RESUMO
PURPOSE: This study aimed to evaluate the prognostic role of the baseline neutrophil/lymphocyte ratio (NLR) in HER2-positive metastatic breast cancer (MBC) patients treated with trastuzumab/pertuzumab. EXPERIMENTAL DESIGN: Data from 780 patients from the CLEOPATRA trial and 248 local patients were collected. Patients were divided into the low and high NLR subgroups by the NLR cutoff value. Propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) methods were used to control bias. Associations between the NLR and progression-free survival (PFS) and overall survival (OS) were analyzed. RESULTS: The baseline characteristics of the subgroups were well balanced after PSM and IPTW. A low baseline NLR was associated with better PFS and OS in the trastuzumab and docetaxel (TH) group in the unadjusted, PSM and IPTW models. After IPTW, a low NLR, versus a high NLR, was associated with improved PFS (HR 1.35, 95% CI 1.07-1.70, P = 0.012) and OS (HR 1.47, 95% CI 1.12-1.94, P = 0.006) in the TH group. In patients undergoing treatment with trastuzumab and pertuzumab and docetaxel (THP), a low baseline NLR was also correlated with better PFS but not OS across the three models. After IPTW, a low NLR was associated with better PFS (HR 1.52, 95% CI 1.20-1.93, P = 0.001) than a high NLR in the THP group. Multivariate analyses showed that a low baseline NLR was a predictor for PFS and OS in the TH group and for PFS in the THP group in all three models. In the real-world setting, a low baseline NLR was a predictor of better PFS among patients treated with docetaxel plus trastuzumab without or with pertuzumab in the multivariate model (P = 0.015 and 0.008, respectively). CONCLUSIONS: A low baseline NLR is associated with better survival outcomes among HER2-positive MBC patients receiving docetaxel plus trastuzumab/pertuzumab as first-line therapy.
Assuntos
Neoplasias da Mama , Feminino , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/patologia , Docetaxel , Linfócitos/patologia , Neutrófilos/patologia , Prognóstico , Receptor ErbB-2 , Trastuzumab/uso terapêuticoRESUMO
BACKGROUND: The relationship of neutrophil/lymphocyte ratio (NLR) to prognosis of HER2-positive breast cancer (BC) is not well studied. We aimed to assess the prognostic role of NLR in HER2-positive BC patients treated with or without trastuzumab. METHODS: The clinical data of 843 HER2-positive BC patients from July 2013 to July 2018 were collected. The difference among variables was calculated by chi-square test. The associations between clinicopathological factors, NLR and disease-free survival (DFS) were analyzed by univariate and multivariate analyses. RESULTS: Patients were divided into three groups. In group 1 containing 255 patients without trastuzumab treatment, pretreatment NLR showed no predictive value. Patients with trastuzumab treatment were divided into two groups on equal, according to pretreatment NLR values, low NLR (group 2) and high NLR (group 3). Patients in group 2 showed significantly higher 3-year DFS rate than patients in group 1 and group 3 (95.3% vs. 91.6% vs. 90.5%, respectively, P = 0.011); patients in the group 1 and group 3 had a similar 3-year DFS outcome. Multivariate analysis showed high pretreatment NLR was significantly associated with shorter DFS (HR = 2.917, 95% CI = 1.055-8.062, P = 0.039) in HER2-positive BC patients treated with trastuzumab. CONCLUSIONS: Among HER2-positive trastuzumab-treated BC patients, low pretreatment NLR value was associated with better DFS, and it might help to differentiate potential beneficiaries of trastuzumab treatment.
Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neutrófilos/citologia , Trastuzumab/uso terapêutico , Antineoplásicos Imunológicos/farmacologia , Neoplasias da Mama/sangue , Neoplasias da Mama/metabolismo , Estudos de Casos e Controles , Feminino , Humanos , Contagem de Linfócitos , Análise Multivariada , Neutrófilos/efeitos dos fármacos , Prognóstico , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-2/metabolismo , Análise de Sobrevida , Trastuzumab/farmacologia , Resultado do TratamentoRESUMO
The integrated stress response (ISR) is critical for cancer cell survival during stress stimuli and has been implicated in the resistance to cancer therapeutics, in which the mechanism, however, is poorly understood. Here, we showed that paclitaxel, the major chemotherapy drug for breast cancer, induced ISR and phosphorylated ser51 residue of EIF2S1 by EIF2AK3 and EIF2AK4. When exposed to paclitaxel, cancer cells activated the EIF2AK3/EIF2AK4-pEIF2S1-ATF4 axis and maintained redox homoeostasis by inducing expression of the major antioxidant enzymes HMOX1, SHMT2 and SLC7A11. Paclitaxel-mediated cell death was significantly increased following loss of ISR or ATF4 expression. This sensitizing effect could be partially rescued by Trolox, a ROS scavenger. We demonstrated that the alternative initiation factor EIF2A was essential for cancer cell survival after paclitaxel-mediated ISR both in vitro and in vivo. Moreover, patients with breast cancer exhibited higher ISR after chemotherapy, and the elevated mRNA levels of HMOX1, SHMT2 and EIF2A were correlated with poor prognosis. Collectively, our findings reveal a novel mechanism for paclitaxel resistance and suggest that targeting EIF2A combined with ISR agonist may be a potential treatment regimen to overcome drug resistance for breast cancer.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Fator de Iniciação 2 em Eucariotos/genética , Paclitaxel/farmacologia , Proteínas Serina-Treonina Quinases/genética , eIF-2 Quinase/genética , Fator 4 Ativador da Transcrição/genética , Sistema y+ de Transporte de Aminoácidos/genética , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glicina Hidroximetiltransferase/genética , Heme Oxigenase-1/genética , Xenoenxertos , Humanos , Paclitaxel/efeitos adversos , Transdução de Sinais/efeitos dos fármacosRESUMO
Epithelial-to-mesenchymal transition (EMT) is a dynamic transitional state from the epithelial to mesenchymal phenotypes. Numerous studies have suggested that EMT and its intermediate states play important roles in tumor invasion and metastasis. To identify novel regulatory molecules of EMT, we screened a siRNA library targeting human 720 kinases in A549 lung adenocarcinoma cells harboring E-cadherin promoter-luciferase reporter vectors. NIMA-related kinase-4 (NEK4) was identified and characterized as a positive regulator of EMT in the screening. Suppression of NEK4 resulted in the inhibition of cell migration and invasion, accompanying with an increased expression of cell adhesion-related proteins such as E-cadherin and ZO1. Furthermore, NEK4 knockdown caused the decreased expression of the transcriptional factor Zeb1 and Smads proteins, which are known to play key roles in EMT regulation. Consistently, overexpression of NEK4 resulted in the decreased expression of E-cadherin and increased expression of Smad3. Using a mouse model with tail vein injection of NEK4 knockdown stable cell line, we found a lower rate of tumor formation and metastasis of the NEK4-knockdown cells in vivo. Thus, this study demonstrates NEK4 as a novel kinase involved in regulation of EMT and suggests that NEK4 may be further explored as a potential therapeutic target for lung cancer metastasis.
Assuntos
Transição Epitelial-Mesenquimal , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/patologia , Quinases Relacionadas a NIMA/metabolismo , Células A549 , Animais , Biomarcadores Tumorais/metabolismo , Caderinas/metabolismo , Movimento Celular , Humanos , Células MCF-7 , Camundongos Nus , Metástase Neoplásica , Transdução de Sinais , Fatores de Transcrição/metabolismoRESUMO
Epigenetic inactivation of genes plays a critical role in many important human diseases, especially in cancer. A core mechanism for epigenetic inactivation of the genes is methylation of CpG islands in genome DNA, which is catalyzed by DNA methyltransferases (DNMTs). The inhibition of DNMTs may lead to demethylation and expression of the silenced tumor suppressor genes. Although DNMT inhibitors are currently being developed as potential anticancer agents, only limited success is achieved due to substantial toxicity. Here, we utilized a multiplex selection system to generate efficient RNA-cleaving DNAzymes targeting DNMT1. The lead molecule from the selection was shown to possess efficient kinetic profiles and high efficiency in inhibiting the enzyme activity. Transfection of the DNAzyme caused significant down-regulation of DNMT1 expression and reactivation of p16 gene, resulting in reduced cell proliferation of bladder cancers. This study provides an alternative for targeting DNMTs for potential cancer therapy.
