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BACKGROUND: Resistance to immune checkpoint inhibitors (ICIs) represents a major unmet medical need in non-small cell lung cancer (NSCLC) patients. Vascular endothelial growth factor (VEGF) inhibition may reverse a suppressive microenvironment and recover sensitivity to subsequent ICIs. METHODS: This phase Ib/IIa, single-arm study, comprised dose-finding (Part A) and expansion (Part B) cohorts. Patients with ICIs-refractory NSCLC were enrolled to receive anlotinib (a multi-target tyrosine kinase inhibitor) orally (from days 1 to 14 in a 21-day cycle) and nivolumab (360 mg every 3 weeks, intravenously) on a 21-day treatment cycle. The first 21-day treatment cycle was a safety observation period (phase Ib) followed by a phase II expansion cohort. The primary objectives were recommended phase 2 dose (RP2D, part A), safety (part B), and objective response rate (ORR, part B), respectively. RESULTS: Between November 2020 and March 2022, 34 patients were screened, and 21 eligible patients were enrolled (6 patients in Part A). The RP2D of anlotinib is 12 mg/day orally (14 days on and 7 days off) and nivolumab (360 mg every 3 weeks). Adverse events (AEs) of any cause and treatment-related AEs (TRAEs) were reported in all treated patients. Two patients (9.5%) experienced grade 3 TRAE. No grade 4 or higher AEs were observed. Serious AEs were reported in 4 patients. Six patients experienced anlotinib interruption and 4 patients experienced nivolumab interruption due to TRAEs. ORR and disease control rate (DCR) was 19.0% and 76.2%, respectively. Median PFS and OS were 7.4 months (95% CI, 4.3-NE) and 15.2 months (95% CI, 12.1-NE), respectively. CONCLUSION: Our study suggests that anlotinib combined with nivolumab shows manageable safety and promising efficacy signals. Further studies are warranted. TRIAL REGISTRATION: NCT04507906 August 11, 2020.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma Pulmonar de Células não Pequenas , Inibidores de Checkpoint Imunológico , Neoplasias Pulmonares , Nivolumabe , Inibidores de Proteínas Quinases , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Resistencia a Medicamentos Antineoplásicos , Inibidores de Checkpoint Imunológico/efeitos adversos , Inibidores de Checkpoint Imunológico/administração & dosagem , Inibidores de Checkpoint Imunológico/uso terapêutico , Indóis/administração & dosagem , Indóis/efeitos adversos , Indóis/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Nivolumabe/administração & dosagem , Nivolumabe/efeitos adversos , Nivolumabe/uso terapêutico , Estudos Prospectivos , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Quinolinas/administração & dosagem , Quinolinas/efeitos adversos , Quinolinas/uso terapêutico , AdolescenteRESUMO
BACKGROUND: Iron metabolism disorder is closely associated with several malignant tumors, however the mechanisms underlying iron and the carcinogenesis in osteosarcoma are not yet well understood. METHODS: Cell proliferation ability of osteosarcoma cell lines was measured by CCK-8, EdU incorporation and colony formation assays. Cell cycle analysis was detected by flow cytometry. The carcinogenesis of osteosarcoma was measured by soft-agar formation, trans-well and Wound healing-scratch assay. Warburg effect was detected by Seahorse respirometry assays. Reactive oxygen species (ROS) level was measured by Dichlorodihydrofluorescein diacetate (DCFH-DA) fluorescent probes. Western blotting was used to measure the expression of mitoferrin 1 (SLC25A37) and mitoferrin 2 (SLC25A28). Iron level in vitro and vivo was detected by iron assay kit. RNAi stable cell lines was generated using shRNA. RESULTS: Iron promoted proliferation, carcinogenesis and Warburg effect of osteosarcoma cells. Iron-induced reactive oxygen species (ROS) played an important role in these processes. Iron accumulated more in mitochondrion than in cytoplasm, suggesting mitochondrion-mediated iron accumulation was involved in the development of osteosarcoma. Moreover, iron upregulated the expression of mitoferrin 1 (SLC25A37) and mitoferrin 2 (SLC25A28). Knock-down of mitoferrin 1 (SLC25A37) and mitoferrin 2 (SLC25A28) decreased the production of ROS. In addition, iron increased the expression of Warburg key enzymes HK2 and Glut1, and affected AMPK/mTORC1 signaling axis. CONCLUSIONS: Mitochondrion-mediated iron accumulation promotes carcinogenesis and Warburg effect of osteosarcoma cells. Meanwhile, iron deprivation might be a novel effective strategy in the treatment of osteosarcoma.
