RESUMEN

3,5,7-Trihydroxy-2-phenylchromen-4-one (THF) possesses a diverse range of pharmacological activities. Evidence suggests that THF exerts anticancer activity by distinct mechanisms of action. This study explores the anticancer potential of THF in human lung (A549) and skin (A431) cancer cells by employing different antiproliferative assays. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, neutral red uptake, sulphorhodamine B, and cell motility assays were used to confirm the anticancer potential of THF. Cell target-based and quantitative reverse transcription polymerase chain reaction (qRT-PCR) assays were used to explore the effect of THF on the initiation, promotion and progression phase biomarkers of carcinogenesis. THF suppresses the activity of lipoxygenase-5 up to ~40% in both A549 and A431 cells and up to ~50% hyaluronidase activity in A549 cells. qRT-PCR assay reveals that THF inhibits the activity of phosphatidyl inositol-3 kinase/protein kinase B/mammalian target of rapamycin in both cell lines, which is responsible for the initiation of cancer. It also arrests the G2/M phase of the cell cycle in A431 cells and increases the sub-diploid population in both A549 and A431 cell lines which leads to cell death. Annexin V-FITC assay confirmed that THF induces apoptosis and necrosis in A431 and A549 cell lines. Further investigation revealed that THF not only enhances reactive oxygen species production but also modulates mitochondrial membrane potential in both cell lines. It significantly inhibits S-180 tumour formation at 5 and 10 mg/kg bw, i.p. dose. An acute skin toxicity study on mice showed that erythema and edema scores are within the acceptable range, besides acceptable drug-likeness properties and non-toxic effects on human erythrocytes. Conclusively, THF showed potent anticancer activity on skin and lung carcinoma cell lines, suppressed the level of the biomarkers and inhibited tumour growth in mice.

Asunto(s)

Apoptosis , Neoplasias Pulmonares , Neoplasias Cutáneas , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/tratamiento farmacológico , Apoptosis/efectos de los fármacos , Animales , Ratones , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/tratamiento farmacológico , Células A549 , Regulación hacia Abajo/efectos de los fármacos , Biomarcadores de Tumor/metabolismo , Biomarcadores de Tumor/genética , Línea Celular Tumoral , Antineoplásicos/farmacología

RESUMEN

Squamous Cell Carcinoma (SCC) is a subtype of Non-Melanoma Skin Cancer, the most common group of malignancies worldwide. Photodynamic therapy (PDT) is a non-invasive treatment approved for specific subtypes of SCC. Some malignancies resist PDT, forming more aggressive tumors and multiple relapses. Thus, new approaches aimed at optimizing the response to PDT are needed. The mTORC1 inhibitor rapamycin, also known as Sirolimus (SRL), interferes with protein synthesis and cell metabolism. The use of SRL as an immunosuppressant is associated to lower rates of SCC in kidney-transplanted patients, which are frequently affected by this pathology. We have evaluated SRL pre-treatment efficacy to enhance the damage induced by PDT with Methyl 5-aminolevulinate in two different cutaneous SCC established cell lines (SCC13 and A431) in vitro and therapy sensitization in PDT-resistant cell lines. We tested for the first time the SRL + PDT combination in a SKH-1 mouse model of photocarcinogenesis, diminishing the frequency of lesions and restraining tumor growth. Molecular studies revealed that protoporphyrin IX and reactive oxygen species production induced by PDT were promoted by SRL pre-treatment. Lastly, SRL modifies the expression and intracellular location of NRF2, interfering with the downstream antioxidant response modulated by NQO1 and HO-1. In conclusion, we propose SRL as a potential adjuvant to enhance PDT efficacy for SCC treatment.

Asunto(s)

Carcinoma de Células Escamosas , Factor 2 Relacionado con NF-E2 , Fotoquimioterapia , Transducción de Señal , Sirolimus , Neoplasias Cutáneas , Factor 2 Relacionado con NF-E2/metabolismo , Fotoquimioterapia/métodos , Animales , Ratones , Sirolimus/farmacología , Sirolimus/uso terapéutico , Humanos , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patología , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/patología , Línea Celular Tumoral , Transducción de Señal/efectos de los fármacos , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Ácido Aminolevulínico/uso terapéutico , Ácido Aminolevulínico/farmacología , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Especies Reactivas de Oxígeno/metabolismo , Femenino

RESUMEN

This Corrigendum relates to the following article: https://doi.org/10.2340/actadv.v104.13381.

