Asunto(s)
Antígeno B7-H1 , Proliferación Celular , Hemangiosarcoma , Transducción de Señal , Neoplasias Cutáneas , Factor de Crecimiento Transformador beta1 , Humanos , Hemangiosarcoma/metabolismo , Hemangiosarcoma/patología , Factor de Crecimiento Transformador beta1/metabolismo , Antígeno B7-H1/metabolismo , Antígeno B7-H1/genética , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/genética , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Línea Celular Tumoral , Regulación Neoplásica de la Expresión GénicaRESUMEN
Angiosarcoma is a rare refractory soft-tissue tumor with a poor prognosis and is treated by radiotherapy. The fibroblast growth factor 1 (FGF1) mutant, with enhanced thermostability due to several substituted amino acids, inhibits angiosarcoma cell metastasis, yet the mechanism of action is unclear. This study aims to clarify the FGF1 mutant mechanism of action using ISOS-1 mouse angiosarcoma cells. The wild-type FGF1 or FGF1 mutant was added to ISOS-1 cells and cultured, evaluating cell numbers over time. The invasive and migratory capacity of ISOS-1 cells was assessed by transwell analysis. ISOS-1 cell radiosensitivity was assessed by colony formation assay after X-ray irradiation. To examine whether mitogen-activated protein kinase (MEK) inhibitor counteracts the FGF1 mutant effects, a combination of MEK inhibitor and FGF1 mutant was added to ISOS-1 cells and cultured. The FGF1 mutant was observed to inhibit ISOS-1 cell proliferation, invasion and migration by sustained FGF1 signaling activation. A MEK inhibitor suppressed the FGF1 mutant-induced inhibition of proliferation, invasion and migration of ISOS-1 cells. Furthermore, the FGF1 mutant enhanced radiosensitivity of ISOS-1 cells, but MEK inhibition suppressed the increased radiosensitivity. In addition, we found that the FGF1 mutant strongly inhibits actin polymerization, suggesting that actin cytoskeletal dynamics are closely related to ISOS-1 cell radiosensitivity. Overall, this study demonstrated that in ISOS-1 cells, the FGF1 mutant inhibits proliferation, invasion and migration while enhancing radiosensitivity through sustained activation of the MEK-mediated signaling pathway.
Asunto(s)
Movimiento Celular , Proliferación Celular , Factor 1 de Crecimiento de Fibroblastos , Hemangiosarcoma , Sistema de Señalización de MAP Quinasas , Invasividad Neoplásica , Tolerancia a Radiación , Animales , Ratones , Movimiento Celular/efectos de los fármacos , Movimiento Celular/efectos de la radiación , Factor 1 de Crecimiento de Fibroblastos/metabolismo , Tolerancia a Radiación/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Proliferación Celular/efectos de la radiación , Línea Celular Tumoral , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Sistema de Señalización de MAP Quinasas/efectos de la radiación , Hemangiosarcoma/patología , Hemangiosarcoma/metabolismo , Hemangiosarcoma/radioterapiaRESUMEN
Canine splenic hemangiosarcoma has a high metastatic rate and short survival time. Currently, the main prognostic parameters are tumor stage and therapy, while data on histologic parameters, such as grade and Ki-67 expression, are scarce. The aims of this study were to compare two methods of assessment of Ki-67, verify their prognostic impact, and define a threshold value based on survival. Thirty-one cases of histologically diagnosed canine splenic hemangiosarcoma, which were treated with splenectomy and had full staging and follow-up information, were collected. Three were stage I, 17 stage II, and 11 stage III. The mean mitotic count (MC) was 23.9 (standard deviation [SD]: 22.1) and the median was 15 (range, 1-93). Immunohistochemistry for Ki-67 was performed, the Ki-67 labeling index (Ki-67LI) was assessed as a percentage of positive neoplastic nuclei per ≥500 cell, and the Ki-67 count (KI-67C) was defined as the average number of positive nuclei using a 1 cm2 optical grid performed in 5, 40× fields. The mean Ki-67LI and Ki-67C were 56.4% (SD: 38.7) and 27.2 (SD: 12.9) and medians were 51% (range, 8.2-55.2) and 26 (range, 5.5-148), respectively. Using a cut-off of 56% and 9, respectively, Kaplan-Meier survival curves showed an association of overall survival with Ki-67LI and MC. In addition to clinical stage, Ki-67LI maintained its prognostic value on multivariate analysis, supporting the role of Ki-67LI as an independent prognostic parameter. Based on these results, we propose a diagnostically applicable cut-off value of 56% for Ki-67LI as a prognostic parameter for canine splenic hemangiosarcoma.