Assuntos
DNA (Citosina-5-)-Metiltransferases/metabolismo , DNA Catalítico/metabolismo , Neoplasias da Bexiga Urinária/enzimologia , Neoplasias da Bexiga Urinária/patologia , Bexiga Urinária/patologia , Sequência de Bases , Linhagem Celular Tumoral , Proliferação de Células , DNA (Citosina-5-)-Metiltransferase 1 , DNA (Citosina-5-)-Metiltransferases/análise , DNA (Citosina-5-)-Metiltransferases/genética , Metilação de DNA , DNA Catalítico/análise , DNA Catalítico/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Cinética , Transfecção , Bexiga Urinária/enzimologia , Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/genéticaRESUMO
The prognostic value of SII (Systemic Immune-Inflammation Index) in HER-2-positive breast cancer (BC) patients, regardless of whether they receive trastuzumab treatment, and its potential value to distinguish patients who may benefit from trastuzumab therapy, warrant further investigation. Clinical data was collected from 797 HER-2-positive BC patients between July 2013 and March 2018. Baseline data differences were adjusted with propensity score matching. Univariate and multivariate analyses explored the correlation between clinical pathological factors, SII, and DFS. Four groups were established. Based on the baseline SII values of the participants, patients who did not receive trastuzumab treatment were divided into Group 1 (Low-SII) and Group 2 (High-SII), where SII had no predictive value for prognosis between groups. Participants who received trastuzumab treatment were also divided into two groups: the Low-SII group (Group 3) and the High-SII group (Group 4). The 5-year DFS was significantly higher in Group 3 than in Group 4 (91.76% vs. 82.76%, P = 0.017). Furthermore, multivariate analysis demonstrated a significant association between high SII and shorter DFS (HR = 3.430, 95% CI = 1.830-6.420, P < 0.001). In HER-2-positive BC patients treated with trastuzumab, those with lower SII showed a longer DFS, suggesting that SII may help in identifying patients who benefit from trastuzumab therapy.
Assuntos
Neoplasias da Mama , Humanos , Feminino , Trastuzumab/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Prognóstico , Receptor ErbB-2 , Inflamação/tratamento farmacológico , Estudos RetrospectivosRESUMO
BACKGROUND: CD74-ROS1 fusion genes have been detected in non-small cell lung carcinomas (NSCLC), but not in inflammatory breast cancer. CASE PRESENTATION: Herein, we report a CD74-ROS1 fusion gene identified in a 64-year-old Chinese woman with inflammatory breast cancer (IBC). The patient initially presented with a rapidly growing mass in the left breast with diffuse erythema developing over a period of 2 months. Diagnosis of invasive breast carcinoma was made by core needle biopsy. Positron emission tomography-computed tomography (PET/CT) demonstrated multiple organ metastases. Genomic DNA was extracted from tumor tissue and analyzed using next-generation sequencing (NGS). The CD74-ROS1 fusion gene was detected in the genomic DNA. The patient refused crizotinib treatment, and could not tolerate the side effects of palliative chemotherapy. Unfortunately, the patient died 4 months after diagnosis. CONCLUSION: We report the case of a CD74-ROS1 fusion gene in a patient with IBC. This may reveal, for the first time, a possible association between CD74-ROS1 gene fusion and rapid progression of inflammatory breast cancer. Multigene panel testing can be performed when rapidly progressive breast cancer occurs and could reveal potential therapeutic strategies.