Asunto(s)

Carcinoma de Células Escamosas , Queratoacantoma , Neoplasias Cutáneas , Humanos , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/metabolismo , Queratoacantoma/patología , Queratoacantoma/metabolismo , Queratoacantoma/inmunología , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/inmunología , Carcinoma de Células Escamosas/metabolismo , Masculino , Femenino , Anciano , Proteínas de Punto de Control Inmunitario/metabolismo , Persona de Mediana Edad , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/metabolismo , Inmunohistoquímica , Anciano de 80 o más Años

RESUMEN

BACKGROUND: To assess the distribution characteristics of immune infiltration and lymphovascular invasion in breast cancer skin recurrence patients. METHODS: We retrospectively analyzed the clinicopathological data of patients who underwent radical surgery for primary breast cancer and experienced skin recurrence between January 2001 and April 2019. Immune and lymphovascular biomarkers were quantified in primary breast cancers, skin lesions and visceral metastatic lesions. Differences in biomarkers distribution between matched tissues were statistically analyzed using the Wilcoxon signed-rank test and Kruskal-Wallis one-way ANOVA. RESULTS: A total of 71 female breast cancer patients were reviewed in this study. Our study found that the expression levels of various lymphocyte immune markers in primary tumor specimens were higher than those in skin recurrences. The expression of CD8, CD57 and CD31 in primary breast cancer was higher than those in the skin. Compared to visceral metastatic lesions, D2-40 was highly expressed in the skin, while CD8 tended to decrease. In the skin specimens, the expression of CD8 (P < 0.001), FOXP3 (P = 0.006) and CD68 (P < 0.001) in the intratumoral area was higher, while the expression of CD57 (P < 0.001) was higher in the peritumoral area. Analyzing specimens from the same patient at different time points of skin progression, it was found that the expression of peritumoral CD4 decreased (P = 0.044) as the disease progressed. The low expression of D2-40 and CD163 in the skin lesions suggested a decrease in DFS. CONCLUSION: The immune microenvironment of breast cancer skin recurrence may be in a state of suppression, and this suppression may intensify with disease progression. The pattern of skin recurrence may be more inclined toward lymphatic invasion. Our study provides new insights into the biological behaviors of this disease and its response to immunotherapy.

Asunto(s)

Neoplasias de la Mama , Linfocitos Infiltrantes de Tumor , Recurrencia Local de Neoplasia , Neoplasias Cutáneas , Humanos , Femenino , Neoplasias de la Mama/patología , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/metabolismo , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/metabolismo , Persona de Mediana Edad , Estudios Retrospectivos , Recurrencia Local de Neoplasia/inmunología , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/metabolismo , Anciano , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Adulto , Metástasis Linfática/patología , Metástasis Linfática/inmunología , Biomarcadores de Tumor/metabolismo , Microambiente Tumoral/inmunología , Invasividad Neoplásica , Pronóstico

RESUMEN

Melanoma is the most severe type of skin cancer and among the most malignant neoplasms in humans. With the growing incidence of melanoma, increased numbers of therapeutic options, and the potential to target specific proteins, understanding the basic mechanisms underlying the disease's progression and resistance to treatment has never been more important. LOXL3, SNAI1, and NES are key factors in melanoma genesis, regulating tumor growth, metastasis, and cellular differentiation. In our study, we explored the potential role of LOXL3, SNAI1, and NES in melanoma progression and metastasis among patients with dysplastic nevi, melanoma in situ, and BRAF+ and BRAF- metastatic melanoma, using immunofluorescence and qPCR analysis. Our results reveal a significant increase in LOXL3 expression and the highest NES expression in BRAF+ melanoma compared to BRAF-, dysplastic nevi, and melanoma in situ. As for SNAI1, the highest expression was observed in the metastatic melanoma group, without significant differences among groups. We found co-expression of LOXL3 and SNAI1 in the perinuclear area of all investigated subgroups and NES and SNAI1 co-expression in melanoma cells. These findings suggest a codependence or collaboration between these markers in melanoma EMT, suggesting new potential therapeutic interventions to block the EMT cascade that could significantly affect survival in many melanoma patients.