Asunto(s)
Enfermedades de los Perros , Hemangiosarcoma , Antígeno Ki-67 , Neoplasias del Bazo , Hemangiosarcoma/veterinaria , Hemangiosarcoma/patología , Hemangiosarcoma/metabolismo , Hemangiosarcoma/diagnóstico , Animales , Antígeno Ki-67/metabolismo , Enfermedades de los Perros/patología , Enfermedades de los Perros/metabolismo , Enfermedades de los Perros/diagnóstico , Perros , Pronóstico , Neoplasias del Bazo/veterinaria , Neoplasias del Bazo/patología , Neoplasias del Bazo/diagnóstico , Neoplasias del Bazo/metabolismo , Masculino , Femenino , Inmunohistoquímica/veterinaria , Esplenectomía/veterinaria , Índice Mitótico/veterinaria , Estadificación de Neoplasias/veterinaria , Biomarcadores de Tumor/metabolismoRESUMEN
Angiosarcomas are rare malignant tumors of the endothelium, arising commonly from the head and neck region (AS-HN) and recently associated with ultraviolet (UV) exposure and human herpesvirus-7 infection. We examined 81 cases of angiosarcomas, including 47 cases of AS-HN, integrating information from whole genome sequencing, gene expression profiling and spatial transcriptomics (10X Visium). In the AS-HN cohort, we observed recurrent somatic mutations in CSMD3 (18%), LRP1B (18%), MUC16 (18%), POT1 (16%) and TP53 (16%). UV-positive AS-HN harbored significantly higher tumor mutation burden than UV-negative cases (p = 0.0294). NanoString profiling identified three clusters with distinct tumor inflammation signature scores (p < 0.001). Spatial transcriptomics revealed topological profiles of the tumor microenvironment, identifying dominant but tumor-excluded inflammatory signals in immune-hot cases and immune foci even in otherwise immune-cold cases. In conclusion, spatial transcriptomics reveal the tumor immune landscape of angiosarcoma, and in combination with multi-omic information, may improve implementation of treatment strategies.
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Hemangiosarcoma , Humanos , Hemangiosarcoma/genética , Hemangiosarcoma/metabolismo , Hemangiosarcoma/patología , Transcriptoma , Perfilación de la Expresión Génica , Microambiente Tumoral/genéticaRESUMEN
Angiosarcomas are a heterogeneous group of rare endothelial malignancies with a complex, not completely unravelled biology. They encompass primary (sporadically occurring) angiosarcomas of several origins and secondary angiosarcomas, which often arise due to DNA damaging factors including radiotherapy or ultraviolet light exposure. The optimal treatment of metastatic angiosarcomas is unclear and the prognosis is poor. In order to discover novel treatment strategies for angiosarcomas it is important to take the heterogeneity of these tumors into account. For this reason it is also important to have preclinical models available for the different clinical subtypes. Owing to the rarity of angiosarcomas, models are scarce. So far, only five human cell lines of angiosarcomas (all of the scalp after UV exposure) are available worldwide. In this paper we describe a novel established patient-derived xenograft model of a radiotherapy-induced angiosarcoma of the breast. The tumor was characterized by a MYC amplification, CD31 and ERG immunohistochemical positivity and was further characterized by using next generation sequencing (TruSight Oncology 500) in combination with the R-package XenofilteR to separate mouse from human sequence reads.
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Hemangiosarcoma , Neoplasias Inducidas por Radiación , Neoplasias Primarias Secundarias , Humanos , Animales , Ratones , Hemangiosarcoma/metabolismo , Xenoinjertos , Neoplasias Inducidas por Radiación/genética , Mama/patologíaRESUMEN
(1) Background: angiogenesis plays an important role in the growth and metastasis of tumors. We established the CAM assay application, an image analysis software of the IKOSA platform by KML Vision, for the quantification of blood vessels with the in ovo chorioallantoic membrane (CAM) model. We added this proprietary deep learning algorithm to the already established laser speckle contrast imaging (LSCI). (2) Methods: angiosarcoma cell line tumors were grafted onto the CAM. Angiogenesis was measured at the beginning and at the end of tumor growth with both measurement methods. The CAM assay application was trained to enable the recognition of in ovo CAM vessels. Histological stains of the tissue were performed and gluconate, an anti-angiogenic substance, was applied to the tumors. (3) Results: the angiosarcoma cells formed tumors on the CAM that appeared to stay vital and proliferated. An increase in perfusion was observed using both methods. The CAM assay application was successfully established in the in ovo CAM model and anti-angiogenic effects of gluconate were observed. (4) Conclusions: the CAM assay application appears to be a useful method for the quantification of angiogenesis in the CAM model and gluconate could be a potential treatment of angiosarcomas. Both aspects should be evaluated in further research.
