RESUMEN
Skin damage is the most common and most important toxicity during and after radiation therapy (RT). Its assessment and understanding of the factors influencing its occurrence, is a major issue in the management of patients irradiated for an early breast cancer. CANTO is a prospective clinical cohort study of 10 150 patients with stage I-III BC treated from 2012 to 2017 in 26 cancer centres. In our study, we used CANTO-RT, a subcohort of CANTO, including 3480 patients who received RT. We are focus on specific skin toxicities: erythema, fibrosis, telangiectasia and cutaneous pigmentation. The prevalence of toxicities of interest varied over time, so at baseline for early toxicity Month (M) 0-3-6, 41.1% of patients had erythema while 24.8% of patients had fibrosis. At M12 and M36, the prevalence of erythema decreased, respectively, while fibrosis remains stable. The prevalence of telangiectasia increases from 1% to 7.1% from M0-3-6 to M36. After adjustments, we showed an association between the occurrence of skin erythema and obesity; the type of surgery; the presence of axillary dissection; the use of taxane-based CT and the 3D vs IMRT irradiation technique. Regarding fibrosis, an association is found, at M0-3-6, with age at diagnosis, obesity, tobacco and the use of boost. Only obesity and the type of surgery received by the patient remained statistically significant at M12 and M36. In our study we identified several risk factors for acute and late skin reactions. The use of a boost was mainly related to the occurrence of fibrosis while the use of IMRT-type technique decreased the occurrence of skin erythema.
Asunto(s)
Neoplasias de la Mama , Telangiectasia , Neoplasias de la Mama/tratamiento farmacológico , Estudios de Cohortes , Eritema/epidemiología , Eritema/etiología , Femenino , Fibrosis , Humanos , Obesidad/complicaciones , Estudios Prospectivos , Telangiectasia/complicaciones , Telangiectasia/etiologíaRESUMEN
Immunotherapy with anti-GD2 monoclonal antibodies (mAbs) provides some benefits for patients with neuroblastoma (NB). However, the therapeutic efficacy remains limited, and treatment is associated with significant neuropathic pain. Targeting O-acetylated GD2 (OAcGD2) by 8B6 mAb has been proposed to avoid pain by more selective tumor cell targeting. Thorough understanding of its mode of action is necessary to optimize this treatment strategy. Here, we found that 8B6-mediated antibody-dependent cellular phagocytosis (ADCP) performed by macrophages is a key effector mechanism. But efficacy is limited by upregulation of CD47 expression on neuroblastoma cells in response to OAcGD2 mAb targeting, inhibiting 8B6-mediated ADCP. Antibody specific for the CD47 receptor SIRPα on macrophages restored 8B6-induced ADCP of CD47-expressing NB cells and improved the antitumor activity of 8B6 mAb therapy. These results identify ADCP as a critical mechanism for tumor cytolysis by anti-disialoganglioside mAb and support a combination with SIRPα blocking agents for effective neuroblastoma therapy.
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Anticuerpos Monoclonales/química , Antígenos de Diferenciación/química , Neuroblastoma/inmunología , Fagocitosis , Receptores Inmunológicos/química , Animales , Anticuerpos/química , Citotoxicidad Celular Dependiente de Anticuerpos/inmunología , Antineoplásicos Inmunológicos/farmacología , Antígeno CD47/biosíntesis , Línea Celular Tumoral , Citometría de Flujo , Gangliósidos/química , Humanos , Inmunoterapia/métodos , Macrófagos/metabolismo , Ratones , Microscopía Fluorescente , Neuroblastoma/metabolismo , Regulación hacia ArribaRESUMEN
Deficiency of ASM (acid sphingomyelinase) causes the lysosomal storage Niemann-Pick disease (NPD). Patients with NPD type B may develop progressive interstitial lung disease with frequent respiratory infections. Although several investigations using the ASM-deficient (ASMKO) mouse NPD model revealed inflammation and foamy macrophages, there is little insight into the pathogenesis of NPD-associated lung disease. Using ASMKO mice, we report that ASM deficiency is associated with a complex inflammatory phenotype characterized by marked accumulation of monocyte-derived CD11b+ macrophages and expansion of airspace/alveolar CD11c+ CD11b- macrophages, both with increased size, granularity, and foaminess. Both the alternative and classical pathways were activated, with decreased in situ phagocytosis of opsonized (Fc-coated) targets, preserved clearance of apoptotic cells (efferocytosis), secretion of Th2 cytokines, increased CD11c+/CD11b+ cells, and more than a twofold increase in lung and plasma proinflammatory cytokines. Macrophages, neutrophils, eosinophils, and noninflammatory lung cells of ASMKO lungs also exhibited marked accumulation of chitinase-like protein Ym1/2, which formed large eosinophilic polygonal Charcot-Leyden-like crystals. In addition to providing insight into novel features of lung inflammation that may be associated with NPD, our report provides a novel connection between ASM and the development of crystal-associated lung inflammation with alterations in macrophage biology.