Asunto(s)

Progresión de la Enfermedad , Melanoma , Factores de Transcripción de la Familia Snail , Melanoma/genética , Melanoma/patología , Melanoma/metabolismo , Humanos , Factores de Transcripción de la Familia Snail/metabolismo , Factores de Transcripción de la Familia Snail/genética , Regulación Neoplásica de la Expresión Génica , Aminoácido Oxidorreductasas/genética , Aminoácido Oxidorreductasas/metabolismo , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/metabolismo , Línea Celular Tumoral , Masculino , Femenino , Metástasis de la Neoplasia , Persona de Mediana Edad

RESUMEN

Resistance biomarkers are needed to identify patients with advanced melanoma obtaining a response to ICI treatment and developing resistance later. We searched a combination of molecular signatures of response to ICIs in patients with metastatic melanoma. In a retrospective study on patients with metastatic melanoma treated with an anti-PD-1 agent carried out at Istituto Nazionale Tumori-IRCCS-Fondazione "G. Pascale", Naples, Italy. We integrated a whole proteome profiling of metastatic tissue with targeted transcriptomics. To assess the prognosis of patients according to groups of low and high risk, we used PFS and OS as outcomes. To identify the proteins and mRNAs gene signatures associated with the patient's response groups, the discriminant analysis for sparse data performed via partial least squares procedure was performed. Tissue samples from 22 patients were analyzed. A combined protein and gene signature associated with poorer response to ICI immunotherapy in terms of PFS and OS was identified. The PFS and OS Kaplan-Meier curves were significantly better for patients with high expression of the protein signature compared to patients with low expression of the protein signature and who were high-risk (Protein: HR = 0.023, 95% CI: 0.003-0.213; p < 0.0001. Gene: HR = 0.053, 95% CI: 0.011-0.260; p < 0.0001). The Kaplan-Meier curves showed that patients with low-risk gene signatures had better PFS (HR = 0 0.221, 95% CI: 0.071-0.68; p = 0.007) and OS (HR = 0.186, 95% CI: 0.05-0.695; p = 0.005). The proteomic and transcriptomic combined analysis was significantly associated with the outcomes of the anti-PD-1 treatment with a better predictive value compared to a single signature. All the patients with low expression of protein and gene signatures had progression within 6 months of treatment (median PFS = 3 months, 95% CI: 2-3), with a significant difference vs. the low-risk group (median PFS = not reached; p < 0.0001), and significantly poorer survival (OS = 9 months, 95% CI: 5-9) compared to patients with high expression of protein and gene signatures (median OS = not reached; p < 0.0001). We propose a combined proteomic and transcriptomic signature, including genes involved in pro-tumorigenic pathways, thereby identifying patients with reduced probability of response to immunotherapy with ICIs for metastatic melanoma.

Asunto(s)

Inhibidores de Puntos de Control Inmunológico , Melanoma , Proteómica , Transcriptoma , Humanos , Melanoma/tratamiento farmacológico , Melanoma/genética , Melanoma/patología , Melanoma/metabolismo , Melanoma/mortalidad , Femenino , Masculino , Estudios Retrospectivos , Proteómica/métodos , Persona de Mediana Edad , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Anciano , Pronóstico , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/metabolismo , Receptor de Muerte Celular Programada 1/genética , Biomarcadores de Tumor/genética , Adulto , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Proteoma/metabolismo , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/mortalidad , Neoplasias Cutáneas/metabolismo , Metástasis de la Neoplasia

RESUMEN

MDM4 is upregulated in the majority of melanoma cases and has been described as a "key therapeutic target in cutaneous melanoma". Numerous isoforms of MDM4 exist, with few studies examining their specific expression in human tissues. The changes in splicing of MDM4 during human melanomagenesis are critical to p53 activity and represent potential therapeutic targets. Compounding this, studies relying on short reads lose "connectivity" data, so full transcripts are frequently only inferred from the presence of splice junction reads. To address this problem, long-read nanopore sequencing was utilized to read the entire length of transcripts. Here, MDM4 transcripts, both alternative and canonical, are characterized in a pilot cohort of human melanoma specimens. RT-PCR was first used to identify the presence of novel splice junctions in these specimens. RT-qPCR then quantified the expression of major MDM4 isoforms observed during sequencing. The current study both identifies and quantifies MDM4 isoforms present in melanoma tumor samples. In the current study, we observed high expression levels of MDM4-S, MDM4-FL, MDM4-A, and the previously undescribed Ensembl transcript MDM4-209. A novel transcript lacking both exons 6 and 9 is observed and named MDM4-A/S for its resemblance to both MDM4-A and MDM4-S isoforms.