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Aprendizaje Profundo , Hemangiosarcoma , Animales , Membrana Corioalantoides/metabolismo , Gluconatos/metabolismo , Gluconatos/farmacología , Hemangiosarcoma/metabolismo , Imágenes de Contraste de Punto Láser , Neovascularización Patológica/metabolismoRESUMEN
Beta adrenergic receptors (ß-AR) play a key role in regulating several hallmark pathways of both benign and malignant human and canine tumors. There is scarce information on the expression of ß-AR in canine vascular tumors. Therefore, the purpose of the present research work was to study the mRNA expression levels of the three subtypes of the ß-AR genes (ADRB1, ADRB2, ADRB3) in hemangiosarcoma (HSA) and hemangioma (HA), as well as in vascular hamartomas (VH) from dogs.Fifty samples (n = 50) were obtained from 38 dogs. Twenty-three animals had HSA, eight animals HA and seven animals VH. HSA were auricular (n = 8), splenic (n = 5), cutaneous (n = 6), auricular and splenic (n = 2), cutaneous-muscular (n = 1) and disseminated (n = 1). There were seven cases of HSA that were divided into primary tumor and secondary (metastatic) tumor. Skin and muscle samples with a normal histological study were used as control group. ADRB gene expression was determinate in all samples by real-time quantitative PCR. Results showed that ADRB1, ADRB2 and ADRB3 were overexpressed in HSA when compared to the control group. ADRB2 was overexpressed in HA when compared to the control group. HSA express higher values of ADBR1 (p = 0.0178) compared to VH. There was a high inter-individual variability in the expression of the three subtypes of ADBR. No statistically significant difference in the expression of ADBR genes were observed between HSA primary when compared to metastatic or in different anatomical locations. In conclusion, canine HSA overexpress the three ß-AR subtypes and canine HA ß2-AR. High variability was observed in ß-AR mRNA levels amongst HSA cases.
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Enfermedades de los Perros , Hemangioma , Hemangiosarcoma , Neoplasias Vasculares , Animales , Enfermedades de los Perros/genética , Enfermedades de los Perros/metabolismo , Perros , Hemangioma/genética , Hemangioma/veterinaria , Hemangiosarcoma/genética , Hemangiosarcoma/metabolismo , Hemangiosarcoma/veterinaria , ARN Mensajero/genética , Transcriptoma , Neoplasias Vasculares/veterinariaRESUMEN
PurposeCutaneous angiosarcoma (CAS) is a rare but typically aggressive malignant vascular neoplasm of the skin. Tumor microenvironment (TME) of CAS and its associations with baseline clinicopathological features and patient outcomes are very important, especially when considering the recent advances in understanding of the tumor biology.Methods/patientsWe retrospectively reviewed medical records of patients who underwent surgical resection for CAS at a tertiary Hospital. The pretreated specimens were evaluated by immunohistochemistry for programmed cell death protein 1 (PD-1) and its ligand (PD-L1), densities of tumor infiltrative lymphocytes (TILs) (CD3+, CD4+, CD8+, CD45RO+, FoxP3+), as well as c-MYC and Ki-67 expressions. Overall survival (OS) was estimated by KaplanMeier method and compared with Log-rank test.ResultsA total of 21 CAS patients were identified. Median age was 67 (ranges: 2081) years, 14 (66.7%) were male, and over 50% had lesions of scalp. Histopathological examination showed a predominantly spindle cell type (57.1%). All patients underwent surgery, 16 (76.2%) were treated further. PD-L1 was positively stained (> 1%) in tumor cells (42.9%) and TILs (23.8%). PD-1 expression (> 1%) was identified in TILs of 11 (52.4%) cases. PD-1/PD-L1 expressions were significantly associated with the higher densities of CD3+, CD4+, CD8+, CD45RO+, and Foxp3+ TILs, but not with patient characteristics or c-MYC or Ki-67 expression. Median OS was 18.5 months (95% CI 6.035.9), although no prognostic significance was observed with respect to any clinicopathological features.ConclusionWe characterized TME and its clinical and prognostic association in CAS. PD-1/PD-L1 expressions were significantly associated with TILs subtypes but not with OS.
