RESUMO
Aberrant activation of the hypoxia-inducible transcription factor HIF-1 and dysfunction of the tumor suppressor p53 have been reported to induce malignant phenotypes and therapy resistance of cancers. However, their mechanistic and functional relationship remains largely unknown. Here, we reveal a mechanism by which p53 deficiency triggers the activation of HIF-1-dependent hypoxia signaling and identify zinc finger and BTB domain-containing protein 2 (ZBTB2) as an important mediator. ZBTB2 forms homodimers via its N-terminus region and increases the transactivation activity of HIF-1 only when functional p53 is absent. The ZBTB2 homodimer facilitates invasion, distant metastasis, and growth of p53-deficient, but not p53-proficient, cancers. The intratumoral expression levels of ZBTB2 are associated with poor prognosis in lung cancer patients. ZBTB2 N-terminus-mimetic polypeptides competitively inhibit ZBTB2 homodimerization and significantly suppress the ZBTB2-HIF-1 axis, leading to antitumor effects. Our data reveal an important link between aberrant activation of hypoxia signaling and loss of a tumor suppressor and provide a rationale for targeting a key mediator, ZBTB2, to suppress cancer aggressiveness.
Assuntos
Neoplasias , Fatores de Transcrição , Humanos , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Hipóxia/genética , Ligação Proteica , Transdução de Sinais , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Hipóxia Celular/genética , Proteínas Repressoras/genéticaRESUMO
Epithelial-mesenchymal transition (EMT) promotes primary tumor progression toward a metastatic state. The role of tumor-associated macrophages (TAMs) in inducing EMT in lung squamous cell carcinoma (LUSC) remains unclear. We aimed to clarify the significance of TAMs in relation to EMT in LUSC. We collected 221 LUSC specimens from patients who had undergone surgery. Immunohistochemistry was performed to evaluate M1-like and M2-like TAM distribution and EMT by E-cadherin and vimentin staining. Human LUSC cell lines (H226 and EBC-1) and a human monocyte cell line (THP-1) were used for in vitro experiments. M2-like polarization of TAMs and EMT marker expression in LUSC cells were evaluated by western blotting. The biological behavior of LUSC cells was evaluated by migration, invasion, and cell proliferation assays. Immunohistochemical analysis showed that 166 (75.1%) tumors were E-cadherin-positive and 44 (19.9%) were vimentin-positive. M2-like TAM density in the tumor stroma was significantly associated with vimentin positivity and worse overall survival. Western blotting demonstrated higher levels of CD163, CD206, vascular endothelial growth factor, and transforming growth factor beta 1 (TGF-ß1) in TAMs versus unstimulated macrophages. Furthermore, increased TGF-ß1 secretion from TAMs was confirmed by ELISA. TAM-co-cultured H226 and EBC-1 cells exhibited EMT (decreased E-cadherin, increased vimentin). Regarding EMT-activating transcriptional factors, phosphorylated Smad3 and ZEB-family proteins were higher in TAM-co-cultured LUSC cells than in parental cells. TAM-co-cultured H226 and EBC-1 cells demonstrated enhanced migration and invasion capabilities and improved proliferation. Overall, the present study suggests that TAMs can induce EMT with increased metastatic potential and tumor cell proliferation in LUSC.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Carcinoma de Células Escamosas , Neoplasias Pulmonares , Humanos , Fator de Crescimento Transformador beta1 , Vimentina/metabolismo , Fator de Crescimento Transformador beta , Genes Homeobox , Macrófagos Associados a Tumor/metabolismo , Fator A de Crescimento do Endotélio Vascular , Linhagem Celular Tumoral , Carcinoma de Células Escamosas/patologia , Proliferação de Células , Transição Epitelial-Mesenquimal , Caderinas/metabolismo , Neoplasias Pulmonares/metabolismo , Dedos de Zinco , Pulmão/patologia , Movimento CelularRESUMO
A 76-year-old man was referred to our hospital because of an abnormal shadow on chest X-ray. His physical exams and laboratory data were not notable. Chest computed tomography (CT) showed 2 nodular lesions with clear margin in anterior mediastinum. The nodule at the left inferior pole of the thymus was 9 cm in diameter, and another one at the right inferior pole was 3.5 cm in diameter. We performed thymo-thymectomy by median sternotomy. Histological study revealed that the left tumor was type B2 thymoma and the other one was type A thymoma. Both were completely encapsulated without invasion, which means stage â by Masaoka's classification. The patient has showed no evidence of recurrence for 11 years following the surgery. This is the 1st case in Japan that reported synchronous multicentric thymoma with apparently different histology of type A and B2.