Asunto(s)
Glicoproteínas/inmunología , Lisofosfolipasa/inmunología , Macrófagos Alveolares/inmunología , Macrófagos/inmunología , Enfermedad de Niemann-Pick Tipo A/inmunología , Enfermedad de Niemann-Pick Tipo B/inmunología , Neumonía/inmunología , Esfingomielina Fosfodiesterasa/inmunología , Animales , Antígenos CD11/genética , Antígenos CD11/inmunología , Antígeno CD11b/genética , Antígeno CD11b/inmunología , Tamaño de la Célula , Quitinasas/genética , Quitinasas/inmunología , Modelos Animales de Enfermedad , Eosinófilos/inmunología , Eosinófilos/patología , Femenino , Expresión Génica , Glicoproteínas/genética , Humanos , Lectinas/genética , Lectinas/inmunología , Pulmón/inmunología , Pulmón/patología , Lisofosfolipasa/genética , Macrófagos/patología , Macrófagos Alveolares/patología , Masculino , Ratones , Ratones Noqueados , Neutrófilos/inmunología , Neutrófilos/patología , Enfermedad de Niemann-Pick Tipo A/enzimología , Enfermedad de Niemann-Pick Tipo A/genética , Enfermedad de Niemann-Pick Tipo A/patología , Enfermedad de Niemann-Pick Tipo B/enzimología , Enfermedad de Niemann-Pick Tipo B/genética , Enfermedad de Niemann-Pick Tipo B/patología , Fagocitosis , Neumonía/enzimología , Neumonía/genética , Neumonía/patología , Esfingomielina Fosfodiesterasa/deficiencia , Esfingomielina Fosfodiesterasa/genética , Balance Th1 - Th2/genética , beta-N-Acetilhexosaminidasas/genética , beta-N-Acetilhexosaminidasas/inmunologíaRESUMEN
Engaging in exercise while undergoing radiotherapy (RT) has been reported to be safe and achievable. The impact of exercise training (ET) on RT efficiency is however largely unknown. Our study aims to investigate the interactions between ET and RT on prostate cancer growth. Athymic mice received a subcutaneous injection of PPC-1 cells and were randomly assigned to either cancer control, cancer ET, cancer RT, or cancer RT combined with ET (CaRT-ET). Mice were sacrificed 24 days post-injection. All three intervention groups had reduced tumor size, the most important decrease being observed in CaRT-ET mice. Apoptotic marker cleaved caspase-3 was not modified by ET, but enhanced with RT. Importantly, this increase was the highest when the two strategies were combined. Furthermore, NK1.1 staining and gene expression of natural killer (NK) cell receptors Klrk1 and Il2rß were not affected by ET alone but were increased with RT, this effect being potentiated when combined with ET. Overall, our study shows that (a) ET enhances RT efficiency by potentiating NK cell infiltration, and (b) while ET alone and ET combined with RT both reduce tumor growth, the mechanisms mediating these effects are different.