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Humanos , Antígeno B7-H1/metabolismo , Linfocitos T CD8-positivos/metabolismo , Factores de Transcripción , Hemangiosarcoma/metabolismo , Hemangiosarcoma/patología , Hemangiosarcoma/cirugía , Microambiente Tumoral , Antígeno Ki-67/metabolismo , Receptor de Muerte Celular Programada 1/metabolismo , Estudios RetrospectivosRESUMEN
Angiosarcoma is a rare, life-threatening soft tissue sarcoma with malignant endothelial cells that is mainly found in the skin. Multidisciplinary approaches are used to treat patients with unresectable metastasized lesions; considering the cellular origin of angiosarcoma, anti-angiogenic therapy has also been used recently. However, these treatments have limited efficacy, and the survival rate remains low. Thus, more effective treatments need to be developed. Nectin cell adhesion molecule 4 (NECTIN4) is highly expressed in malignant tumors and promotes tumor progression. Thus, NECTIN4 is expected to be a novel therapeutic target for cancer. However, the significance of NECTIN4 in angiosarcoma remains unknown. Using immunohistochemistry, we investigated NECTIN4 expression in 74 tissue samples from angiosarcoma patients, finding variable NECTIN4 expression. In addition, we investigated NECTIN4 expression and function in human angiosarcoma cell lines. NECTIN4 expression was higher in angiosarcoma cells than normal endothelial cells, and angiosarcoma cells were sensitive to monomethyl auristatin E, the cytotoxic part of a NECTIN4-targetting antibody-drug conjugate. NECTIN4 knockdown inhibited the proliferation and angiogenesis of angiosarcoma cells, and Src kinase signaling was shown to be involved in NECTIN4 function, at least in part. NECTIN4-targeted therapy has the potential to be a novel treatment strategy for angiosarcoma.
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Moléculas de Adhesión Celular , Hemangiosarcoma , Neoplasias Cutáneas , Familia-src Quinasas , Moléculas de Adhesión Celular/inmunología , Moléculas de Adhesión Celular/metabolismo , Células Endoteliales/metabolismo , Hemangiosarcoma/irrigación sanguínea , Hemangiosarcoma/tratamiento farmacológico , Hemangiosarcoma/metabolismo , Humanos , Inmunoconjugados/farmacología , Nectinas , Neovascularización Patológica/tratamiento farmacológico , Neoplasias Cutáneas/irrigación sanguínea , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/metabolismo , Familia-src Quinasas/metabolismoRESUMEN
Hemangiosarcoma (HSA) is a malignant neoplasm that occurs in humans and canines with a poor prognosis owing to metastatic spread, despite effective treatment. The frequency of spontaneous HSA development is higher in canines than in humans. Therefore, canine HSA is a useful model of intractable human disease, which requires early detection and an effective therapeutic strategy. A high frequency of the p110α phosphatidylinositol4,5bisphosphate 3kinase catalytic subunit alpha (PIK3CA) mutations is detected in a comprehensive genomewide analysis of canine cases of HSA. The present cloned the fulllength cDNA of canine PIK3CA and identified a mutation in codon 1047 from canine cases of HSA and cell lines that were established from these. The enforced expression of the 1047th histidine residue (H1047)R or L mutants of canine PIK3CA in HeLa cells enhanced epidermal growth factor receptor (EGFR) signaling via Akt phosphorylation. PIK3CA mutant canine HSA cell lines exhibited the hyperphosphorylation of Akt upon EGF stimulation as well. Alpelisib, a molecular targeted drug against PIK3CA activating mutations, exerted a significant antitumor effect in canine PIK3CAmutated HSA cell lines. By contrast, it had no significant effect on canine mammary gland tumor cell lines harboring PIK3CA mutations. On the whole, the findings of the present study suggest that alpelisib may be highly effective against PIK3CA mutations that occur frequently in canine HSA.
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Hemangiosarcoma , Animales , Línea Celular Tumoral , Fosfatidilinositol 3-Quinasa Clase I/genética , Perros , Células HeLa , Hemangiosarcoma/tratamiento farmacológico , Hemangiosarcoma/genética , Hemangiosarcoma/metabolismo , Humanos , Mutación , TiazolesRESUMEN
Angiosarcoma (AS) is a rare malignancy with a poor prognosis. It can develop spontaneously or due to previous radiotherapy (RT), ultraviolet (UV) radiation, or lymphoedema (Stewart Treves AS). Novel therapeutic approaches are needed, but progress is hindered because of the heterogeneity and rarity of AS. In order to explore the potential of immune checkpoint inhibition (ICI), we investigated the protein expression of programmed cell death 1 (PD-1), programmed death-ligand 1 (PD-L1), and CD8 + T cells in 165 AS cases in relation to AS subgroups based on clinical classification and in relation to whole-genome methylation profiling based clusters (A1, A2, B1, B2). High PD-L1 and PD-1 expression were predominantly shown in UV-associated, visceral, and soft tissue AS. RT-associated AS showed predominantly high PD-1 expression. CD8 + T cell infiltration was present in the majority of AS samples. Within the UV-associated AS, two different clusters can be distinguished by DNA methylation profiling. Cases in cluster A1 showed higher PD-1 (p = 0.015), PD-L1 (p = 0.015), and CD8 + T cells (p = 0.008) compared to those in cluster B2, suggesting that these UV-AS tumors are more immunogenic than B2 tumors showing a difference even within one subgroup. In soft tissue AS, combined PD-1 and PD-L1 expression showed a trend toward poor survival (p = 0.051), whereas in UV-associated AS, PD-1 expression correlated with better survival (p = 0.035). In conclusion, we show the presence of PD-1, PD-L1, and CD8 + T cells in the majority of AS but reveal differences between and within AS subgroups, providing prognostic information and indicating to be predictive for ICI.