Assuntos
Timoma , Neoplasias do Timo , Idoso , Humanos , Japão , Masculino , Recidiva Local de Neoplasia , TimectomiaRESUMO
OBJECTIVE: A precise preoperative diagnosis of in situ or minimally invasive carcinoma may identify patients who can be treated by limited resection. Although some clinical trials of limited resection for lung cancer have started, it will take a long time before the results will be published. We have already reported a large-scale study of limited resection. We herein report the data for a subclass analysis according to differences in pathology. METHODS: Data from multiple institutions were collected on 1710 patients who had undergone limited resection (segmentectomy or wedge resection) for cT1N0M0 non-small cell carcinoma. The disease-free survival (DFS) and recurrence-free proportion (RFP) were analyzed. Small cell carcinomas and carcinoid tumors were excluded from this analysis. Adenocarcinomas were sub-classified into four groups using two factors, the ratio of consolidation to the tumor diameter (C/T) and the tumor diameter alone. RESULTS: The median patient age was 64 (20-75) years old. The mean maximal diameter of the tumors was 1.5 ± 0.5 cm. The DFS and RFP at 5 years based on the pathology were 92.2 and 94.7 % in adenocarcinoma (n = 1575), 76.3 and 82.4 % in squamous cell carcinoma (SqCC) (n = 100), and 73.6 and 75.9 % in patients with other tumors (n = 35). The prognosis of adenocarcinoma in both groups A (C/T ≤0.25 and tumor diameter ≤2.0 cm) and B (C/T ≤0.25 and tumor diameter >2.0 cm) was good. In SqCC, only segmentectomy was a favorable prognostic factor. In the groups with other pathologies, large cell carcinomas were worse in prognosis (the both DFS and RFP: 46.3 %). CONCLUSION: Knowing the pathological diagnosis is important to determine the indications for limited resection. Measurement of the tumor diameter and C/T was useful to determine the indications for limited resection for adenocarcinoma. Limited resection for adenocarcinomas is similar with a larger resection, while the technique should be performed with caution in squamous cell carcinoma and other pathologies.
Assuntos
Carcinoma in Situ/cirurgia , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Neoplasias Pulmonares/cirurgia , Pneumonectomia/métodos , Adulto , Idoso , Carcinoma in Situ/patologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: The vascular division sequence in video-assisted thoracic surgery (VATS) lung resection is usually determined by the handling difficulty due to the limited surgical view through the scope. However, upfront pulmonary vein division is theoretically desirable to avoid tumor cells spreading by surgical manipulation. Epithelial-mesenchymal transition (EMT) is associated with poor prognosis and an increased number of circulating tumor cells. The purpose of this study is to evaluate the effect of vascular division sequence and EMT on postoperative recurrence. METHODS: We retrospectively investigated tissue microarrays of 282 lung adenocarcinomas surgically resected between 2001 and 2007. We excluded the cases with segmentectomy, wedge resection, dissemination, insufficient material for staining, or lack of medical records. The effect of vascular division sequence and clinicopathologic factors on recurrence was evaluated in 195 cases. RESULTS: The upfront pulmonary vein division (V-first) was performed in 60 patients, and the upfront pulmonary artery division (A-first) was performed in 135 patients. The recurrence was observed in 67 patients (13 in V-first and 54 in A-first). Epithelial-mesenchymal transition activation was observed in 104 patients. Multivariable analysis with 195 patients revealed that lymph node metastasis and pleural invasion were risk factors for the recurrence. The stratified multivariable analysis showed that vascular division sequence (A-first) was a risk factor only in the EMT-negative group (91 patients). In the EMT-negative subset, the 5-year relapse-free survival rate was significantly lower in the A-first group than the V-first group (72.6% vs. 92.2%, p = 0.0136). CONCLUSIONS: The upfront pulmonary artery division might be a risk factor in patients without EMT activation.