Asunto(s)
Condicionamiento Físico Animal/métodos , Neoplasias de la Próstata/radioterapia , Radioterapia/métodos , Animales , Antígenos Ly/genética , Antígenos Ly/metabolismo , Apoptosis , Caspasa 3/genética , Caspasa 3/metabolismo , Línea Celular Tumoral , Terapia Combinada , Humanos , Subunidad beta del Receptor de Interleucina-2/genética , Subunidad beta del Receptor de Interleucina-2/metabolismo , Masculino , Ratones , Subfamilia B de Receptores Similares a Lectina de Células NK/genética , Subfamilia B de Receptores Similares a Lectina de Células NK/metabolismo , Subfamilia K de Receptores Similares a Lectina de Células NK/genética , Subfamilia K de Receptores Similares a Lectina de Células NK/metabolismo , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/terapiaRESUMEN
The levels and composition of sphingolipids and related metabolites are altered in aging and in common disorders such as diabetes and cancers, as well as in neurodegenerative, cardiovascular, and respiratory diseases. Changes in sphingolipids have been implicated as being an essential step in mitochondria-driven cell death. However, little is known about the precise sphingolipid composition and modulation in mitochondria or related organelles. Here, we used LC-MS/MS to analyze the presence of key components of the ceramide metabolic pathway in vivo and in vitro in purified ER, mitochondria-associated membranes (MAMs), and mitochondria. Specifically, we analyzed the sphingolipids in the three pathways that generate ceramide: sphinganine in the de novo ceramide pathway, SM in the breakdown pathway, and sphingosine in the salvage pathway. We observed sphingolipid profiles in mouse liver, mouse brain, and a human glioma cell line (U251). We analyzed the quantitative and qualitative changes of these sphingolipids during staurosporine-induced apoptosis in U251 cells. Ceramide (especially C16-ceramide) levels increased during early apoptosis possibly through a conversion from mitochondrial sphinganine and SM, but sphingosine and lactosyl- and glycosyl-ceramide levels were unaffected. We also found that ceramide generation is enhanced in mitochondria when SM levels are decreased in the MAM. This decrease was associated with an increase in acid sphingomyelinase activity in MAM. We conclude that meaningful sphingolipid modifications occur in MAM, the mitochondria, and the ER during the early steps of apoptosis.
Asunto(s)
Apoptosis , Membranas Mitocondriales/metabolismo , Esfingolípidos/metabolismo , Apoptosis/efectos de los fármacos , Línea Celular , Ceramidas/metabolismo , Humanos , Membranas Mitocondriales/efectos de los fármacos , Esfingosina/análogos & derivados , Esfingosina/farmacologíaRESUMEN
Stem cell chemoresistance remains challenging the efficacy of the front-line temozolomide against glioblastoma. Novel therapies are urgently needed to fight those cells in order to control tumor relapse. Here, we report that anti-O-acetyl-GD2 adjuvant immunotherapy controls glioma stem-like cell-driven chemoresistance. Using patient-derived glioblastoma cells, we found that glioma stem-like cells overexpressed O-acetyl-GD2. As a result, monoclonal antibody 8B6 immunotherapy significantly increased temozolomide genotoxicity and tumor cell death in vitro by enhancing temozolomide tumor uptake. Furthermore, the combination therapy decreased the expression of the glioma stem-like cell markers CD133 and Nestin and compromised glioma stem-like cell self-renewal capabilities. When tested in vivo, adjuvant 8B6 immunotherapy prevented the extension of the temozolomide-resistant glioma stem-like cell pool within the tumor bulk in vivo and was more effective than the single agent therapies. This is the first report demonstrating that anti-O-acetyl-GD2 monoclonal antibody 8B6 targets glioblastoma in a manner that control temozolomide-resistance driven by glioma stem-like cells. Together our results offer a proof of concept for using anti-O-acetyl GD2 reagents in glioblastoma to develop more efficient combination therapies for malignant gliomas.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Gangliósidos/antagonistas & inhibidores , Glioblastoma/tratamiento farmacológico , Células Madre Neoplásicas/efectos de los fármacos , Adyuvantes Inmunológicos/farmacología , Adyuvantes Inmunológicos/uso terapéutico , Animales , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Línea Celular Tumoral , Autorrenovación de las Células/efectos de los fármacos , Autorrenovación de las Células/inmunología , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/inmunología , Sinergismo Farmacológico , Gangliósidos/inmunología , Glioblastoma/inmunología , Glioblastoma/patología , Humanos , Ratones , Células Madre Neoplásicas/inmunología , Temozolomida/farmacología , Temozolomida/uso terapéutico , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Oxidative stress is a leading cause of endothelial dysfunction. The p38 MAPK pathway plays a determinant role in allowing cells to cope with oxidative stress and is tightly regulated by a balanced interaction between p38 protein and its interacting partners. By using a proteomic approach, we identified nucleophosmin (NPM) as a new partner of p38 in HUVECs. Coimmunoprecipitation and microscopic analyses confirmed the existence of a cytosolic nucleophosmin (NPM)/p38 interaction in basal condition. Oxidative stress, which was generated by exposure to 500 µM H2O2, induces a rapid dephosphorylation of NPM at T199 that depends on phosphatase PP2A, another partner of the NPM/p38 complex. Blocking PP2A activity leads to accumulation of NPM-pT199 and to an increased association of NPM with p38. Concomitantly to its dephosphorylation, oxidative stress promotes translocation of NPM to the nucleus to affect the DNA damage response. Dephosphorylated NPM impairs the signaling of oxidative stress-induced DNA damage via inhibition of the phosphorylation of ataxia-telangiectasia mutated and DNA-dependent protein kinase catalytic subunit. Overall, these results suggest that the p38/NPM/PP2A complex acts as a dynamic sensor, allowing endothelial cells to react rapidly to acute oxidative stress.-Guillonneau, M., Paris, F., Dutoit, S., Estephan, H., Bénéteau, E., Huot, J., Corre, I. Oxidative stress disassembles the p38/NPM/PP2A complex, which leads to modulation of nucleophosmin-mediated signaling to DNA damage response.