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Antígeno B7-H1 , Hemangiosarcoma , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Linfocitos T CD8-positivos , Hemangiosarcoma/genética , Hemangiosarcoma/metabolismo , Hemangiosarcoma/patología , Humanos , Inhibidores de Puntos de Control Inmunológico , Linfocitos Infiltrantes de Tumor , Pronóstico , Receptor de Muerte Celular Programada 1/genética , Receptor de Muerte Celular Programada 1/metabolismoRESUMEN
PURPOSE: Cutaneous angiosarcoma (CAS) is a rare but typically aggressive malignant vascular neoplasm of the skin. Tumor microenvironment (TME) of CAS and its associations with baseline clinicopathological features and patient outcomes are very important, especially when considering the recent advances in understanding of the tumor biology. METHODS/PATIENTS: We retrospectively reviewed medical records of patients who underwent surgical resection for CAS at a tertiary Hospital. The pretreated specimens were evaluated by immunohistochemistry for programmed cell death protein 1 (PD-1) and its ligand (PD-L1), densities of tumor infiltrative lymphocytes (TILs) (CD3+, CD4+, CD8+, CD45RO+, FoxP3+), as well as c-MYC and Ki-67 expressions. Overall survival (OS) was estimated by Kaplan-Meier method and compared with Log-rank test. RESULTS: A total of 21 CAS patients were identified. Median age was 67 (ranges: 20-81) years, 14 (66.7%) were male, and over 50% had lesions of scalp. Histopathological examination showed a predominantly spindle cell type (57.1%). All patients underwent surgery, 16 (76.2%) were treated further. PD-L1 was positively stained (> 1%) in tumor cells (42.9%) and TILs (23.8%). PD-1 expression (> 1%) was identified in TILs of 11 (52.4%) cases. PD-1/PD-L1 expressions were significantly associated with the higher densities of CD3+, CD4+, CD8+, CD45RO+, and Foxp3+ TILs, but not with patient characteristics or c-MYC or Ki-67 expression. Median OS was 18.5 months (95% CI 6.0-35.9), although no prognostic significance was observed with respect to any clinicopathological features. CONCLUSION: We characterized TME and its clinical and prognostic association in CAS. PD-1/PD-L1 expressions were significantly associated with TILs subtypes but not with OS.
Asunto(s)
Antígeno B7-H1 , Hemangiosarcoma , Anciano , Antígeno B7-H1/metabolismo , Linfocitos T CD8-positivos/metabolismo , Femenino , Factores de Transcripción Forkhead/metabolismo , Hemangiosarcoma/metabolismo , Hemangiosarcoma/patología , Hemangiosarcoma/cirugía , Humanos , Antígeno Ki-67/metabolismo , Linfocitos Infiltrantes de Tumor/metabolismo , Masculino , Pronóstico , Receptor de Muerte Celular Programada 1/metabolismo , Estudios Retrospectivos , Microambiente TumoralRESUMEN
ABSTRACT: Cutaneous clear cell proliferations encompass a heterogenous group of several primary cutaneous neoplasms and metastatic tumors with different histogenesis. Many of these clear cell proliferations may seem strikingly similar under the microscope resulting in challenging diagnosis. In many of these clear cell lesions, the reason for the clear or pale appearance of proliferating cells is unknown, whereas in other ones, this clear cell appearance is due to intracytoplasmic accumulation of glycogen, mucin, or lipid. Artifacts of tissue processing and degenerative phenomenon may also be responsible for the clear cell appearance of proliferating cells. Awareness of the histopathologic findings as well as histochemical and immunohistochemical techniques are crucial to the accurate diagnosis. This review details the histopathologic features of clear cell cutaneous proliferations, classifying them according their type of differentiation and paying special attention to the histopathologic differential diagnosis among them.