Assuntos
Neoplasias Inflamatórias Mamárias , Neoplasias Pulmonares , Feminino , Fusão Gênica , Humanos , Neoplasias Inflamatórias Mamárias/diagnóstico por imagem , Neoplasias Inflamatórias Mamárias/genética , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Pessoa de Meia-Idade , Proteínas de Fusão Oncogênica/genética , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Proteínas Tirosina Quinases , Proteínas Proto-Oncogênicas/genéticaRESUMO
INTRODUCTION: The neutrophil-to-lymphocyte ratio (NLR) and stromal tumor-infiltrating lymphocytes (sTILs) are associated with immunogenicity and prognosis of patients with triple-negative breast cancer (TNBC). OBJECTIVE: To investigated the prognostic roles of NLR and sTILs and their rela-tionship of TNBC patients treated with neoadjuvant chemotherapy (NAC). METHODS: The clinical data of 170 patients with locally advanced TNBC who received NAC from January 2010 to December 2014 were collected. The difference among variables was calculated by χ2 test. The association between essential clinicopathological characteristics, pathological complete response (pCR), NLR, and sTILs with disease-free survival (DFS) was analyzed. Kaplan-Meier and Cox analysis were performed to address the effects of clinical parameters on prognosis. RESULTS: There was a trend that TNBC patients with lower baseline NLR (NLR1) or higher sTILs scoring would obtain a better pCR rate. NLR1 and sTILs were not associated (p > 0.05). Patients with low NLR1 or high sTILs scoring had a significantly improved DFS compared to those with high NLR1 or low sTILs scoring (p = 0.002 and p = 0.001, respectively). The increased lymphocyte count in peripheral blood after NAC was associated with the improved DFS outcome in both high and low NLR1 groups. Cox analysis revealed that NLR1 and sTILs were independent prognostic predictors of DFS outcome (p < 0.001). CONCLUSION: Low NLR1 and high sTILs were associated with better DFS outcome in locally advanced TNBC patients treated with NAC. Further studies are needed to explore the connection between systemic and local inflammatory/immune markers.
RESUMO
BACKGROUND: We explored the therapeutic and prognostic effect of YAP/TAZ intensityinHER2-positive breast cancer patients. We also investigated the relationship between YAP/TAZ expression and Trastuzumab-resistance. METHODS: We collected clinicopathological information from 397 cases. We evaluated therapeutic and prognostic effect of YAP/TAZ and other variables. We also cultivated Trastuzumab-resistance cell lines and explored relationship between YAP/TAZ and Trastuzumab-resistance. RESULTS: Over-expression of YAP/TAZ was remarkable in Trastuzumab-resistant cells, and so did HER3 and HER2/HER3 heterodimer. Inhibition of YAP/TAZ expression reversed Trastuzumab-resistance.YAP/TAZ deficiency contributed to favorable therapeutic response, and so did hormone receptor insufficiency and chemotherapy dosage inferiority. Deficient YAP/TAZ intensity and abundant hormone receptor intensity contributed to better survival. Over-expression of YAP/TAZ was obvious in recurrent cases in comparison with their matching primary lesions. Prognostic superiority of insufficient YAP/TAZ intensity was more outstanding in hormone receptor negative cases. Over-expression of YAP/TAZ and HER3 was generally synchronous. Absence of HER3 expression in residual lesions might correlate with better breast cancer-free survival. CONCLUSIONS: Over-expression of YAP/TAZ as well as HER-3 and HER2/HER3 heterodimer was synchronously remarkable in Trastuzumab-resistant cell lines. Inhibition of YAP/TAZ expression reversed Trastuzumab resistance. Deficient YAP/TAZ intensity as well as insufficient hormone receptor intensity and high chemotherapy dosage contributed to favorable therapeutic response. Deficient YAP/TAZ intensity and abundant hormone receptor intensity contributed to better survival, and so did absence of HER3expression in residual lesions. Prognostic superiority of YAP/TAZ expression depended on hormone receptor status. Cases with synchronous over-expression of YAP/TAZ and HER3 suffered poor survival, which revealed the potential effect of YAP/TAZ-HER2/HER3 crosstalk in prognosis of HER2-positive patients.