Asunto(s)
Células Endoteliales/fisiología , Proteínas Nucleares/metabolismo , Estrés Oxidativo/fisiología , Proteína Fosfatasa 2/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Transporte Activo de Núcleo Celular/fisiología , Daño del ADN , Regulación Enzimológica de la Expresión Génica , Humanos , Proteínas Nucleares/genética , Nucleofosmina , Fosforilación , Proteína Fosfatasa 2/genética , Transducción de Señal , Proteínas Quinasas p38 Activadas por Mitógenos/genéticaRESUMEN
The expression and activity of DNA-dependent protein kinase (DNA-PK) is related to DNA repair status in the response of cells to exogenous and endogenous factors. Recent studies indicate that Epidermal Growth Factor Receptor (EGFR) is involved in modulating DNA-PK. It has been shown that a compound 4-nitro-7-[(1-oxidopyridin-2-yl)sulfanyl]-2,1,3-benzoxadiazole (NSC), bearing a nitro-benzoxadiazole (NBD) scaffold, enhances tyrosine phosphorylation of EGFR and triggers downstream signaling pathways. Here, we studied the behavior of DNA-PK and other DNA repair proteins in prostate cancer cells exposed to compound NSC. We showed that both the expression and activity of DNA-PKcs (catalytic subunit of DNA-PK) rapidly decreased upon exposure of cells to the compound. The decline in DNA-PKcs was associated with enhanced protein ubiquitination, indicating the activation of cellular proteasome. However, pretreatment of cells with thioglycerol abolished the action of compound NSC and restored the level of DNA-PKcs. Moreover, the decreased level of DNA-PKcs was associated with the production of intracellular hydrogen peroxide by stable dimeric forms of Cu/Zn SOD1 induced by NSC. Our findings indicate that reactive oxygen species and electrophilic intermediates, generated and accumulated during the redox transformation of NBD compounds, are primarily responsible for the rapid modulation of DNA-PKcs functions in cancer cells.
Asunto(s)
Proteína Quinasa Activada por ADN/metabolismo , Regulación hacia Abajo/efectos de los fármacos , Oxadiazoles/farmacología , Neoplasias de la Próstata/metabolismo , Línea Celular Tumoral , Reparación del ADN/efectos de los fármacos , Proteína Quinasa Activada por ADN/genética , Glicerol/análogos & derivados , Glicerol/farmacología , Humanos , Peróxido de Hidrógeno/metabolismo , Masculino , Superóxido Dismutasa/metabolismo , UbiquitinaciónRESUMEN
We have recently shown that the in vitro differentiation of human mesenchymal stem cells (hMSCs) was accompanied by an increased sensitivity toward apoptosis; however, the mechanism responsible for this shift is not known. Here, we show that the repair of DNA double-strand breaks (DSBs) was more rapid in undifferentiated hMSCs than in differentiated osteoblasts by quantification of the disappearance of γ-H2AX foci in the nuclei after γ-irradiation-induced DNA damage. In addition, there was a marked and prolonged increase in the level of nuclear Ku70 and an increased phosphorylation of DNA-PKcs. This was accompanied by an augmentation in the phosphorylation of ATM in hMSCs post-irradiation suggesting the nonhomologous end joining repair mechanism. However, when hMSCs were induced to differentiate along the osteogenic or adipogenic pathways; irradiation of these cells caused an expeditious and robust cell death, which was primarily apoptotic. This was in sharp contrast to undifferentiated hMSCs, which were highly resistant to irradiation and/or temozolomide-induced DSBs. In addition, we observed a 95% recovery from DSB in these cells. Our results suggest that apoptosis and DNA repair are major safeguard mechanisms in the control of hMSCs differentiation after DNA damage.