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Carcinoma Basocelular/patología , Carcinoma de Células Escamosas/patología , Epidermis/patología , Melanoma/patología , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/patología , Acantoma/patología , Carcinoma Basocelular/metabolismo , Carcinoma de Células Escamosas/metabolismo , Tumor de Células Granulares/metabolismo , Tumor de Células Granulares/patología , Folículo Piloso/patología , Hemangiosarcoma/metabolismo , Hemangiosarcoma/patología , Histiocitoma Fibroso Benigno/metabolismo , Histiocitoma Fibroso Benigno/patología , Humanos , Inmunohistoquímica , Queratosis Seborreica/patología , Liposarcoma/metabolismo , Liposarcoma/patología , Melanoma/metabolismo , Neurofibroma/metabolismo , Neurofibroma/patología , Neoplasias de Células Epitelioides Perivasculares/metabolismo , Neoplasias de Células Epitelioides Perivasculares/patología , Neoplasias de las Glándulas Sebáceas/metabolismo , Neoplasias de las Glándulas Sebáceas/patología , Neoplasias Cutáneas/secundario , Neoplasias de las Glándulas Sudoríparas/metabolismo , Neoplasias de las Glándulas Sudoríparas/patología , Xantomatosis/metabolismo , Xantomatosis/patologíaRESUMEN
ABSTRACT: Angiosarcoma is a rare, highly aggressive malignant tumor originating from endothelial cells that line the lumen of blood or lymphatic vessels. The molecular mechanisms of scalp and face angiosarcoma still need to be elucidated. This study aimed to investigate the expression of phosphatase and tensin homolog (PTEN), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), phosphorylated mitogen-activated kinase-like protein (pMAPK), and tumor protein p53 (TP53) in scalp and face angiosarcoma and to assess tumor tissue apoptosis.The expression and intracellular distribution of PTEN, PIK3CA, pMAPK, and TP53 proteins in 21 specimens of human scalp and face angiosarcoma and 16 specimens of human benign hemangioma were evaluated using immunohistochemistry. Tumor cell apoptosis was assessed by terminal deoxyribonucleotide transferase-mediated dUTP nick end-labeling staining.Significantly lower PTEN but higher PIK3CA, pMAPK, and TP53 immunostaining were detected in the angiosarcoma specimens than in the benign hemangioma specimens(Pâ<â.01). The angiosarcoma tissues exhibited significantly higher apoptosis indices than the benign hemangioma tissues (Pâ<â.01). The positive expression rates of PIK3CA, pMAPK, and TP53 were correlated with the degree of tumor differentiation in the human scalp and face angiosarcoma.The PI3K, MAPK, and TP53 pathways might be involved in angiosarcoma tumorigenesis in humans and may serve as therapeutic targets for the effective treatment of this malignancy.
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Fosfatidilinositol 3-Quinasa Clase I/metabolismo , Neoplasias de Cabeza y Cuello/metabolismo , Hemangiosarcoma/metabolismo , Fosfohidrolasa PTEN/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proteínas Quinasas Activadas por Mitógenos/metabolismoRESUMEN
Angiosarcoma is an aggressive malignancy of endothelial cells that carries a high mortality rate. Cytotoxic chemotherapy can elicit clinical responses, but the duration of response is limited. Sequencing reveals multiple mutations in angiogenesis pathways in angiosarcomas, particularly in vascular endothelial growth factor (VEGFR) and mitogen-activated protein kinase (MAPK) signaling. We aimed to determine the biological relevance of these pathways in angiosarcoma. Tissue microarray consisting of clinical formalin-fixed paraffin embedded tissue archival samples were stained for phospho- extracellular signal-regulated kinase (p-ERK) with immunohistochemistry. Angiosarcoma cell lines were treated with the mitogen-activated protein kinase kinase (MEK) inhibitor trametinib, pan-VEGFR inhibitor cediranib, or combined trametinib and cediranib and viability was assessed. Reverse phase protein array (RPPA) was performed to assess multiple oncogenic protein pathways. SVR angiosarcoma cells were grown in vivo and gene expression effects of treatment were assessed with whole exome RNA sequencing. MAPK signaling was found active in over half of clinical angiosarcoma samples. Inhibition of MAPK signaling with the MEK inhibitor trametinib decreased the viability of angiosarcoma cells. Combined inhibition of the VEGF and MAPK pathways with cediranib and trametinib had an additive effect in in vitro models, and a combinatorial effect in an in vivo model. Combined treatment led to smaller tumors than treatment with either agent alone. RNA-seq demonstrated distinct expression signatures between the trametinib treated tumors and those treated with both trametinib and cediranib. These results indicate a clinical study of combined VEGFR and MEK inhibition in angiosarcoma is warranted.
