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Application of physical forces, ranging from ultrasound to electric fields, is recommended in various clinical practice guidelines, including those for treating cancers and bone fractures. However, the mechanistic details of such treatments are often inadequately understood, primarily due to the absence of comprehensive study models. In this study, we demonstrate that an alternating magnetic field (AMF) inherently possesses a direct anti-cancer effect by enhancing oxidative phosphorylation (OXPHOS) and thereby inducing metabolic reprogramming. We observed that the proliferation of human glioblastoma multiforme (GBM) cells (U87 and LN229) was inhibited upon exposure to AMF within a specific narrow frequency range, including around 227 kHz. In contrast, this exposure did not affect normal human astrocytes (NHA). Additionally, in mouse models implanted with human GBM cells in the brain, daily exposure to AMF for 30 min over 21 days significantly suppressed tumor growth and prolonged overall survival. This effect was associated with heightened reactive oxygen species (ROS) production and increased manganese superoxide dismutase (MnSOD) expression. The anti-cancer efficacy of AMF was diminished by either a mitochondrial complex IV inhibitor or a ROS scavenger. Along with these observations, there was a decrease in the extracellular acidification rate (ECAR) and an increase in the oxygen consumption rate (OCR). This suggests that AMF-induced metabolic reprogramming occurs in GBM cells but not in normal cells. Our results suggest that AMF exposure may offer a straightforward strategy to inhibit cancer cell growth by leveraging oxidative stress through metabolic reprogramming.
Assuntos
Neoplasias Encefálicas , Proliferação de Células , Glioblastoma , Magnetoterapia , Reprogramação Metabólica , Fosforilação Oxidativa , Espécies Reativas de Oxigênio , Animais , Humanos , Camundongos , Astrócitos/metabolismo , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Glioblastoma/metabolismo , Glioblastoma/patologia , Magnetoterapia/métodos , Campos Magnéticos , Reprogramação Metabólica/efeitos da radiação , Mitocôndrias/metabolismo , Consumo de Oxigênio , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
We report a case of delayed bleeding after video-assisted thoracic surgery (VATS) that was successfully treated with transcatheter arterial embolization. An 81-year-old woman underwent a pleural biopsy via VATS for pleural dissemination of lung cancer. The postoperative course was good, but 8 days later she was hospitalized for swelling in the right axilla and was admitted to our hospital with a diagnosis of delayed postoperative hemorrhage. Gauze compression was performed, and the patient was discharged without exacerbation of hematoma. However, 4 days later, she was hospitalized for rapidly worsening swelling and pain. Chest computed tomography at the time of rebleeding showed an increase in the hematoma and extravasation in the peripheral right lateral thoracic artery. The patient was immediately treated with emergency angiography, and coil embolization was performed. After this treatment, the patient has done well and there has been no subsequent recurrence of bleeding.
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BACKGROUND: The increasing prevalence of heated tobacco products (HTPs) has heightened concerns regarding their potential health risks. Previous studies have demonstrated the toxicity of cigarette smoke extract (CSE) from traditional tobacco's mainstream smoke, even after the removal of nicotine and tar. Our study aimed to investigate the cytotoxicity of CSE derived from HTPs and traditional tobacco, with a particular focus on the role of reactive oxygen species (ROS) and intracellular Ca2+. METHODS: A human oral squamous cell carcinoma (OSCC) cell line, HSC-3 was utilized. To prepare CSE, aerosols from HTPs (IQOS) and traditional tobacco products (1R6F reference cigarette) were collected into cell culture media. A cell viability assay, apoptosis assay, western blotting, and Fluo-4 assay were conducted. Changes in ROS levels were measured using electron spin resonance spectroscopy and the high-sensitivity 2',7'-dichlorofluorescein diacetate assay. We performed a knockdown of calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) by shRNA lentivirus in OSCC cells. RESULTS: CSE from both HTPs and traditional tobacco exhibited cytotoxic effects in OSCC cells. Exposure to CSE from both sources led to an increase in intracellular Ca2+ concentration and induced p38 phosphorylation. Additionally, these extracts prompted cell apoptosis and heightened ROS levels. N-acetylcysteine (NAC) mitigated the cytotoxic effects and p38 phosphorylation. Furthermore, the knockdown of CaMKK2 in HSC-3 cells reduced cytotoxicity, ROS production, and p38 phosphorylation in response to CSE. CONCLUSION: Our findings suggest that the CSE from both HTPs and traditional tobacco induce cytotoxicity. This toxicity is mediated by ROS, which are regulated through Ca2+ signaling and CaMKK2 pathways.