Asunto(s)

Melanoma , Isoformas de Proteínas , Humanos , Melanoma/genética , Melanoma/patología , Melanoma/metabolismo , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/metabolismo , Empalme Alternativo , Regulación Neoplásica de la Expresión Génica , Secuenciación de Nanoporos/métodos

RESUMEN

The pathogenesis of cutaneous tumors has been known for decades yet remains largely unexplained or incompletely understood. The reason for this mystery lies in the concepts of photosensitivity and phototoxicity: how do they arise or what actually causes them? Recently published data in the medical literature link certain nitrosamines such as nitrosomorpholine, for example, to gene and phototoxicity in humans. A number of other nitrosamines analogous in action and structure are found as contaminants in about 300 of the most widely distributed pharmaceuticals worldwide: NDEA, NDMA, NMBA and many others. These contaminated drugs include beta blockers/ bisoprolol/, thiazide diuretics/ hydrochlorothiazide/, antiarrhythmics/ propafenone/, ACE inhibitors/ lisinopril/, but also a number of other drugs which are, according to the FDA, found to have contaminants with a certain carcinogenic potency ranging between 1 and 5. The phototoxicity and genotoxicity of these contaminants, attributed to the pathogenesis of skin tumors, still remain a mystery. The problems of the intake of the above-mentioned groups of drugs arise mainly on the basis of the official bulletins of the regulatory bodies, namely that: in practice, the intake of polymedication could in many cases also be considered as regular, permanent, long-term intake of contaminants/carcinogens/mutagens of heterogeneous type, also known as nitrosamines or NDSRIs. Nitrosamines are genome modifiers in humans and cause acquired mutations. Their concomitant administration in the context of standard, but currently not yet officially declared as contaminated polymedication, would be able to block certain tumor suppressor genes (p53) as well as activate RAS oncogenes. Or in practice- daily administration of a particular combination of drugs could activate the cascades of carcinogenesis regulating the genesis of skin cancer. Precisely because of this fact, it should not be surprising to anyone that the concurrent intake of the aforementioned drugs could also be associated with the clinical manifestation of multiple keratinocytic tumors. We describe a consecutive case of a patient who developed 4 keratinocytic tumors: 2 basal cell carcinomas, 1 keratoacanthoma, and 1 squamous cell carcinoma on a background of potentially contaminated polymedication with propafenone, lisinopril, hydrochlorothiazide, and bisoprolol. Recently published innovative international data on the topic are discussed in the context of concepts such as drug-mediated nitrosogenesis, photonitrosо-carcinogenesis and metabolic programming/ reprogramming of the tumor cell.

Asunto(s)

Antihipertensivos , Neoplasias Cutáneas , Humanos , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/genética , Antihipertensivos/farmacología , Lisinopril/farmacología , Lisinopril/uso terapéutico , Bisoprolol/farmacología , Bisoprolol/uso terapéutico , Nitrosaminas , Masculino , Hidroclorotiazida/farmacología , Carcinoma Basocelular/metabolismo , Carcinoma Basocelular/tratamiento farmacológico , Carcinoma Basocelular/patología , Carcinoma Basocelular/genética , Antiarrítmicos/farmacología , Femenino , Reprogramación Metabólica

RESUMEN

Contamination of a heterogeneous class of drugs with nitrosamines of an also different type underlies or defines the occurrence of drug-induced skin cancer Nitrosogenesis or keratinocyte cancer Oncopharmacogenesis. Further identification of some of these carcinogens in drugs as both phototoxic and genotoxic in turn defines concepts such as Drug-Mediated Nitroso-Photo Carcinogenesis. Its first formal representative was and remains at present Nitrosomorpholine (Nmor). Unfortunately, further data on the propensity of individual nitrosamines and/or their derivatives to absorb photons and generate phototoxicity are lacking. The simultaneous intake of a heterogeneous class of drugs in the context of Nitrosocontamination, now officially announced by regulators, makes the initiation of cutaneous carcinogenesis a perfectly possible scenario. Continuous, permanent intake of several types of carcinogens/mutagens or nitrosamines in the context of potential/or real Nitrosocontamination is probably able to activate certain oncogenes such as RAS oncogenes and neutralize certain tumor suppressor genes such as p53. We report another case of a female patient who developed over the years 3 high-risk basal cell carcinomas in the facial area in a stepwise fashion in the context of potentially contaminated drug treatment with ACE inhibitor/Ramipril/Beta blocker/bisoprolol/, anticoagulant/ rivaroxaban/ and folic acid. The possible role of Nitroso contamination in polymedication in the context of drug related Nitroso-Photocarcinogenesis for the triggering of multiple basal cell carcinomas is commented. The performed Mustardé rotation flap for the tumour near the lower eyelid was with optimal final reconstructive result. Nitroso-Folic acid and Nitroso- Riviroxabanan are described for the first time in the medical literature as possible key elements that could have an activating effect on skin carcinogenesis on the background of the so-called metabolic reprogramming of the future tumour cell.