Assuntos
Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Humanos , Estudos Retrospectivos , Prognóstico , Recidiva Local de Neoplasia , Neoplasias Pulmonares/patologia , Transição Epitelial-Mesenquimal/fisiologiaRESUMO
OBJECTIVES: Preoperative intravenous epoprostenol therapy can cause thrombocytopaenia, which may increase the risk of perioperative bleeding during lung transplantation. This study aimed to determine whether lung transplantation can be safely performed in patients with epoprostenol-induced thrombocytopaenia. METHODS: From June 2008 to July 2022, we performed 37 lung transplants in patients with pulmonary arterial hypertension (PAH), including idiopathic PAH (n = 26), congenital heart disease-associated PAH (n = 7), pulmonary veno-occlusive disease (n = 3) and peripheral pulmonary artery stenosis (n = 1) at our institution. Of these, 26 patients received intravenous epoprostenol therapy (EPO group), whereas 11 patients were treated with no epoprostenol (no-EPO group). We retrospectively analysed the preoperative and postoperative platelet counts and post-transplant outcomes in each group. RESULTS: Preoperative platelet counts were relatively lower in the EPO group than in the no-EPO group (median EPO: 127 000 vs no-EPO: 176 000/µl). However, blood loss during surgery was similar between the 2 groups (EPO: 2473 ml vs no-EPO: 2615 ml). The platelet counts significantly increased over 1 month after surgery, and both groups showed similar platelet counts (EPO: 298 000 vs no-EPO: 284 000/µl). In-hospital mortality (EPO: 3.9% vs no-EPO: 18.2%) and the 3-year survival rate (EPO: 91.4% vs no-EPO: 80.8%) were similar between the 2 groups. CONCLUSIONS: Patients with PAH treated with intravenous epoprostenol showed relatively lower platelet counts, which improved after lung transplantation with good post-transplant outcomes.
Assuntos
Hipertensão Pulmonar , Transplante de Pulmão , Hipertensão Arterial Pulmonar , Trombocitopenia , Humanos , Epoprostenol/uso terapêutico , Epoprostenol/efeitos adversos , Anti-Hipertensivos/efeitos adversos , Hipertensão Pulmonar/tratamento farmacológico , Hipertensão Pulmonar/cirurgia , Estudos Retrospectivos , Hipertensão Pulmonar Primária Familiar , Trombocitopenia/induzido quimicamente , Trombocitopenia/tratamento farmacológicoRESUMO
BACKGROUND: We have shown the efficacy of CD26/dipeptidyl peptidase 4 (CD26/DPP-4) inhibitors, antidiabetic agents, in allograft protection after experimental lung transplantation (LTx). We aimed to elucidate whether CD26/DPP-4 inhibitors effectively improve postoperative outcomes after clinical LTx. METHODS: We retrospectively reviewed the records of patients undergoing LTx at our institution between 2010 and 2021 and extracted records of patients with diabetes mellitus (DM) at 6 months post-LTx. The patient characteristics and postoperative outcomes were analyzed. We established 6 months post-LTx as the landmark point for predicting overall survival (OS) and chronic lung allograft dysfunction (CLAD)-free survival. Hazard ratios were estimated by Cox regression after propensity score weighting, using CD26/DPP-4 inhibitor treatment up to 6 months post-LTx as the exposure variable. We evaluated CLAD samples pathologically, including for CD26/DPP-4 immunohistochemistry. RESULTS: Of 102 LTx patients with DM, 29 and 73 were treated with and without CD26/DPP-4 inhibitors, respectively. Based on propensity score adjustment using standardized mortality ratio weighting, the 5-year OS rates were 77.0% and 44.3%, and the 5-year CLAD-free survival rates 77.8% and 49.1%, in patients treated with and without CD26/DPP-4 inhibitors, respectively. The hazard ratio for CD26/DPP-4 inhibitor use was 0.34 (95% confidence interval (CI) 0.14-0.82, p = 0.017) for OS and 0.47 (95% CI 0.22-1.01, p = 0.054) for CLAD-free survival. We detected CD26/DPP-4 expression in the CLAD grafts of patients without CD26/DPP-4 inhibitors. CONCLUSIONS: Analysis using propensity score weighting showed that CD26/DPP-4 inhibitors positively affected the postoperative prognosis of LTx patients with DM.