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Roturas del ADN de Doble Cadena , Daño del ADN/genética , Reparación del ADN/genética , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/metabolismo , Adulto , Apoptosis/genética , Apoptosis/efectos de la radiación , Western Blotting , Diferenciación Celular/genética , Diferenciación Celular/efectos de la radiación , Células Cultivadas , Femenino , Rayos gamma , Humanos , Inmunohistoquímica , Masculino , Células Madre Mesenquimatosas/efectos de la radiación , Persona de Mediana EdadRESUMEN
In recent years, there has been a surge in the development of methods for cell segmentation and tracking, with initiatives like the Cell Tracking Challenge driving progress in the field. Most studies focus on regular cell population videos in which cells are segmented and followed, and parental relationships annotated. However, DNA damage induced by genotoxic drugs or ionizing radiation produces additional abnormal events since it leads to behaviors like abnormal cell divisions (resulting in a number of daughters different from two) and cell death. With this in mind, we developed an automatic mitosis classifier to categorize small mitosis image sequences centered around one cell as "Normal" or "Abnormal." These mitosis sequences were extracted from videos of cell populations exposed to varying levels of radiation that affect the cell cycle's development. We explored several deep-learning architectures and found that a network with a ResNet50 backbone and including a Long Short-Term Memory (LSTM) layer produced the best results (mean F1-score: 0.93 ± 0.06). In the future, we plan to integrate this classifier with cell segmentation and tracking to build phylogenetic trees of the population after genomic stress.
Asunto(s)
División Celular , Aprendizaje Profundo , Mitosis , Humanos , Procesamiento de Imagen Asistido por Computador/métodos , Rastreo Celular/métodosRESUMEN
BACKGROUND: Glioblastoma (GBM) is a highly aggressive tumor with unmet therapeutic needs, which can be explained by extensive intra-tumoral heterogeneity and plasticity. In this study, we aimed to investigate the specific metabolic features of Glioblastoma stem cells (GSC), a rare tumor subpopulation involved in tumor growth and therapy resistance. METHODS: We conducted comprehensive analyses of primary patient-derived GBM cultures and GSC-enriched cultures of human GBM cell lines using state-of-the-art molecular, metabolic, and phenotypic studies. RESULTS: We showed that GSC-enriched cultures display distinct glycolytic profiles compared with differentiated tumor cells. Further analysis revealed that GSC relies on pyruvate carboxylase (PC) activity for survival and self-renewal capacity. Interestingly, inhibition of PC led to GSC death, particularly when the glutamine pool was low, and increased differentiation. Finally, while GSC displayed resistance to the chemotherapy drug etoposide, genetic or pharmacological inhibition of PC restored etoposide sensitivity in GSC, both in vitro and in orthotopic murine models. CONCLUSIONS: Our findings demonstrate the critical role of PC in GSC metabolism, survival, and escape to etoposide. They also highlight PC as a therapeutic target to overcome therapy resistance in GBM.
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Neoplasias Encefálicas , Glioblastoma , Células Madre Neoplásicas , Piruvato Carboxilasa , Glioblastoma/metabolismo , Glioblastoma/patología , Glioblastoma/tratamiento farmacológico , Humanos , Piruvato Carboxilasa/metabolismo , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Células Madre Neoplásicas/efectos de los fármacos , Animales , Ratones , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/tratamiento farmacológico , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto , Resistencia a Antineoplásicos , Etopósido/farmacología , Proliferación Celular , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacosRESUMEN
Tumor areas can now be very precisely delimited thanks to technical progress in imaging and ballistics. This has also led to the development of novel radiotherapy protocols, delivering higher doses of ionizing radiation directly to cancer cells. Despite this, radiation toxicity in healthy tissue remains a major issue, particularly with dose-escalation in these new protocols. Acute and late tissue damage following irradiation have both been linked to the endothelium irrigating normal tissues. The molecular mechanisms involved in the endothelial response to high doses of radiation are associated with signaling from the plasma membrane, mainly via the acid sphingomyelinase/ceramide pathway. This review describes this signaling pathway and discusses the relevance of targeting endothelial signaling to protect healthy tissues from the deleterious effects of high doses of radiation.