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BACKGROUND: Dietary fiber is effective for colorectal cancer (CRC) treatment. Interleukin-6 (IL-6) and its adaptors are potential targets for CRC therapy. Butyrate, a metabolite of dietary fiber, is a new, highly safe type of targeted drug. METHODS: In this study, Cell Counting Kit-8 cell viability and wound healing assays, western blot analysis, immunofluorescence staining, and xenograft tumor mouse models were used to evaluate the anticancer effect of butyrate and its possible mechanism in vivo and in vitro. RESULTS: Dietary fiber and sodium butyrate (NaB) decreased CRC burden by decreasing IL-6 receptor gp130 and blocking IL-6/JAK2/STAT3 axis activation in vitro and in vivo. Furthermore, NaB reduced the gp130 protein level by regulating its degradation rate via targeting TRAF5. CONCLUSIONS: The fiber metabolite butyrate inhibits CRC development by reducing gp130 via TRAF5.
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Aberrant expression of sperm-associated antigen 5 (SPAG5) is implicated to play oncogenic roles in several types of cancers. However, the functions of SPAG5 in lung adenocarcinoma remain unclear. In this study, we investigated the role of SPAG5 in lung adenocarcinoma. We found that SPAG5 was upregulated in most of the lung adenocarcinoma cell lines as compared to normal lung epithelial cells. SPAG5 knockdown suppressed proliferation, colony forming, and migration of lung adenocarcinoma A549â¯cells in vitro and inhibited tumor growth in vivo. These suggest that upregulated SPAG5 promotes lung tumor progression. Importantly, treatment with MDM2 inhibitor, Nutlin-3a, restored p53 and p21 expression and suppressed SPAG5 expression in wild-type p53 lung adenocarcinoma cells, A549 and H460, but not in p53-null lung cancer cells, H1299. This suggests that the p53 signal pathway is essential for SPAG5 suppression. In addition, knocking-down p53 or p21 in A549 and H460â¯cells attenuated Nutlin-3a-induced repression of SPAG5, which further supports that the p53-p21 axis is required for SPAG5 repression. Thus, SPAG5 can serve as a prognostic marker, and therapeutic strategy targeting the p53-p21-SPAG5 axis may have important clinical implications.
Assuntos
Adenocarcinoma de Pulmão/genética , Proteínas de Ciclo Celular/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/genética , Proteína Supressora de Tumor p53/genética , Animais , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Camundongos Nus , Oncogenes , Regulação para CimaRESUMO
Epidermal growth factor receptor (EGFR) gene mutations occur in multiple human cancers; therefore, the detection of EGFR mutations could lead to early cancer diagnosis. This study describes a novel EGFR mutation detection technique. Compared to direct DNA sequencing detection methods, this method is based on allele-specific amplification (ASA), recombinase polymerase amplification (RPA), peptide nucleic acid (PNA), and SYBR Green I (SYBR), referred to as the AS-RPA-PNA-SYBR (ARPS) system. The principle of this technique is based on three continuous steps: ASA or ASA combined with PNA to prevent non-target sequence amplification (even single nucleotide polymorphisms, SNPs), the rapid amplification advantage of RPA, and appropriate SYBR Green I detection (the samples harboring EGFR mutations show a green signal). Using this method, the EGFR 19Del(2) mutation was detected in 5 min, while the EGFR L858R mutation was detected in 10 min. In this study, the detection of EGFR mutations in clinical samples using the ARPS system was compatible with that determined by polymerase chain reaction (PCR) and DNA sequencing methods. Thus, this newly developed methodology that uses the ARPS system with appropriate primer sets is a rapid, reliable, and practical way to assess EGFR mutations in clinical samples.