Asunto(s)

Carcinoma Basocelular , Ácido Fólico , Neoplasias Cutáneas , Humanos , Femenino , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/patología , Ácido Fólico/química , Ácido Fólico/metabolismo , Carcinoma Basocelular/metabolismo , Carcinoma Basocelular/patología , Nitrosaminas , Reprogramación Metabólica

RESUMEN

Skin cancer is a widespread worldwide health concern, manifesting in many subtypes such as squamous cell carcinoma, basal cell carcinoma, and melanoma. Although all these types occur frequently, they generally lack the possibility of being cured, emphasizing the importance of early discovery and treatment. This comprehensive study explores the role of programmed cell death protein 1 (PD-1) in skin cancer, focusing on its molecular mechanisms in immune regulation and its critical role in tumor immune evasion, while also clarifying the complexities of immune checkpoints in cancer pathogenesis. It critically evaluates the clinical applications of PD-1 inhibitors, spotlighting their therapeutic potential in treating skin cancer, while also addressing the significant challenge of resistance. This work further discusses the evolution of resistance mechanisms against PD-1 inhibitors and suggests potential approaches to mitigate these issues, thereby enhancing the effectiveness of these therapies. The study further highlights the current state of PD-1 targeted therapies and sets the stage for future research aimed at optimizing these treatments for better clinical outcomes in skin cancer.

Asunto(s)

Resistencia a Antineoplásicos , Receptor de Muerte Celular Programada 1 , Neoplasias Cutáneas , Humanos , Receptor de Muerte Celular Programada 1/metabolismo , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/patología , Resistencia a Antineoplásicos/efectos de los fármacos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/farmacología

RESUMEN

Melanoma incidence is increasing globally. Although novel therapies have improved the survival of primary melanoma patients over the past decade, the overall survival rate for metastatic melanoma remains low. In addition to traditional prognostic factors such as Breslow thickness, ulceration, and mitotic rate, novel genetic and molecular markers have been investigated. In our study, we analyzed the expression of G-protein coupled estrogen receptor 1 (GPER1) and the endodomain of collagen XVII (COL17) in relation to clinicopathological factors in primary cutaneous melanomas with known lymph node status in both sexes, using immunohistochemistry. We found, that GPER1 expression correlated with favorable clinicopathological factors, including lower Breslow thickness, lower mitotic rate and absence of ulceration. In contrast, COL17 expression was associated with poor prognostic features, such as higher tumor thickness, higher mitotic rate, presence of ulceration and presence of regression. Melanomas positive for both GPER1 and COL17 had significantly lower mean Breslow thickness and mitotic rate compared to cases positive for COL17 only. Our data indicate that GPER1 and COL17 proteins may be of potential prognostic value in primary cutaneous melanomas.

Asunto(s)

Autoantígenos , Biomarcadores de Tumor , Colágeno Tipo XVII , Melanoma , Colágenos no Fibrilares , Receptores de Estrógenos , Receptores Acoplados a Proteínas G , Neoplasias Cutáneas , Humanos , Melanoma/patología , Melanoma/metabolismo , Femenino , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/genética , Pronóstico , Masculino , Receptores de Estrógenos/metabolismo , Persona de Mediana Edad , Biomarcadores de Tumor/metabolismo , Anciano , Colágenos no Fibrilares/metabolismo , Colágenos no Fibrilares/genética , Autoantígenos/metabolismo , Adulto , Melanoma Cutáneo Maligno , Anciano de 80 o más Años

RESUMEN

The diagnosis of Sézary syndrome (SS) relies on the identification of blood Sézary cells (SC) by different markers via flow cytometry. Treatment of SS is challenging since its pathogenesis is characterized by cell death resistance rather than hyperproliferation. In this study, we establish an integrated approach that considers both the expression of SC markers and sensitivity to cell death both spontaneously and upon in vitro treatment. Peripheral blood mononuclear cells were isolated from 20 SS patients and analysed for the SC markers CD7 and CD26 loss as well as CD158k and PD1 gain. The cells were then treated with different established and experimental therapies in vitro and cell death was measured. Spontaneous and therapeutically induced cell death were measured and correlated to cellular marker profiles. In the marker-positive cells, spontaneous cell death sensitivity was reduced. Different treatments in vitro managed to specifically induce cell death in the putative CTCL cell populations. Interestingly, a repeated analysis after 3 months of treatment revealed the CTCL cell death sensitivity to be restored by therapy. We propose this novel integrated approach comprising the evaluation of SC marker expression and analysis of cell death sensitivity upon treatment that can also enable a better therapy stratification.