RESUMO
BACKGROUND: The neutrophil/lymphocyte ratio (NLR) and platelet/lymphocyte ratio (PLR) have been associated with the prognosis in breast cancer (BC). The relationship of the NLR and PLR with chemotherapy sensitivity and prognosis in luminal B-like (human epidermal growth factor receptor 2-negative [HER2-]) BC are not well studied. PATIENTS AND METHODS: The clinical data from 980 patients with luminal B-like (HER2-) BC from June 2012 to June 2016 were collected. The differences among the variables were calculated using the χ2 test. The associations among the clinicopathologic factors, pretreatment NLR, pretreatment PLR, and disease-free survival (DFS) were analyzed using Kaplan-Meier curves and Cox analyses. RESULTS: The median follow-up was 37 months (range, 5-77 months). For the 480 patients who had received neoadjuvant chemotherapy, low pretreatment PLR values were associated with higher pathologic complete response (pCR) rates compared with the high PLR group (15.8% for low vs. 9.2% for high PLR group; P = .027). Multivariate analyses showed that larger tumors, a greater number of lymph nodes involved, a high Ki-67 score, and a high PLR were independent prognostic factors of worse outcomes for the patients with luminal B-like (HER2-) BC. The risk of metastasis and/or recurrence was greater for the high PLR group than for the low PLR group (hazard ratio, 1.576; 95% confidence interval, 1.039-2.390; P = .032). The pretreatment NLR showed no such associations among this cohort of patients. CONCLUSIONS: The results of the present study have shown that the pretreatment PLR is superior to the NLR as a predictor of pCR and DFS outcomes in patients with luminal B-like (HER2-) BC. A low pretreatment PLR was associated with higher pCR rates after neoadjuvant chemotherapy and was an independent predictive factor for better DFS outcomes among patients with luminal B-like (HER2-) BC.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Plaquetas , Neoplasias da Mama/terapia , Linfócitos , Recidiva Local de Neoplasia/epidemiologia , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/metabolismo , Mama/patologia , Mama/cirurgia , Neoplasias da Mama/sangue , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/mortalidade , Quimioterapia Adjuvante/métodos , Intervalo Livre de Doença , Resistencia a Medicamentos Antineoplásicos , Feminino , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Contagem de Linfócitos , Mastectomia , Terapia Neoadjuvante/métodos , Recidiva Local de Neoplasia/prevenção & controle , Neutrófilos , Contagem de Plaquetas , Receptor ErbB-2/análise , Receptores de Estrogênio/análise , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/análise , Receptores de Progesterona/metabolismo , Estudos Retrospectivos , Medição de Risco/métodos , Medição de Risco/estatística & dados numéricosRESUMO
Yes-associated protein (YAP) protein acts as tumorigenic factor in many solid tumors, but the situation in breast cancer is under debate. Here, we would analyze its status in breast cancer. YAP expression in the 110 primary breast cancer and their paired local recurrent tumors was investigated. Clinicopathologic data for age, histologic grading, hormone status, lymph nodes and HER2 status were also gathered and analyzed. 46.4% (51/110) primary breast cancer tissues were positive for total YAP expression which was significantly higher than that in the recurrent tissues (10.9%; P < 0.05). The expression of total YAP protein in the primary breast cancer tissues was positively associated with the tumor size, especially in triple negative breast cancer (TNBC) subtype (P < 0.05). Higher total or nuclear YAP expression in the primary tumor was correlated with poor disease-free survival among patients with TNBC (P < 0.05). In the multivariate models, nuclear YAP expression was an independently prognostic factor in TNBC. High total or nuclear YAP expression predicts poor prognosis among patients with TNBC. It might be a therapeutic target for TNBC in the future.