Assuntos
Inibidores da Dipeptidil Peptidase IV , Transplante de Pulmão , Humanos , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Dipeptidil Peptidase 4/metabolismo , Estudos Retrospectivos , Transplante de Pulmão/efeitos adversos , Transplante HomólogoRESUMO
Mutations in the tumor suppressor p53 (p53) promote cancer progression. This is mainly due to loss of function (LOS) as a tumor suppressor, dominant-negative (DN) activities of missense mutant p53 (mutp53) over wild-type p53 (wtp53), and wtp53-independent oncogenic activities of missense mutp53 by interacting with other tumor suppressors or oncogenes (gain of function: GOF). Since p53 mutations occur in ~50% of human cancers and rarely occur in normal tissues, p53 mutations are cancer-specific and ideal therapeutic targets. Approaches to target p53 mutations include (1) restoration or stabilization of wtp53 conformation from missense mutp53, (2) rescue of p53 nonsense mutations, (3) depletion or degradation of mutp53 proteins, and (4) induction of p53 synthetic lethality or targeting of vulnerabilities imposed by p53 mutations (enhanced YAP/TAZ activities) or deletions (hyperactivated retrotransposons). This review article focuses on clinically available FDA-approved drugs and drugs in clinical trials that target p53 mutations and summarizes their mechanisms of action and activities to suppress cancer progression.
RESUMO
Today's advances in diagnostic image-technologies often enable us to find small lung cancers. However, we have few definite strategies including how to diagnosis and treat them. In this study, we performed a retrospective analysis of 122 consecutive patients who underwent surgery for non-small cell lung cancer 20 mm or less in diameter to clarify the clinical features of small lung cancer. Of 122 patients, there were 114 patients of pN0, and 8 patients with lymph node metastasis. Seventy three patients underwent lobectomy, 45 underwent segmentectomy, and 4 underwent wedge resection based on the findings of preoperative CT and anatomical and oncological view during operation. Overall survival rate( OS) and progression free survival( PFS) at 3-year was, 94% and 84%, respectively. There were no differences in OS or PFS between lobectomy group and limited resection group, which might suggest that we adapted appropriate surgical procedures. Multivariate analysis revealed that pathological pleural invasion, lymphatic vessel invasion, and vascular vessel invasion were likely to be unfavorable prognostic-factors. We believe that further investigations should be required to clarify the characteristics of small lung cancer.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Feminino , Humanos , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Pneumonectomia/métodos , Estudos RetrospectivosRESUMO
Cancers are frequently addicted to oncogenic missense mutant p53 (mutp53). DNAJA1, a member of heat shock protein 40 (HSP40), also known as J-domain proteins (JDPs), plays a crucial role in the stabilization and oncogenic activity of misfolded or conformational mutp53 by binding to and preventing mutp53 from proteasomal degradation. However, strategies to deplete mutp53 are not well-established, and no HSP40/JDPs inhibitors are clinically available. To identify compounds that bind to DNAJA1 and induce mutp53 degradation, we performed an in silico docking study of ~10 million of compounds from the ZINC database for the J-domain of DNAJA1. A compound 7-3 was identified, and its analogue A11 effectively reduced the levels of DNAJA1 and conformational mutp53 with minimal effects on the levels of wild-type p53 and DNA-contact mutp53. A11 suppressed migration and filopodia formation in a manner dependent on DNAJA1 and conformational mutp53. A mutant DNAJA1 with alanine mutations at predicted amino acids (tyrosine 7, lysine 44, and glutamine 47) failed to bind to A11. Cells expressing the mutant DNAJA1 became insensitive to A11-mediated depletion of DNAJA1 and mutp53 as well as A11-mediated inhibition of cell migration. Thus, A11 is the first HSP40/JDP inhibitor that has not been previously characterized for depleting DNAJA1 and subsequently conformational mutp53, leading to inhibition of cancer cell migration. A11 can be exploited for a novel treatment against cancers expressing conformational mutp53.