Assuntos
Receptores ErbB/genética , Testes Genéticos/métodos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Mutação , Alelos , Benzotiazóis , Linhagem Celular Tumoral , DNA de Neoplasias/química , Diaminas , Detecção Precoce de Câncer/métodos , Humanos , Compostos Orgânicos/química , Sistemas Automatizados de Assistência Junto ao Leito , Reação em Cadeia da Polimerase/métodos , Quinolinas , Recombinases/metabolismoRESUMO
Background: Programmed cell death 1 (PD-1) inhibitors are beneficial for patients with advanced lung cancer. However, the population who will benefit from PD-1 inhibitors is limited, and their efficacy needs to be further improved. Antiangiogenic agents may regulate tumor microenvironment to improve immunotherapy efficacy. This real-world study sought to investigate the efficacy and safety of anlotinib combined with PD-1 inhibitors in the treatment of advanced non-small cell lung cancer (NSCLC). Methods: In total, 42 advanced NSCLC patients were included in this retrospective study. All the patients received anlotinib combined with PD-1 inhibitors from May 2020 to November 2022. The progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and adverse events (AEs) of the patients were evaluated. Results: The patients had an overall median PFS of 5.721 months [95% confidence interval (CI): 1.365-10.076]. The median PFS and ORRs of the male patients compared to the female patients were 10.553 vs. 4.340 months, and 36.4% vs. 0.0%, respectively (P=0.010 and 0.041). The DCRs for the first-, second-, and third-line therapies were 100%, 83.3%, and 64.3%, respectively (P=0.096). In relation to the pathological types, the ORRs of the sarcoma, squamous, and adenocarcinoma patients were 100.0%, 33.3%, and 18.5%, respectively (P=0.025). The DCRs of patients with the tumor protein 53 (TP53) mutation, other status, and epidermal growth factor receptor (EGFR) mutations were 100.0%, 81.5%, and 40.0%, respectively (P=0.020). All-grade AEs occurred in 52.38% of the patients. The grade 3 AEs were hypertension (7.14%), pneumonia (2.38%), and oral mucositis (2.38%). In total, 3 patients discontinued treatment due to anemia, oral mucositis, and pneumonia, respectively. Conclusions: Anlotinib combined with PD-1 inhibitors has potentially good efficacy and a tolerated safety profile in the treatment of advanced NSCLC patients.
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Chronic inflammation is associated with lung tumorigenesis, in which NF-κB-mediated epigenetic regulation plays a critical role. Lung tumor suppressor G protein-coupled receptor, family C, member 5A (GPRC5A), is repressed in most non-small cell lung cancer (NSCLC); however, the mechanisms remain unclear. Here, we show that NF-κB acts as a transcriptional repressor in suppression of GPRC5A. NF-κB induced GPRC5A repression both in vitro and in vivo. Intriguingly, transactivation of NF-κB downstream targets was not required, but the transactivation domain of RelA/p65 was required for GPRC5A repression. NF-κB did not bind to any potential cis-element in the GPRC5A promoter. Instead, p65 was complexed with retinoic acid receptor α/ß (RARα/ß) and recruited to the RA response element site at the GPRC5A promoter, resulting in disrupted RNA polymerase II complexing and suppressed transcription. Notably, phosphorylation on serine 276 of p65 was required for interaction with RARα/ß and repression of GPRC5A. Moreover, NF-κB-mediated epigenetic repression was through suppression of acetylated histone H3K9 (H3K9ac), but not DNA methylation of the CpG islands, at the GPRC5A promoter. Consistently, a histone deacetylase inhibitor, but not DNA methylation inhibitor, restored GPRC5A expression in NSCLC cells. Thus, NF-κB induces transcriptional repression of GPRC5A via a complex with RARα/ß and mediates epigenetic repression via suppression of H3K9ac.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , NF-kappa B/metabolismo , Carcinoma Pulmonar de Células não Pequenas/genética , Ativação Transcricional , Epigênese Genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Pulmão/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Receptores do Ácido Retinoico/genética , Receptores do Ácido Retinoico/metabolismo , Células Epiteliais/metabolismoRESUMO
Iron is a critical element for living cells in terrestrial life. Although iron metabolism is strictly controlled in the body, disturbance of iron homeostasis under certain type of condition leads to innate and adaptive immune response. In innate immunity, iron regulates macrophage polarizations, neutrophils recruitment, and NK cells activity. In adaptive immunity, iron had an effect on the activation and differentiation of Th1, Th2, and Th17 and CTL, and antibody response in B cells. In this review, we focused on iron and immune regulation and listed the specific role of iron in macrophage polarization, T-cell activation, and B-cells antibody response. In addition, correlations between iron and several diseases such as cancer and aging degenerative diseases and some therapeutic strategies targeting those diseases are also discussed.