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Mama/patologia , Carcinoma Ductal de Mama/mortalidade , Metástase Linfática/patologia , Recidiva Local de Neoplasia/mortalidade , Fatores de Transcrição/metabolismo , Neoplasias de Mama Triplo Negativas/mortalidade , Proteínas Adaptadoras de Transdução de Sinal/análise , Adulto , Idoso , Carcinoma Ductal de Mama/patologia , Carcinoma Ductal de Mama/terapia , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Linfonodos/patologia , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Prognóstico , Receptor ErbB-2/análise , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/análise , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/análise , Receptores de Progesterona/metabolismo , Fatores de Transcrição/análise , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/terapia , Proteínas de Sinalização YAPRESUMO
This study aimed to examine the prognostic factors of luminal B-like breast cancer. Clinical data of 695 luminal B-like breast cancer patients who had been treated in our hospital during the period of past 4.5 years were collected and analyzed. Estrogen receptor (ER), progesterone receptor (PgR), antigen identified by monoclonal antibody Ki-67 (Ki67) were immunohistochemically detected. Different cutoffs of ER, PgR, and Ki67 were evaluated. Pearson χ2 test was performed to compare categorical parameters. Univariate and multivariate models were used to evaluate predictors of disease free survival (DFS). The results showed that patients who were younger, and had larger tumors, and more positive lymph nodes were more likely to receive neo-adjuvent chemotherapy (NAC). Patients with ER-positive tumors having <10% positive cells received more anthracycline- and taxane-based chemotherapy and less endocrine therapy than those with ER-positive tumors having ≥10% positive cells (P=0.004 and P=0.007, respectively); however, patients with ER-positive tumors having <10% positive cells experienced more recurrence (P<0.001). PgR expression levels were not associated with therapeutic schedule and DFS. Patients with tumor tissue Ki67 score ≥30% received more anthracycline- and taxane-based chemotherapy and had worse DFS than those with tumor tissue Ki67 score <30%. Univariate and multivariate analysis showed that clinical T stage, lymph nodes, ER, Ki67, and HER2 status were independent prognostic factors. In conclusion, ER-positive rate <10% and Ki67 score ≥30%, similar to higher clinical T stage, more metastatic lymph nodes, and HER2 positive status, may indicate a worse prognosis for luminal B-like breast cancer patients. Multi-center prospective trials with larger sample sizes are necessary for the continued perfection of our work.
Assuntos
Biomarcadores Tumorais/genética , Neoplasias da Mama/diagnóstico , Antígeno Ki-67/genética , Recidiva Local de Neoplasia/diagnóstico , Receptor ErbB-2/genética , Receptores de Estrogênio/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Neoplasias da Mama/cirurgia , Feminino , Expressão Gênica , Humanos , Metástase Linfática , Pessoa de Meia-Idade , Análise Multivariada , Gradação de Tumores , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/cirurgia , Estadiamento de Neoplasias , Prognóstico , Receptores de Progesterona/genética , Estudos Retrospectivos , Análise de SobrevidaRESUMO
Radiofrequency ablation (RFA) promotes tumor antigen-specific T cell responses and enhances the effect of immunotherapy in preclinical settings. Here we report that the existence of remnant tumor masses due to incomplete RFA (iRFA) is associated with earlier new metastases and poor survival in patients with colorectal cancer liver metastases (CRCLM). Using mouse models, we demonstrate that iRFA promotes tumor progression and hinders the efficacy of anti-PD-1 therapy. Immune analysis reveals that iRFA induces sustained local inflammation with predominant myeloid suppressor cells, which inhibit T cell function in tumors. Mechanistically, tumor cell-derived CCL2 is critical for the accumulation of monocytes and tumor-associated macrophages (TAMs). The crosstalk between TAMs and tumor cells enhances the CCL2 production by tumor cells. Furthermore, we find that administration of a CCR2 antagonist or the loss of CCL2 expression in tumor cells enhances the antitumor activity of PD-1 blockade, providing a salvage alternative for residual tumors after iRFA.