RESUMO
Accumulation of missense mutant p53 (mutp53) in cancers promotes malignant progression. DNAJA1, a member of HSP40 (also known as J-domain proteins: JDPs), is shown to prevent misfolded or conformational mutp53 from proteasomal degradation. Given frequent addiction of cancers to oncogenic mutp53, depleting mutp53 by DNAJA1 inhibition is a promising approach for cancer therapy. However, there is no clinically available inhibitor for DNAJA1. Our in silico molecular docking study with a natural compound-derived small molecule library identified a plumbagin derivative, PLIHZ (plumbagin-isoniazid analog), as a potential compound binding to the J domain of DNAJA1. PLIHZ efficiently reduced the levels of DNAJA1 and several conformational mutp53 with minimal impact on DNA contact mutp53 and wild-type p53 (wtp53). An analog, called PLTFBH, which showed a similar activity to PLIHZ in reducing DNAJA1 and mutp53 levels, inhibited migration of cancer cells specifically carrying conformational mutp53, but not DNA contact mutp53, p53 null, and wtp53, which was attenuated by depletion of DNAJA1 or mutp53. Moreover, PLTFBH reduced levels of multiple other HSP40/JDPs with tyrosine 7 (Y7) and/or tyrosine 8 (Y8) but failed to deplete DNAJA1 mutants with alanine substitution of these amino acids. Our study suggests PLTFBH as a potential inhibitor for multiple HSP40/JDPs.
RESUMO
Various marking techniques for lung nodules may be complex and can cause serious complications. In this study, we aimed to describe and evaluate the feasibility of CTFRC marking, a novel preoperative skin marking technique guided by computed tomography (CT) at functional residual capacity (FRC). This simple and non-invasive marking technique only requires a preoperative CT scan without any anaesthesia. We retrospectively reviewed CTFRC markings performed for 109 lung nodules in 108 patients. The mean nodule size was 11.4 ± 5.0 mm. The mean distance from the nodule to the lung marking point was 3.8 ± 7.3 mm. We found no procedure-associated complications. CTFRC marking is a simple, safe and non-invasive method to predict the precise location of lung nodules during thoracoscopic surgery.
Assuntos
Cuidados Pré-Operatórios , Nódulo Pulmonar Solitário/diagnóstico por imagem , Nódulo Pulmonar Solitário/cirurgia , Cirurgia Torácica Vídeoassistida , Tomografia Computadorizada por Raios X , Idoso , Feminino , Capacidade Residual Funcional , Humanos , Masculino , Pessoa de Meia-Idade , Testes de Função Respiratória , Estudos Retrospectivos , Nódulo Pulmonar Solitário/fisiopatologiaRESUMO
BACKGROUND/AIM: Transforming growth factor ß1 (TGF-ß1) is an important epithelial-mesenchymal transition (EMT) activator that regulates the expression of E-cadherin and vimentin through Smad signalling. Tranilast is an anti-allergic drug that inhibits TGF-ß1, and is used in the treatment of keloids and hypertrophic scars. We investigated whether tranilast inhibits TGF-ß1-induced EMT and invasiveness in human non-small cell lung cancer cell lines. MATERIALS AND METHODS: We examined the effects of tranilast treatment on EMT markers, TGF-ß1/Smad signalling, and cell invasiveness in A549 and PC14 cells. Tumours from a mouse orthotopic lung cancer model with or without tranilast treatment were also immunohistochemically evaluated. RESULTS: Tranilast increased E-cadherin expression via Smad4 suppression and inhibited cell invasion in TGF-ß1-stimulated cells. Tranilast treatment of the in vivo mouse model reduced the pleural dissemination of cancer cells and suppressed vimentin and Smad4 expression. CONCLUSION: Tranilast inhibited TGF-ß1-induced EMT and cellular invasion/metastasis by suppressing Smad4 expression in cancer cells.
Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Neoplasias Pulmonares/genética , Proteína Smad4/genética , Fator de Crescimento Transformador beta1/efeitos dos fármacos , ortoaminobenzoatos/uso terapêutico , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Linhagem Celular Tumoral , Humanos , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Camundongos Nus , Invasividade Neoplásica , Metástase Neoplásica , ortoaminobenzoatos/farmacologiaRESUMO
Treatment of post-extrapleural pneumonectomy empyema (PEPPE) is more difficult than that for post-pneumonectomy empyema for two reasons: first, a large infectious dead space remains after extrapleural pneumonectomy (EPP); and second, defects of the pericardium and diaphragm are reconstructed with artificial materials, which ideally should be removed for treatment of infection. Here, we report the case of a 56-year-old male with PEPPE that occurred long after EPP for mesothelioma. The patient was treated successfully by minimally invasive procedures of irrigation, instillation of urokinase and antibiotics, and surgical debridement without peeling off artificial materials.