Asunto(s)

Biomarcadores de Tumor , Muerte Celular , Citometría de Flujo , Síndrome de Sézary , Neoplasias Cutáneas , Síndrome de Sézary/metabolismo , Humanos , Biomarcadores de Tumor/metabolismo , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/patología , Dipeptidil Peptidasa 4/metabolismo , Femenino , Persona de Mediana Edad , Anciano , Masculino , Leucocitos Mononucleares/metabolismo , Antígenos CD7/metabolismo , Receptor de Muerte Celular Programada 1/metabolismo

RESUMEN

Melanocytes derived from neural crest cells harbor the BRAF V600E mutation, which is the predominant driver of nevus formation in humans. This mutation leads to malignant cell proliferation and subsequent cell cycle arrest, culminating in oncogene-induced senescence and nevus development. Nevertheless, emerging evidence has highlighted the heterogeneity of cellular senescence markers in BRAF V600E-induced senescent melanocytes. Moreover, the capacity of melanocytes within nevi to regain their proliferative ability raises questions about the molecular mechanisms by which BRAF V600E, via the mitogen-activated protein kinase signaling pathway, triggers nevus formation. This study provides an overview and discussion of the molecular mechanisms underpinning BRAF V600E-induced melanocyte nevus formation and the relevant animal models employed for their elucidation. It also highlights the significance of elucidating dynamic changes in cytoplasmic and nuclear substrates that interact with phosphorylated extracellular signal-regulated protein kinases 1 and 2 and underscores the value of using targeted BRAF V600E animal models created through gene editing technologies.

Asunto(s)

Nevo , Proteínas Proto-Oncogénicas B-raf , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas B-raf/metabolismo , Humanos , Animales , Nevo/genética , Nevo/metabolismo , Melanocitos/metabolismo , Mutación , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/metabolismo

RESUMEN

The transcription factor ΔNp63 plays a pivotal role in maintaining the integrity of stratified epithelial tissues by regulating the expression of distinct target genes involved in lineage specification, cell stemness, cell proliferation and differentiation. Here, we identified the ABC transporter subfamily member ABCC1 as a novel ΔNp63 target gene. We found that in immortalized human keratinocytes and in squamous cell carcinoma (SCC) cells, ∆Np63 induces the expression of ABCC1 by physically occupying a p63-binding site (p63 BS) located in the first intron of the ABCC1 gene locus. In cutaneous SCC and during the activation of the keratinocyte differentiation program, ∆Np63 and ABCC1 levels are positively correlated raising the possibility that ABCC1 might be involved in the regulation of the proliferative/differentiative capabilities of squamous tissue. However, we did not find any gross alteration in the structure and morphology of the epidermis in humanized hABCC1 knock-out mice. Conversely, we found that the genetic ablation of ABCC1 led to a marked reduction in inflammation-mediated proliferation of keratinocytes, suggesting that ABCC1 might be involved in the regulation of keratinocyte proliferation upon inflammatory/proliferative signals. In line with these observations, we found a significant increase in ABCC1 expression in squamous cell carcinomas (SCCs), a tumor type characterized by keratinocyte hyper-proliferation and a pro-inflammatory tumor microenvironment. Collectively, these data uncover ABCC1 as an additional ∆Np63 target gene potentially involved in those skin diseases characterized by dysregulation of proliferation/differentiation balance.

Asunto(s)

Carcinoma de Células Escamosas , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Queratinocitos , Proteínas Asociadas a Resistencia a Múltiples Medicamentos , Neoplasias Cutáneas , Factores de Transcripción , Proteínas Supresoras de Tumor , Humanos , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patología , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/genética , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/metabolismo , Animales , Queratinocitos/metabolismo , Queratinocitos/patología , Ratones , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/metabolismo , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismo , Proliferación Celular/genética , Diferenciación Celular/genética , Ratones Noqueados , Transactivadores/genética , Transactivadores/metabolismo , Línea Celular Tumoral

RESUMEN

Keratinocytes are major cellular components of the skin and are strongly involved in its homeostasis. Oncogenic events, starting mainly from excessive sun exposure, lead to the dysregulation of their proliferation and differentiation programs and promote the initiation and progression of non-melanoma skin cancers (NMSCs). Primary melanomas, which originate from melanocytes, initiate and develop in close interaction with keratinocytes, whose role in melanoma initiation, progression, and immune escape is currently being explored. Recent studies highlighted, in particular, unexpected modes of communication between melanocytic cells and keratinocytes, which may be of interest as sources of new biomarkers in melanomagenesis or potential therapeutic targets. This review aims at reporting the various contributions of keratinocytes in skin basal cell carcinoma (BCC), cutaneous squamous cell carcinoma (cSCC), and melanoma, with a greater focus on the latter in order to highlight some recent breakthrough findings. The readers are referred to recent reviews when contextual information is needed.