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Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Biomarcadores de Tumor/metabolismo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Hemangiosarcoma/tratamiento farmacológico , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Animales , Apoptosis , Biomarcadores de Tumor/genética , Proliferación Celular , Hemangiosarcoma/metabolismo , Hemangiosarcoma/patología , Humanos , Ratones , Ratones Desnudos , Pronóstico , Piridonas/administración & dosificación , Pirimidinonas/administración & dosificación , Quinazolinas/administración & dosificación , Transcriptoma , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Angiosarcomas are soft-tissue sarcomas that form malignant vascular tissues. Angiosarcomas are very rare, and due to their aggressive behavior and high metastatic propensity, they have poor clinical outcomes. Hemangiosarcomas commonly occur in domestic dogs, and share pathological and clinical features with human angiosarcomas. Typical pathognomonic features of this tumor are irregular vascular channels that are filled with blood and are lined by a mixture of malignant and nonmalignant endothelial cells. The current gold standard is the histological diagnosis of angiosarcoma; however, microscopic evaluation may be complicated, particularly when tumor cells are undetectable due to the presence of excessive amounts of nontumor cells or when tissue specimens have insufficient tumor content. In this study, we implemented machine learning applications from next-generation transcriptomic data of canine hemangiosarcoma tumor samples (n = 76) and nonmalignant tissues (n = 10) to evaluate their training performance for diagnostic utility. The 10-fold cross-validation test and multiple feature selection methods were applied. We found that extra trees and random forest learning models were the best classifiers for hemangiosarcoma in our testing datasets. We also identified novel gene signatures using the mutual information and Monte Carlo feature selection method. The extra trees model revealed high classification accuracy for hemangiosarcoma in validation sets. We demonstrate that high-throughput sequencing data of canine hemangiosarcoma are trainable for machine learning applications. Furthermore, our approach enables us to identify novel gene signatures as reliable determinants of hemangiosarcoma, providing significant insights into the development of potential applications for this vascular malignancy.
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Bases de Datos de Ácidos Nucleicos , Enfermedades de los Perros , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Hemangiosarcoma , Aprendizaje Automático , Transcriptoma , Animales , Enfermedades de los Perros/genética , Enfermedades de los Perros/metabolismo , Perros , Hemangiosarcoma/genética , Hemangiosarcoma/metabolismo , Hemangiosarcoma/veterinariaRESUMEN
BACKGROUND: Secondary angiosarcoma (AS) most commonly follows breast cancer and includes postirradiation AS (PRAS) and lymphedema-associated AS. The frequent amplification of MYC (8q24.21) in secondary AS and the rising incidence of PRAS and atypical vascular lesions (AVLs) have prompted interest in the diagnostic and prognostic utility of MYC in AS. METHODS: Retrospective series with ≥2 cases of cutaneous AS and describing the use of fluorescence in situ hybridization (FISH) for MYC amplification or immunohistochemistry (IHC) for MYC overexpression were included. RESULTS: Sixteen studies met inclusion criteria. Overall, 93% of cases evaluated by FISH and IHC were concordant. The sensitivity of FISH in primary AS was only 6.8%, and protein overexpression occurred without amplification in sun-damaged skin. FISH and IHC were over 78% sensitive in secondary AS but negative in over 98% of AVLs. MYC amplification and FLT4 coamplification were associated with shorter overall survival in secondary AS. CONCLUSION: FISH for MYC amplification and IHC for MYC overexpression are useful in distinguishing PRAS from AVLs and may also have prognostic value in secondary AS. In contrast, these methods have little diagnostic or prognostic value in primary AS and should not be used to distinguish primary AS from benign vascular neoplasms.
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Amplificación de Genes/genética , Hemangiosarcoma/genética , Inmunohistoquímica/métodos , Hibridación Fluorescente in Situ/métodos , Proteínas Proto-Oncogénicas c-myc/genética , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Neoplasias de la Mama/radioterapia , Femenino , Hemangiosarcoma/diagnóstico , Hemangiosarcoma/metabolismo , Hemangiosarcoma/mortalidad , Hemangiosarcoma/patología , Humanos , Linfedema/complicaciones , Linfedema/metabolismo , Linfedema/patología , Neoplasias Inducidas por Radiación/diagnóstico , Neoplasias Inducidas por Radiación/metabolismo , Neoplasias Inducidas por Radiación/patología , Pronóstico , Estudios Retrospectivos , Sensibilidad y Especificidad , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patologíaRESUMEN
Statins are inhibitors of the mevalonate cascade that is responsible for cholesterol biosynthesis and the formation of intermediate metabolites, farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP) used in the prenylation of proteins. Although statins are widely used in the treatment of hypercholesterolemia, recent studies suggest that they also inhibit proliferation of tumour cells by reducing prenylation of small GTP-binding proteins, such as, Ras. This study aimed to evaluate the effect of simvastatin on cell proliferation and Ras activation in various canine tumour cell lines, including hemangiosarcoma (HSA), melanoma, and lymphoma cell lines. Simvastatin inhibited cell proliferation of all cell lines tested in a concentration- and time-dependent manner, but the susceptibilities were different amongst the cell lines. Simvastatin induced apoptotic cell death via activation of caspase-3 and cell cycle arrest. The cytotoxic effects of simvastatin were attenuated by GGPP and FPP. Simvastatin decreased the amount of prenylated Ras and GTP-bound Ras in HSA and melanoma cell lines, but not in lymphoma cell lines. These results indicate that simvastatin induces cytotoxic effects through the depletion of GGPP and FPP in a variety of canine tumour cells, whereas multiple mechanisms are involved in the effects. Further study is required to elucidate the underlying mechanisms of simvastatin-induced cytotoxic effects in a variety of canine tumour cells.