RESUMO
PURPOSE: Src family tyrosine kinases, including Fyn, are non-receptor tyrosine kinases that drive malignancy in various kinds of cancers. Fyn has also been suggested to be an effector of epidermal growth factor receptor (EGFR) signaling, and is recognized as a potential therapeutic target. However, little is known about the clinical importance of phosphorylated Fyn (pFyn) in lung adenocarcinoma. The purpose of this study is to examine the prognostic significance of pFyn in this disease. METHODS: A total of 282 lung adenocarcinoma specimens were collected from patients who underwent surgery at our institute. A tissue microarray was assembled from paraffin-embedded tumor blocks. pFyn expression was analyzed through immunostaining of the tissue microarray and each case was classified as positive or negative. The association of clinical information with pFyn expression was analyzed statistically. RESULTS: pFyn was positive in 107 cases. A pFyn-positive status was significantly associated with male gender, p53 mutant, pathological stage, tumor size, plural invasion, lymphatic invasion, vascular invasion, and differentiation. pFyn positivity was associated with poor relapse-free survival (RFS; hazard ratio [HR]: 2.11, 95% confidence interval [CI]: 1.32-3.42, p <0.01) and poor overall survival (OS; HR: 1.95, 95% CI: 1.17-3.33, p = 0.01). CONCLUSION: pFyn expression may affect the prognosis of patients with lung adenocarcinoma after lung resection.
Assuntos
Adenocarcinoma de Pulmão/enzimologia , Biomarcadores Tumorais/análise , Neoplasias Pulmonares/enzimologia , Pneumonectomia , Proteínas Proto-Oncogênicas c-fyn/análise , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/mortalidade , Adenocarcinoma de Pulmão/cirurgia , Idoso , Biomarcadores Tumorais/genética , Feminino , Humanos , Imuno-Histoquímica , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/cirurgia , Masculino , Mutação , Fosforilação , Pneumonectomia/efeitos adversos , Pneumonectomia/mortalidade , Intervalo Livre de Progressão , Proteínas Proto-Oncogênicas c-fyn/genética , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Análise Serial de Tecidos , Proteína Supressora de Tumor p53/genéticaRESUMO
Purpose: The epithelial to mesenchymal transition (EMT) is pivotal for driving metastasis and recurrence in lung cancer. Some in vitro reports have shown that statins suppress EMT by inactivating mutant p53 functions. Several clinical trials of conventional treatments with statins have been performed, but the effect of these drugs on prognosis is still uncertain. The purpose of this study is to examine the impact of statins on EMT and the prognosis of patients with lung adenocarcinoma. Materials and methods: Morphological changes were evaluated and EMT markers (E-cadherin, vimentin) were analyzed by Western blotting in p53-overexpressing H1650 and mutant p53-harboring H1975 lung adenocarcinoma cells, with and without simvastatin administration. The invasive ability of these cells was analyzed in a Matrigel chemoinvasion assay. A total of 250 lung adenocarcinoma specimens were also collected from patients who underwent surgery in our institute. EMT markers in these tumor specimens were evaluated by immunostaining and p53 mutation status was determined by direct sequencing. Associations among EMT status, p53 mutation status, and statin use were evaluated, and prognosis was analyzed using a marginal structural model. Results: Mutant p53 induced EMT and increased the invasive ability of H1650 cells. Simvastatin restored the epithelial phenotype and decreased the invasive ability of both H1650 and H1975 cells. Statin administration was associated with inactivation of EMT only in patients with mutant p53, which was consistent with the in vitro results. Moreover, in patients with mutant p53, statin users had significantly better survival than non-statin users. In contrast, statins significantly worsened the prognosis of patients with wild type p53 (HR 2.10, 95% CI 1.14-3.85). Conclusion: Statins suppress EMT and change the prognosis of patients with lung adenocarcinoma in a p53 mutation-dependent manner.