Asunto(s)

Carcinoma Basocelular , Carcinoma de Células Escamosas , Progresión de la Enfermedad , Queratinocitos , Neoplasias Cutáneas , Humanos , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/metabolismo , Queratinocitos/metabolismo , Queratinocitos/patología , Carcinoma Basocelular/patología , Carcinoma Basocelular/metabolismo , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/metabolismo , Melanoma/metabolismo , Melanoma/patología , Animales , Carcinogénesis/patología , Carcinogénesis/metabolismo

RESUMEN

Given the importance of peroxisome proliferator-activated receptor (PPAR)-gamma in epidermal inflammation and carcinogenesis, we analyzed the transcriptomic changes observed in epidermal PPARγ-deficient mice (Pparg-/-epi). A gene set enrichment analysis revealed a close association with epithelial malignancy, inflammatory cell chemotaxis, and cell survival. Single-cell sequencing of Pparg-/-epi mice verified changes to the stromal compartment, including increased inflammatory cell infiltrates, particularly neutrophils, and an increase in fibroblasts expressing myofibroblast marker genes. A comparison of transcriptomic data from Pparg-/-epi and publicly available human and/or mouse actinic keratoses (AKs) and cutaneous squamous cell carcinomas (SCCs) revealed a strong correlation between the datasets. Importantly, PPAR signaling was the top common inhibited canonical pathway in AKs and SCCs. Both AKs and SCCs also had significantly reduced PPARG expression and PPARγ activity z-scores. Smaller reductions in PPARA expression and PPARα activity and increased PPARD expression but reduced PPARδ activation were also observed. Reduced PPAR activity was also associated with reduced PPARα/RXRα activity, while LPS/IL1-mediated inhibition of RXR activity was significantly activated in the tumor datasets. Notably, these changes were not observed in normal sun-exposed skin relative to non-exposed skin. Finally, Ppara and Pparg were heavily expressed in sebocytes, while Ppard was highly expressed in myofibroblasts, suggesting that PPARδ has a role in myofibroblast differentiation. In conclusion, these data provide strong evidence that PPARγ and possibly PPARα represent key tumor suppressors by acting as master inhibitors of the inflammatory changes found in AKs and SCCs.

Asunto(s)

Carcinoma de Células Escamosas , Inflamación , Queratosis Actínica , PPAR gamma , Transducción de Señal , Neoplasias Cutáneas , PPAR gamma/metabolismo , PPAR gamma/genética , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/genética , Animales , Humanos , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/metabolismo , Queratosis Actínica/patología , Queratosis Actínica/metabolismo , Queratosis Actínica/genética , Ratones , Inflamación/patología , Inflamación/metabolismo , Inflamación/genética , Regulación Neoplásica de la Expresión Génica , Células del Estroma/metabolismo , Células del Estroma/patología

RESUMEN

The keratinocyte carcinomas, basal cell carcinoma (BCC), and cutaneous squamous cell carcinoma (cSCC), are the most common cancers in humans. Recently, an increasing body of literature has investigated the role of miRNAs in keratinocyte carcinoma pathogenesis, progression and their use as therapeutic agents and targets, or biomarkers. However, there is very little consistency in the literature regarding the identity of and/or role of individual miRNAs in cSCC (and to a lesser extent BCC) biology. miRNA analyses that combine clinical evidence with experimental elucidation of targets and functional impact provide far more compelling evidence than studies purely based on clinical findings or bioinformatic analyses. In this study, we review the clinical evidence associated with miRNA dysregulation in KCs, assessing the quality of validation evidence provided, identify gaps, and provide recommendations for future studies based on relevant studies that investigated miRNA levels in human cSCC and BCC. Furthermore, we demonstrate how miRNAs contribute to the regulation of a diverse network of cellular functions, and that large-scale changes in tumor cell biology can be attributed to miRNA dysregulation. We highlight the need for further studies investigating the role of miRNAs as communicators between different cell types in the tumor microenvironment. Finally, we explore the clinical benefits of miRNAs as biomarkers of keratinocyte carcinoma prognosis and treatment.