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Proliferación Celular/efectos de los fármacos , Enfermedades de los Perros/metabolismo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Simvastatina/farmacología , Proteínas ras/metabolismo , Clorometilcetonas de Aminoácidos/farmacología , Animales , Apoptosis/efectos de los fármacos , Apoptosis/fisiología , Inhibidores de Caspasas/farmacología , Caspasas/metabolismo , Puntos de Control del Ciclo Celular , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Perros , Hemangiosarcoma/metabolismo , Hemangiosarcoma/veterinaria , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Linfoma/metabolismo , Linfoma/veterinaria , Melanoma/metabolismo , Melanoma/veterinaria , Proteínas ras/genéticaRESUMEN
Angiosarcomas (AS) represent a heterogenous group of tumors with variable clinical presentation. AS share an important morphologic and immunohistochemical overlap with other sarcomas, hence the differential diagnosis is challenging, especially in poorly-differentiated tumors. Although molecular studies provide significant clues, especially in the differential diagnosis with other vascular neoplasms, a thorough hematoxylin and eosin analysis remains an essential tool in AS diagnosis. In this review, we discuss pathological and molecular insights with emphasis on implications for differential diagnosis in cutaneous, breast, soft tissue and visceral AS.
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Hemangiosarcoma/diagnóstico , Hemangiosarcoma/patología , Inmunohistoquímica/métodos , Neoplasias de los Tejidos Blandos/diagnóstico , Neoplasias de los Tejidos Blandos/patología , Biomarcadores de Tumor/análisis , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Diferenciación Celular , Diagnóstico Diferencial , Femenino , Hemangiosarcoma/metabolismo , Humanos , Sarcoma/patología , Neoplasias Cutáneas/diagnóstico , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/patología , Neoplasias de los Tejidos Blandos/metabolismo , Microambiente Tumoral , Neoplasias Vasculares/diagnóstico , Neoplasias Vasculares/metabolismo , Neoplasias Vasculares/patologíaRESUMEN
ABSTRACT: Cutaneous angiosarcomas may express programmed death ligand-1 (PD-L1) and PD-L1 expression, and the presence of tumor-infiltrating lymphocytes (TILs) correlates with outcome. These observations provide a basis for PD-1/PD-L1 inhibitor therapy. Lymphocyte activation gene 3 (LAG-3) is an inhibitory receptor that interacts with the PD-L1 axis and is considered to be a marker of immune exhaustion. The presence of LAG-3-positive lymphocytes in cutaneous angiosarcoma has not been established. We reviewed 10 cases of treatment naive angiosarcoma of skin and superficial soft tissue and assessed for PD-L1 (ZR3) expression, presence of TILs, and expression of CD8, PD1, and LAG-3 by tumor-associated inflammatory cells by immunohistochemistry. All 10 angiosarcomas were positive for PD-L1: 7 with high expression and 3 with low expression. TILs were present in all tumors: brisk in 7 and nonbrisk in 3. CD8 lymphocytes were present in all tumors with a range of 212-1274 cells per square millimeter (mean 557 CD8 cells/mm2). LAG-3-positive lymphocytes were present in 9 of 10 angiosarcomas with a range of 0-728 cells/mm2 (mean 146 LAG-3 cells cells/mm2). The ratio of LAG-3 lymphocytes to CD8 lymphocytes was 0%-59% (mean 27%). The PD1 cell counts were intermediate between CD8 and LAG3 counts. Cutaneous angiosarcomas frequently express PD-L1, have prominent numbers of CD8 positive, and have smaller numbers of LAG-3-positive and PD-1-positive TILs. Our findings provide further evidence of PD-L1 expression in cutaneous angiosarcoma and the promise for immune checkpoint inhibitor therapy.