Assuntos
Quinase da Proteína Quinase Dependente de Cálcio-Calmodulina , Carcinoma de Células Escamosas , Neoplasias Bucais , Espécies Reativas de Oxigênio , Fumaça , Produtos do Tabaco , Humanos , Espécies Reativas de Oxigênio/metabolismo , Neoplasias Bucais/metabolismo , Neoplasias Bucais/patologia , Linhagem Celular Tumoral , Fumaça/efeitos adversos , Carcinoma de Células Escamosas/metabolismo , Quinase da Proteína Quinase Dependente de Cálcio-Calmodulina/metabolismo , Produtos do Tabaco/efeitos adversos , Apoptose/efeitos dos fármacos , Nicotiana/química , Cálcio/metabolismo , Sobrevivência Celular/efeitos dos fármacosRESUMO
Lymph node metastasis, primarily caused by the migration of oral squamous cell carcinoma (OSCC) cells, stands as a crucial prognostic marker. We have previously demonstrated that EP4, a subtype of the prostaglandin E2 (PGE2) receptor, orchestrates OSCC cell migration via Ca2+ signaling. The exact mechanisms by which EP4 influences cell migration through Ca2+ signaling, however, is unclear. Our study aims to clarify how EP4 controls OSCC cell migration through this pathway. We find that activating EP4 with an agonist (ONO-AE1-473) increased intracellular Ca2+ levels and the migration of human oral cancer cells (HSC-3), but not human gingival fibroblasts (HGnF). Further RNA sequencing linked EP4 to calmodulin-like protein 6 (CALML6), whose role remains undefined in OSCC. Through protein-protein interaction network analysis, a strong connection is identified between CALML6 and calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2), with EP4 activation also boosting mitochondrial function. Overexpressing EP4 in HSC-3 cells increases experimental lung metastasis in mice, whereas inhibiting CaMKK2 with STO-609 markedly lowers these metastases. This positions CaMKK2 as a potential new target for treating OSCC metastasis. Our findings highlight CALML6 as a pivotal regulator in EP4-driven mitochondrial respiration, affecting cell migration and metastasis via the CaMKK2 pathway.
Assuntos
Proteínas de Ligação ao Cálcio , Carcinoma de Células Escamosas , Movimento Celular , Mitocôndrias , Neoplasias Bucais , Receptores de Prostaglandina E Subtipo EP4 , Animais , Humanos , Camundongos , Quinase da Proteína Quinase Dependente de Cálcio-Calmodulina/metabolismo , Quinase da Proteína Quinase Dependente de Cálcio-Calmodulina/genética , Calmodulina/metabolismo , Calmodulina/genética , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/genética , Linhagem Celular Tumoral , Mitocôndrias/metabolismo , Neoplasias Bucais/patologia , Neoplasias Bucais/metabolismo , Neoplasias Bucais/genética , Receptores de Prostaglandina E Subtipo EP4/metabolismo , Receptores de Prostaglandina E Subtipo EP4/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/metabolismoRESUMO
OBJECTIVES: Metachronous lung cancer arising after resection of non-small-cell lung cancer is either a second primary lung cancer (SPLC) or intrapulmonary metastasis (IPM) of the initial lung cancer; however, differential diagnosis is difficult. We evaluated the surgical outcomes of metachronous lung cancer in a combined population of patients with SPLC and IPM. METHODS: A retrospective study of 3534 consecutive patients with resected non-small-cell lung cancer between 1992 and 2016 was conducted at 4 institutions. RESULTS: A total of 105 patients (66 males; median age, 70 years) who underwent a second pulmonary resection for metachronous lung cancer were included. Most patients (81%) underwent sublobar resection, and there was no 30-day mortality. All metachronous lung cancers were cN0, 5 were pN1-2. The postoperative comprehensive histologic assessment revealed SPLC (n = 77) and IPM (n = 28). The 5-year overall survival rate after the second resection was 70.6% (median follow-up: 69.7 months). A multivariable analysis showed that age >70 years at the second resection (P = 0.013), male sex (P = 0.003), lymph node involvement in metachronous cancer (P < 0.001), pathological invasive size of metachronous cancer >15 mm (P < 0.001) and overlapping squamous cell carcinoma histology of the initial and metachronous cancers (P = 0.003) were significant prognostic factors for poor survival after the second resection, whereas histological IPM was not (P = 0.065). CONCLUSIONS: Surgery for cN0 metachronous lung cancer is safe and shows good outcomes. There were no statistically significant differences in the SPLC and IPM results. Caution should be exercised when operating on patients with overlapping squamous cell carcinoma.
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Myxoid pleomorphic liposarcoma (MPLS) is an extremely rare tumor listed in the fifth edition of the WHO classification (2020). Histologically, it mainly comprises a mixture of myxoid and pleomorphic liposarcoma-like components. Genetically, it lacks FUS/EWSR1::DDIT3 fusion and MDM2 amplification. Herein, we describe an example of MPLS with rhabdoid cells in a 10-year-old girl who presented with a growing mass in the right inguinal region. The specimen from the wide excision measured 68â mm × 55â mm × 43â mm, and a circumscribed and lobulated mass was observed in the subcutaneous tissue. Histologically, oval-to-short, spindle-shaped, proliferating tumor cells with moderate nuclear atypia and mesh-like capillaries against a myxoid background were noted. Adipocytes were observed focally, while rhabdoid cells were observed multifocally. Immunohistochemically, the tumor showed inconsistent reactivity for desmin but was negative for MYOD1, myogenin, MDM2, and CDK4. Fluorescence in situ hybridization revealed no DDIT3 rearrangement. Despite adjuvant chemotherapy, the tumor metastasized to the thoracic cavity 24 months after excision. The metastatic lesions contained abundant lipoblasts rather than rhabdoid cells, and we concluded this tumor was a MPLS. The presence of rhabdoid cells could be a diagnostic pitfall, and recognizing such a variation in histology would help improve diagnostic accuracy.