agents for some patients but have not been proven to be as beneficial in other patient cohorts. Recent investigation into this observation has implicated the gut microbiome as a potential immunomodulator in regulating patient response to therapy. Numerous studies have provided evidence for this link. Bacterial colonization patterns have been associated with therapeutic outcomes, under the notion that favorable commensal organisms improve host immune response. This review aims to report the most recent and pertinent findings related to the relationship between gut microbial communities and melanoma therapy efficacy. This article also highlights the emerging frontier of artificial intelligence in its application regarding patient microbial composition evaluation, predictive models for therapy response, and recommendations for the future of probiotics and dietary interventions to optimize melanoma survival and outcomes.