RESUMO
Objectives Thrombosis in the pulmonary vein stump after a left upper lobectomy is a rare but potentially life-threatening complication, and the pulmonary vein stump length plays an important role here. We assessed the frequency and risk factors for thrombosis in patients undergoing lobectomy with division of the superior pulmonary vein using ligation. Methods We retrospectively reviewed 425 patients with primary lung cancer who underwent lobectomy or bilobectomy in our institution from 2008 to 2016, with contrast-enhanced chest computed tomography within a year after lobectomy. The superior pulmonary vein was divided by thread ligation, while the inferior pulmonary vein was divided using a linear stapler. The pulmonary vein stump length was measured using contrast-enhanced chest computed tomography. Results Four (0.9%) of the 425 patients experienced thrombosis in the pulmonary vein stump within 6 months after lobectomy. All 4 patients had undergone a left upper lobectomy, and 4.1% of this subset developed thrombus. One patient with a thrombus in the pulmonary vein stump experienced renal and cerebral infarction after a left upper lobectomy. The left superior pulmonary vein stump was significantly longer than the other pulmonary vein stumps. Conclusions Thrombosis in the pulmonary vein stump occurred in 4.1% of patients undergoing a left upper lobectomy with pulmonary vein stump closure by thread ligation, which is a relatively low frequency. Superior pulmonary vein stump closure using thread ligation might help prevent pulmonary vein stump thrombus after a left upper lobectomy.
Assuntos
Pneumonectomia/efeitos adversos , Complicações Pós-Operatórias , Veias Pulmonares/cirurgia , Procedimentos Cirúrgicos Vasculares/efeitos adversos , Trombose Venosa/etiologia , Idoso , Feminino , Seguimentos , Humanos , Ligadura/efeitos adversos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/cirurgia , Imageamento por Ressonância Magnética , Masculino , Pneumonectomia/métodos , Veias Pulmonares/diagnóstico por imagem , Estudos Retrospectivos , Fatores de Risco , Cirurgia Torácica Vídeoassistida/efeitos adversos , Fatores de Tempo , Tomografia Computadorizada por Raios X/métodos , Trombose Venosa/diagnósticoRESUMO
The vinorelbine (VRB) plus cisplatin regimen is widely used to treat non-small cell lung cancer (NSCLC), but its cure rate is poor. Drug resistance is the primary driver of chemotherapeutic failure, and the causes of resistance remain unclear. By focusing on the focal adhesion (FA) pathway, we have highlighted a signaling pathway that promotes VRB resistance in lung cancer cells. First, we established VRB-resistant (VR) lung cancer cells (NCI-H1299 and A549) and examined its transcriptional changes, protein expressions, and activations. We treated VR cells by Src Family Kinase (SFK) inhibitors or gene silencing and examined cell viabilities. ATP-binding Cassette Sub-family B Member 1 (ABCB1) was highly expressed in VR cells. A pathway analysis and western blot analysis revealed the high expression of integrins ß1 and ß3 and the activation of FA pathway components, including Src family kinase (SFK) and AKT, in VR cells. SFK involvement in VRB resistance was confirmed by the recovery of VRB sensitivity in FYN knockdown A549 VR cells. Saracatinib, a dual inhibitor of SFK and ABCB1, had a synergistic effect with VRB in VR cells. In conclusion, ABCB1 is the primary cause of VRB resistance. Additionally, the FA pathway, particularly integrin, and SFK, are promising targets for VRB-resistant lung cancer. Further studies are needed to identify clinically applicable target drugs and biomarkers that will improve disease prognoses and predict therapeutic efficacies.