Asunto(s)
Membranas/efectos de la radiación , Neoplasias/radioterapia , Tolerancia a Radiación/genética , Transducción de Señal/genética , Apoptosis/efectos de la radiación , Células Endoteliales/patología , Humanos , Neoplasias/patología , Dosis de Radiación , Radiación IonizanteRESUMEN
Cancer treatment protocols depend on tumor type, localization, grade, and patient. Despite aggressive treatments, median survival of patients with Glioblastoma (GBM), the most common primary brain tumor in adults, does not exceed 18 months, and all patients eventually relapse. Thus, novel therapeutic approaches are urgently needed. Radiotherapy (RT) induces a multitude of alterations within the tumor ecosystem, ultimately modifying the degree of tumor immunogenicity at GBM relapse. The present manuscript reviews the diverse effects of RT radiotherapy on tumors, with a special focus on its immunomodulatory impact to finally discuss how RT could be exploited in GBM treatment through immunotherapy targeting. Indeed, while further experimental and clinical studies are definitively required to successfully translate preclinical results in clinical trials, current studies highlight the therapeutic potential of immunotherapy to uncover novel avenues to fight GBM.
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Neoplasias Encefálicas , Glioblastoma , Traumatismos por Radiación , Adulto , Humanos , Glioblastoma/patología , Neoplasias Encefálicas/patología , Ecosistema , Recurrencia Local de Neoplasia , InmunoterapiaRESUMEN
Purpose: Radiation-induced lung injury (RILI) is strongly associated with various clinical conditions and dosimetric parameters. Former studies have led to reducing radiotherapy (RT) doses to the lung and have favored the discontinuation of tamoxifen during RT. However, the monocentric design and variability of dosimetric parameters chosen have limited further improvement. The aim of our study was to assess the incidence of RILI in current practice and to determine clinical and dosimetric risk factors associated with RILI occurrence. Material and methods: Data from 3 out of the 10 top recruiting centers in CANTO-RT, a subset of the CANTO prospective longitudinal cohort (NCT01993498), were retrospectively analyzed for RILI occurrence. This cohort, which recruited invasive cT0-3 cN0-3 M0 breast cancer patients from 2012 to 2018, prospectively recorded the occurrence of adverse events by questionnaires and medical visits at the end of, and up to 60 months after treatment. RILI adverse events were defined in all patients by the association of clinical symptoms and compatible medical imaging. Results: RILI was found in 38/1565 (2.4%) patients. Grade II RILI represented 15/38 events (39%) and grade III or IV 2/38 events (6%). There were no grade V events. The most frequently used technique for treatment was 3D conformational RT (96%). In univariable analyses, we confirmed the association of RILI occurrence with pulmonary medical history, absence of cardiovascular disease medical history, high pT and pN, chemotherapy use, nodal RT. All dosimetric parameters were highly correlated and had close predictive value. In the multivariable analysis adjusted for chemotherapy use and nodal involvement, pulmonary medical history (OR=3.05, p<0.01) and high V30 Gy (OR=1.06, p=0.04) remained statistically significant risk factors for RILI occurrence. V30 Gy >15% was significantly associated with RILI occurrence in a multivariable analysis (OR=3.07, p=0.03). Conclusion: Our study confirms the pulmonary safety of breast 3D RT in CANTO-RT. Further analyses with modern radiation therapy techniques such as IMRT are needed. Our results argue in favor of a dose constraint to the ipsilateral lung using V30 Gy not exceeding 15%, especially in patients presenting pulmonary medical history. Pulmonary disease records should be taken into account for RT planning.
RESUMEN
Although stem cells succumbing to reproductive death are assumed to be the single relevant targets in radiation tissue damage, recent studies showed intestinal stem cell damage is conditionally linked to crypt endothelial apoptosis, defining a two-target model. Here we report that when mouse intestines were protected against microvascular apoptosis, radiation switched as the dose escalated to a previously unrecognized crypt stem cell target, activating ceramide synthase-mediated apoptosis to initiate intestinal damage. Whereas ataxia telangiectasia-mutated (ATM) kinase normally represses ceramide synthase, its derepression in Atm(-/-) mice increased crypt stem cell radiosensitivity 3.7-fold without sensitizing the microvascular response. Discovery of this intestinal radiosensitivity mechanism allowed design of an antisense Atm oligonucleotide treatment which phenocopied the Atm(-/-) mouse, reordering ceramide synthase-mediated stem cell death to become the first-line gastrointestinal response of wild-type littermates. These experiments indicate that tissues operate multiple potential targets activated consecutively according to their inherent radiosensitivities that may be reordered therapeutically to control radiation tissue responses.