Assuntos
Quimiocina CCL2/imunologia , Neoplasias Colorretais/patologia , Inflamação/imunologia , Neoplasias Hepáticas/cirurgia , Macrófagos/imunologia , Neoplasia Residual/imunologia , Ablação por Radiofrequência , Linfócitos T/imunologia , Adulto , Idoso , Animais , Anticorpos Monoclonais , Antineoplásicos Imunológicos/farmacologia , Linhagem Celular Tumoral , Neoplasias Colorretais/tratamento farmacológico , Modelos Animais de Doenças , Progressão da Doença , Feminino , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/secundário , Masculino , Camundongos , Pessoa de Meia-Idade , Monócitos , Células Supressoras Mieloides/imunologia , Prognóstico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptores CCR2/antagonistas & inibidores , Fator de Necrose Tumoral alfa/imunologiaRESUMO
Paclitaxel (Taxol) is currently used as the front-line chemotherapeutic drug for many types of human cancers. However, the emergence of drug resistance has been a major obstacle to the effective treatment of cancers in clinical settings. The transcription factor Forkhead box protein C2 (FOXC2) was recently demonstrated to activate the epithelial-mesenchymal transition (EMT). In this article, we present a novel role of FOXC2 in regulating chemoresistance of nasopharyngeal carcinoma (NPC) through the EMT. Using an EMT PCR array based on the screening of 84 genes, the expression of FOXC2 was notably upregulated in paclitaxel-resistant NPC cells (CNE2/t). We observed that the paclitaxel-resistant cells exhibited characteristic EMT phenotypes. The silencing of FOXC2 expression in the resistant cells can reverse the EMT molecular markers and chemoresistant phenotypes, such as cellular morphology, proliferation and anoikis. In an NPC xenograft mouse model, the downregulation of FOXC2 expression in the resistant NPC cells increased their sensitivity to paclitaxel treatment, resulting in reduced tumor growth. Taken together, our results suggest that FOXC2-mediated EMT may be an alternative mechanism through which cancer cells can initiate and maintain drug resistance. Thus, targeting FOXC2 may provide a novel strategy for overcoming chemoresistance in NPC therapy.
Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , Transição Epitelial-Mesenquimal/genética , Fatores de Transcrição Forkhead/biossíntese , Neoplasias Nasofaríngeas/genética , Animais , Anoikis/genética , Carcinoma , Proliferação de Células/genética , Fatores de Transcrição Forkhead/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/tratamento farmacológico , Neoplasias Nasofaríngeas/patologia , Paclitaxel/administração & dosagemRESUMO
Radiation-induced lung fibrosis (RILF) is a severe side effect of radiotherapy in lung cancer patients that presents as a progressive pulmonary injury combined with chronic inflammation and exaggerated organ repair. RILF is a major barrier to improving the cure rate and well-being of lung cancer patients because it limits the radiation dose that is required to effectively kill tumor cells and diminishes normal lung function. Although the exact mechanism is unclear, accumulating evidence suggests that various cells, cytokines and regulatory molecules are involved in the tissue reorganization and immune response modulation that occur in RILF. In this review, we will summarize the general symptoms, diagnostics, and current understanding of the cells and molecular factors that are linked to the signaling networks implicated in RILF. Potential approaches for the treatment of RILF will also be discussed. Elucidating the key molecular mediators that initiate and control the extent of RILF in response to therapeutic radiation may reveal additional targets for RILF treatment to significantly improve the efficacy of radiotherapy for lung cancer patients.