Assuntos
Trifosfato de Adenosina/farmacologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Resistencia a Medicamentos Antineoplásicos , Adesões Focais/patologia , Neoplasias Pulmonares/patologia , Transdução de Sinais/efeitos dos fármacos , Vinorelbina/farmacologia , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Adulto , Idoso , Antineoplásicos Fitogênicos/farmacologia , Apoptose , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Grandes/tratamento farmacológico , Carcinoma de Células Grandes/metabolismo , Carcinoma de Células Grandes/patologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Proliferação de Células , Feminino , Adesões Focais/efeitos dos fármacos , Adesões Focais/metabolismo , Seguimentos , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Masculino , Pessoa de Meia-Idade , Prognóstico , Taxa de Sobrevida , Células Tumorais Cultivadas , Quinases da Família src/metabolismoRESUMO
Lung cancer treatment is difficult owing to chemoresistance. Hypoxia-inducible factor 1 (HIF-1) and HIF-1-induced glycolysis are correlated with chemoresistance; however, this is not evident in lung cancer. We investigated the effect of HIF-1α and carbonic anhydrase IX (CAIX), a transmembrane protein neutralizing intracellular acidosis, on chemoresistance and prognosis of lung cancer patients after induction chemoradiotherapy. Associations of HIF-1α, glucose transporter 1 (GLUT1), and CAIX with chemoresistance of lung cancer were investigated using A549 lung cancer cells under normoxia or hypoxia in vitro. HIF-1α-induced reprogramming of glucose metabolic pathway in A549 cells and the effects of HIF-1 and CAIX on the cytotoxicity of vinorelbine were investigated. Immunohistochemical analyses were performed to determine HIF-1α, GLUT1, and CAIX expression levels in cancer specimens from lung cancer patients after induction chemoradiotherapy. Hypoxia induced HIF-1α expression in A549 cells. Moreover, hypoxia induced GLUT1 and CAIX expression in A549 cells in a HIF-1-dependent manner. Glucose metabolic pathway was shifted from oxidative phosphorylation to glycolysis by inducing HIF-1α in A549 cells. HIF-1 and CAIX induced chemoresistance under hypoxia, and their inhibition restored the chemosensitivity of A549 cells. The expression levels of HIF-1α, GLUT1, and CAIX were associated with poor overall survival of lung cancer patients after induction chemoradiotherapy. HIF-1 and CAIX affected the chemosensitivity of A549 cells and prognosis of lung cancer patients. Therefore, inhibition of HIF-1 and CAIX might improve prognosis of lung cancer patients after induction chemoradiotherapy. Further analysis might be helpful in developing therapies for lung cancer.
Assuntos
Antígenos de Neoplasias/metabolismo , Anidrase Carbônica IX/metabolismo , Resistencia a Medicamentos Antineoplásicos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neoplasias Pulmonares/terapia , Vimblastina/análogos & derivados , Células A549 , Idoso , Hipóxia Celular , Quimiorradioterapia , Feminino , Transportador de Glucose Tipo 1/metabolismo , Glicólise , Humanos , Neoplasias Pulmonares/metabolismo , Masculino , Pessoa de Meia-Idade , Vimblastina/farmacologia , Vimblastina/uso terapêutico , VinorelbinaRESUMO
OBJECTIVES: In 2015, we reported the outcomes of patients undergoing intentional limited resection (ILR) for non-small-cell lung cancer (NSCLC) from a retrospective, multi-institutional large database in Japan. Here, we analyse the clinicopathological characteristics of the patients extracted from this database with late recurrence and compare them with those with early recurrence. METHODS: Of 1538 patients in the database with cT1aN0M0 NSCLC, 92 (6%) had recurrence. In this study, early recurrence was defined as recurrence within 5 years and late recurrence as recurrence beyond 5 years after surgery. We compared the clinicopathological characteristics and post-recurrence survival (PRS) between patients with early and late recurrence. RESULTS: Of the 92 patients with recurrence, 21 (23%) had late recurrence. Compared with the early recurrence group, there were significantly more adenocarcinomas and local recurrences in the late recurrence group (P = 0.04 for both). The 3- and 5-year PRS rates were 53 and 24%, respectively, and the median PRS period was 38 months. There were no significant differences in the PRS curves between patients with early and late recurrence (P = 0.12). Only 3 patients (0.2%) had recurrence more than 10 years after ILR. Of the 21 late-recurrence patients, 17 (81%) had tumours with a consolidation/tumour ratio (CTR) >0.25. CONCLUSIONS: Late recurrence occurred in 21 (23%) of 92 patients with recurrence after ILR for cT1aN0M0 NSCLC. Late recurrence was more likely to involve adenocarcinoma and local recurrence. It is thus considered reasonable to follow patients with a CTR >0.25 for 10 years after ILR.