Asunto(s)
Apoptosis/efectos de la radiación , Proteínas de Ciclo Celular/metabolismo , Proteínas de Unión al ADN/metabolismo , Neoplasias/radioterapia , Oxidorreductasas/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Células Madre/efectos de la radiación , Ensayo de Tumor de Célula Madre , Proteínas Supresoras de Tumor/metabolismo , Irradiación Corporal Total , Animales , Proteínas de la Ataxia Telangiectasia Mutada , Proteínas de Ciclo Celular/genética , Ceramidas/metabolismo , Proteínas de Unión al ADN/genética , Relación Dosis-Respuesta en la Radiación , Células Endoteliales/metabolismo , Activación Enzimática/efectos de la radiación , Técnicas Histológicas , Yeyuno/citología , Yeyuno/metabolismo , Yeyuno/efectos de la radiación , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Oligonucleótidos , Proteínas Serina-Treonina Quinasas/genética , Tolerancia a Radiación/genética , Proteínas Supresoras de Tumor/genéticaRESUMEN
Brain tumors actively reprogram their cellular metabolism to survive and proliferate, thus offering potential therapeutic opportunities. Over the past decade, extensive research has been done on mutant IDH enzymes as markers of good prognosis in glioblastoma, a highly aggressive brain tumor in adults with dismal prognosis. Yet, 95% of glioblastoma are IDH wild-type. Here, we review current knowledge about IDH wild-type enzymes and their putative role in mechanisms driving tumor progression. After a brief overview on tumor metabolic adaptation, we present the diverse metabolic function of IDH enzymes and their roles in glioblastoma initiation, progression and response to treatments. Finally, we will discuss wild-type IDH targeting in primary glioblastoma.
Asunto(s)
GlioblastomaRESUMEN
BACKGROUND: Fatigue is a common and disabling symptom after breast cancer (BC) treatment, significantly impacting patients' quality of life. We aimed to assess the impact of radiation therapy (RT) modalities on fatigue one year after treatment among patients with early-stage BC. METHODS: We used CANTO-RT, a subcohort of CANcer TOxicity (CANTO; NCT01993498), a multicentric nationwide prospective cohort of stages I-III BC treated from 2012 to 2017. Our primary outcome was severe global fatigue 1 year after RT completion (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 score ≥40/100). The secondary outcomes included severe physical, emotional and cognitive fatigue (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-FA12). RT-related variables were used as independent variables. Multivariable logistic regression models assessed associations between RT-related variables and fatigue. RESULTS: The final analytic cohort included 3295 patients. The prevalence of severe global fatigue 1 year after treatment was 33.3%. Internal mammary chain RT (adjusted odds ratio [OR] 1.48 [95% confidence interval [CI] 1.03-2.13; p = 0.0355]) and normofractionated RT (adjusted OR 1.88 [95% CI 1.06-3.31; p = 0.0298]) were associated with increased odds of severe global fatigue. In addition, there was a significant association between normofractionated RT (adjusted OR 1.849 [95% CI 1.04-3.3; p = 0.0354]) and an increased likelihood of severe physical fatigue. CONCLUSION: We found a significant association between internal mammary chain RT (versus No), normofractionated RT (versus hypofractionated RT) and increased likelihood of persistent severe global fatigue. Our data add to the current understanding of treatment-related factors affecting fatigue after BC and could lead to personalised interventions to improve the prevention and management of this disabling symptom.
Asunto(s)
Neoplasias de la Mama , Supervivientes de Cáncer , Humanos , Femenino , Neoplasias de la Mama/terapia , Calidad de Vida , Estudios Prospectivos , MamaRESUMEN
Endothelial cells of the microvasculature are major target of ionizing radiation, responsible of the radiation-induced vascular early dysfunctions. Molecular signaling pathways involved in endothelial responses to ionizing radiation, despite being increasingly investigated, still need precise characterization. Small GTPase RhoA and its effector ROCK are crucial signaling molecules involved in many endothelial cellular functions. Recent studies identified implication of RhoA/ROCK in radiation-induced increase in endothelial permeability but other endothelial functions altered by radiation might also require RhoA proteins. Human microvascular endothelial cells HMEC-1, either treated with Y-27632 (inhibitor of ROCK) or invalidated for RhoA by RNA interference were exposed to 15Gy. We showed a rapid radiation-induced activation of RhoA, leading to a deep reorganisation of actin cytoskeleton with rapid formation of stress fibers. Endothelial early apoptosis induced by ionizing radiation was not affected by Y-27632 pre-treatment or RhoA depletion. Endothelial adhesion to fibronectin and formation of focal adhesions increased in response to radiation in a RhoA/ROCK-dependent manner. Consistent with its pro-adhesive role, ionizing radiation also decreased endothelial cells migration and RhoA was required for this inhibition. These results highlight the role of RhoA GTPase in ionizing radiation-induced deregulation of essential endothelial functions linked to actin cytoskeleton.