Asunto(s)

Biomarcadores de Tumor , Carcinoma Basocelular , Carcinoma de Células Escamosas , Regulación Neoplásica de la Expresión Génica , Queratinocitos , MicroARNs , Neoplasias Cutáneas , Humanos , MicroARNs/genética , Queratinocitos/metabolismo , Queratinocitos/patología , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/metabolismo , Carcinoma Basocelular/genética , Carcinoma Basocelular/patología , Carcinoma Basocelular/metabolismo , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/metabolismo , Biomarcadores de Tumor/genética , Microambiente Tumoral/genética , Pronóstico

RESUMEN

This study investigates the carcinogenic potential of chronic dermal exposure (16 weeks) to sulfuric acid (SA) in immunocompetent mice. Clinical assessments, histopathological analyses, immunohistochemical analyses and biochemical assays were conducted to evaluate skin irritation, oxidative stress biomarkers and the potential carcinogenic effect of SA. Results indicated that prolonged exposure to SA leads to various alterations in skin structure, notably inflammation, preneoplastic and neoplastic proliferation in hair follicles, as well as hyperkeratosis and acanthosis, resulting in an increased epidermal thickness of 98.50 ± 21.6 µm. Immunohistochemistry analysis further corroborates these observations, showcasing elevated nuclear expression of p53 and Ki-67, with a significant mitotic index of (57.5% ± 2.5%). Moreover, biochemical analyses demonstrate that SA induces lipid peroxidation in the skin, evidenced by a high level of Malondialdehyde and a consequential reduction in catalase activity. These findings suggest that prolonged exposure to SA can induce skin neoplasms, highlighting the need for stringent safety measures in environments where SA is frequently used. This study underscores the potential occupational health risks associated with SA exposure.

Asunto(s)

Neoplasias Cutáneas , Ácidos Sulfúricos , Animales , Neoplasias Cutáneas/inducido químicamente , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/metabolismo , Ratones , Ácidos Sulfúricos/efectos adversos , Ácidos Sulfúricos/toxicidad , Estrés Oxidativo/efectos de los fármacos , Peroxidación de Lípido/efectos de los fármacos , Femenino , Malondialdehído/metabolismo , Inmunocompetencia , Catalasa/metabolismo , Piel/patología , Piel/metabolismo , Piel/efectos de los fármacos , Antígeno Ki-67/metabolismo , Proteína p53 Supresora de Tumor/metabolismo

RESUMEN

Melanocytes evolved to produce the melanin that gives colour to our hair, eyes and skin. The melanocyte lineage also gives rise to melanoma, the most lethal form of skin cancer. The melanocyte lineage differentiates from neural crest cells during development, and most melanocytes reside in the skin and hair, where they are replenished by melanocyte stem cells. Because the molecular mechanisms necessary for melanocyte specification, migration, proliferation and differentiation are co-opted during melanoma initiation and progression, studying melanocyte development is directly relevant to human disease. Here, through the lens of advances in cellular omic and genomic technologies, we review the latest findings in melanocyte development and differentiation, and how these developmental pathways become dysregulated in disease.

Asunto(s)

Diferenciación Celular , Linaje de la Célula , Melanocitos , Melanoma , Melanocitos/metabolismo , Melanocitos/citología , Humanos , Animales , Melanoma/patología , Melanoma/metabolismo , Melanoma/genética , Cresta Neural/metabolismo , Proliferación Celular , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/genética

RESUMEN

Targeting the PD1/PD-L1 immune checkpoint pathway has rapidly become a therapeutic strategy for melanoma patients. Indeed, the quantification of PD-L1 expression by immunohistochemistry (IHC) in melanoma samples is already required, in some contexts, to allow access to anti-PD-1/PD-L1 immunotherapy. Despite a rising demand for PD-L1 testing, paralleling increasing cumulative experience in its assessment and quantification, it is fair to recognize that PD-L1 evaluation in melanoma samples still presents some critical issues. The aim of this technical report is to develop and validate a multiplex double staining protocol for PD-L1/SOX10 in Ventana Benchmark Ultra for routine practice. Our results show that double labeling provides the necessary tools to identify PD-L1 + melanoma cells clearly. The simultaneous visualization of 2 different proteins targets allows the topographical relationship between the 2 labeling to be evaluated within the context of the tissue morphology. Future studies are needed to test this technique's real-world applicability and effectiveness in implementing interpathologist agreement.

Asunto(s)

Antígeno B7-H1 , Inmunohistoquímica , Melanoma , Melanoma/metabolismo , Melanoma/diagnóstico , Melanoma/patología , Humanos , Inmunohistoquímica/métodos , Antígeno B7-H1/metabolismo , Factores de Transcripción SOXE/metabolismo , Biomarcadores de Tumor/metabolismo , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/diagnóstico