Assuntos
Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/fisiopatologia , Pneumonite por Radiação/tratamento farmacológico , Pneumonite por Radiação/fisiopatologia , Transdução de Sinais/genética , Animais , Biomarcadores Tumorais/análise , Carcinoma Pulmonar de Células não Pequenas/complicações , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Descoberta de Drogas , Humanos , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/radioterapia , Camundongos , Terapia de Alvo Molecular , Fibrose Pulmonar/etiologia , Transdução de Sinais/efeitos dos fármacosRESUMO
Pancreatic cancer is a devastating malignancy, characterized by intrinsic or acquired resistance to conventional chemotherapies. Recent evidences suggest an involvement of tyrosine kinase pathway in the regulation of multidrug resistance (MDR) protein gene expression. The aim of this study was to test whether gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor could regulate the MDR protein gene expression and sensitize the resistant cancer cells to chemotherapy. The gene expression of MDR proteins (MRP1, MRP2, MRP3, and PGP) were evaluated by quantitative RT-PCR, and expression levels of various tyrosine kinases were investigated by quantitative RT-PCR and Western blot in pancreatic cancer cell line. MTT assay was used for evaluating the effect of chemotherapeutic agents. Chemotherapeutics induced drug resistance by regulating the gene expression of MDR proteins (MRP1, MRP2, and MRP3), and increased the gene expression of RAF1/ERK and the phosphorylation of ERK in pancreatic cancer Bxpc-3 cells. Gefitinib caused an inhibition of p-ERK tyrosine kinase activation in a dose-dependent manner, and reversed gemcitabine-induced RAF1/ERK gene expression and p-ERK activation. In addition, a reversal of MDR proteins gene expression was achieved by gefitinib, which sensitized resistant cells to gemcitabine. This study demonstrated that MDR of Bxpc-3 cell is involved in the RAF1/ERK tyrosine kinase pathway. Gefitinib reverses the MDR protein gene expression and restores sensitivity of resistant cells to gemcitabine via RAF1/ERK signaling pathway. Combination of gefitinib with conventional chemotherapeutic agents may offer a new approach for the treatment of patients with pancreatic cancer.
Assuntos
Antineoplásicos/farmacologia , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Neoplasias Pancreáticas/enzimologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-raf/metabolismo , Quinazolinas/farmacologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/efeitos dos fármacos , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Western Blotting , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Doxorrubicina/farmacologia , Resistência a Múltiplos Medicamentos/genética , Resistencia a Medicamentos Antineoplásicos/genética , Ativação Enzimática , MAP Quinases Reguladas por Sinal Extracelular/genética , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Gefitinibe , Regulação Neoplásica da Expressão Gênica , Humanos , Proteína 2 Associada à Farmacorresistência Múltipla , Proteínas Associadas à Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Fosforilação , Proteínas Proto-Oncogênicas c-raf/genética , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
The fruA gene encodes a DNA-binding response regulator protein essential for the development of Myxococcus xanthus. This gene is transcribed with an unusually long (235 nucleotides) 5' untranslated region (UTR) that has been shown to be absolutely necessary for the induction of FruA synthesis during development. With lacZ as a reporter, it was found in this report that each regional deletion mutation within 5' UTR caused a decrease in beta-galactosidase production. Base substitution mutations that were designed to alter local stem-loop structures also decreased fruA-lacZ expression, however their compensatory mutations could not rescue fruA-lacZ expression at all. A moderate decrease in beta-galactosidase activity was observed from the fruA-lacZ transcriptional fusion lacking fruA 5' UTR; in contrast, expression of the fruA-lacZ translational fusion lacking the 5' UTR was severely impaired. In addition, both the amount and stability of fruA-lacZ mRNA were just moderately reduced in the absence of this 5' UTR. These results suggest that the function of the 5' UTR of fruA mRNA requires integrity of almost the entire region and may depend on the primary sequence. More importantly, fruA 5' UTR modulates the expression of its own gene mainly by enhancing translation efficiency of the transcript.