Asunto(s)
Movimiento Celular/efectos de la radiación , Endotelio Vascular/efectos de la radiación , Proteína de Unión al GTP rhoA/metabolismo , Actinas/metabolismo , Amidas/farmacología , Apoptosis/efectos de la radiación , Adhesión Celular/efectos de la radiación , Línea Celular , Citoesqueleto/metabolismo , Endotelio Vascular/enzimología , Endotelio Vascular/fisiología , Fibronectinas/metabolismo , Humanos , Piridinas/farmacología , Quinasas Asociadas a rho/antagonistas & inhibidores , Quinasas Asociadas a rho/genética , Quinasas Asociadas a rho/metabolismo , Proteína de Unión al GTP rhoA/antagonistas & inhibidores , Proteína de Unión al GTP rhoA/genéticaRESUMEN
OBJECTIVE: Purposes of this work were i) to develop an in silico model of tumor response to radiotherapy, ii) to perform an exhaustive sensitivity analysis in order to iii) propose a simplified version and iv) to predict biochemical recurrence with both the comprehensive and the reduced model. METHODS: A multiscale computational model of tumor response to radiotherapy was developed. It integrated the following radiobiological mechanisms: oxygenation, including hypoxic death; division of tumor cells; VEGF diffusion driving angiogenesis; division of healthy cells and oxygen-dependent response to irradiation, considering, cycle arrest and mitotic catastrophe. A thorough sensitivity analysis using the Morris screening method was performed on 21 prostate computational tissues. Tumor control probability (TCP) curves of the comprehensive model and 15 reduced versions were compared. Logistic regression was performed to predict biochemical recurrence after radiotherapy on 76 localized prostate cancer patients using an output of the comprehensive and the reduced models. RESULTS: No significant difference was found between the TCP curves of the comprehensive and a simplified version which only considered oxygenation, division of tumor cells and their response to irradiation. Biochemical recurrence predictions using the comprehensive and the reduced models improved those made from pre-treatment imaging parameters (AUC = 0.81 ± 0.02 and 0.82 ± 0.02 vs. 0.75 ± 0.03, respectively). CONCLUSION: A reduced model of tumor response to radiotherapy able to predict biochemical recurrence in prostate cancer was obtained. SIGNIFICANCE: This reduced model may be used in the future to optimize personalized fractionation schedules.
Asunto(s)
Neoplasias de la Próstata , Simulación por Computador , Humanos , Masculino , Neoplasias de la Próstata/radioterapiaRESUMEN
Cellular senescence is an essential tumor suppressive mechanism that prevents the propagation of oncogenically activated, genetically unstable, and/or damaged cells. Induction of tumor cell senescence is also one of the underlying mechanisms by which cancer therapies exert antitumor activity. However, an increasing body of evidence from preclinical studies demonstrates that radiation and chemotherapy cause accumulation of senescent cells (SnCs) both in tumor and normal tissue. SnCs in tumors can, paradoxically, promote tumor relapse, metastasis, and resistance to therapy, in part, through expression of the senescence-associated secretory phenotype. In addition, SnCs in normal tissue can contribute to certain radiation- and chemotherapy-induced side effects. Because of its multiple roles, cellular senescence could serve as an important target in the fight against cancer. This commentary provides a summary of the discussion at the National Cancer Institute Workshop on Radiation, Senescence, and Cancer (August 10-11, 2020, National Cancer Institute, Bethesda, MD) regarding the current status of senescence research, heterogeneity of therapy-induced senescence, current status of senotherapeutics and molecular biomarkers, a concept of "one-two punch" cancer therapy (consisting of therapeutics to induce tumor cell senescence followed by selective clearance of SnCs), and its integration with personalized adaptive tumor therapy. It also identifies key knowledge gaps and outlines future directions in this emerging field to improve treatment outcomes for cancer patients.