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Imunidade Inata , Ativação de Macrófagos , Imunidade Adaptativa , Ferro/metabolismo , Ativação LinfocitáriaRESUMO
While initiation is established as a critical step in tumorigenesis, the identity of the cell of origin for lung adenocarcinoma and the mechanism controlling susceptibility to initiation remain elusive. Here we show that lung tumor suppressor Gprc5a-knockout (KO) mice are susceptible to initiation of lung tumorigenesis. Bronchioalveolar stem cells (BASC) and alveolar type 2 (AT2) cells were aberrantly expanded in Gprc5a-KO mouse lungs compared with those in wild-type (WT) mice, suggesting that Gprc5a-KO might confer susceptibility to initiation by increasing the cell of origin in mouse lungs. BASCs from Gprc5a-KO mice (KO-BASC) exhibited significantly increased stemness and self-renewal potential and reduced differentiation capacity compared with BASCs from WT mice (WT-BASC). AT2 cells did not possess self-renewal potential regardless of Gprc5a status. KO-BASCs expressed a stem-like gene profile with upregulated Abcg2, EGFR, and NF-κB signaling compared with WT-BASCs. Blockade of EGFR and NF-κB signaling inhibited both expansion of BASC and AT2 cells and lung tumorigenesis. Abcg2 was expressed in active KO-BASCs as well as in lung tumor cells but not in quiescent WT-BASCs or AT2 cells, supporting that lung adenocarcinoma cells are derived from Abcg2-positive KO-BASCs (active). Taken together, Gprc5a deletion leads to expansion of active BASCs via dysregulated EGFR and NF-κB signaling that confers susceptibility to initiation of lung tumorigenesis, marking Abcg2-positive BASCs as candidate cell of origin for lung adenocarcinoma. SIGNIFICANCE: Identification of active bronchioalveolar stem cells as lung adenocarcinoma cells of origin provides insights into mechanisms of lung tumorigenesis and could facilitate development of effective strategies for cancer prevention and therapy. See related commentary by Osborne and Minna, p. 972.
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Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Células-Tronco , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/metabolismo , Animais , Carcinogênese , Transformação Celular Neoplásica , Receptores ErbB/genética , Receptores ErbB/metabolismo , Humanos , Pulmão/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Camundongos , Camundongos Knockout , NF-kappa B/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismoRESUMO
Ferroptosis is a new form of regulated cell death. Several studies have demonstrated that ferroptosis was involved in multiple diseases. However, the precise role of ferroptosis in osteoporosis remains unclear. Here, we demonstrated that ferroptosis was involved in osteoclasts over the course of RANKL-induced differentiation, and it was induced by iron-starvation response and ferrintinophagy. Mechanistically, under normoxia but not hypoxia, ferroptosis could be induced due to iron-starvation response (increased transferrin receptor 1, decreased ferritin) followed by RANKL stimulation, and this was attributed to the down-regulation of aconitase activity. We further investigated intracellular iron homeostasis and found that ferritinophagy, a process initiated by FTH-NCOA4 complex autophagosome degradation, was activated followed by RANKL stimulation under normoxia. Interestingly, these processes could not be observed under hypoxia. Moreover, we demonstrated that HIF-1α contributed to the decrease of ferritinophagy and autophagy flux under hypoxia. Additionally, HIF-1α impair autophagy flux via inhibition of autophagosome formation under hypoxia in BMDMs. In vivo study, we indicated that HIF-1α specific inhibitor 2ME2 prevent OVX bone loss. In conclusion, our study comprehensively investigated the role of ferroptosis in osteoclasts in vitro and in vivo, and innovatively suggested that targeting HIF-1α and ferritin thus inducing ferroptosis in osteoclasts could be an alternative in treatment of osteoporosis.
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Ferroptose , Ferritinas , Humanos , Hipóxia , Ferro/metabolismo , Osteoclastos/metabolismo , Ligante RANK/farmacologiaRESUMO
Heme oxygenase1 (HO1) has been reported to be upregulated following renal ischemiareperfusion injury (IRI) and plays a key cytoprotective role; however, the underlying molecular mechanisms of its protective effects remain poorly understood. In the present study, in order to further elucidate the molecular mechanisms underlying the cytoprotective role of HO1 in renal IRI, HO1+/+ and HO1+/ mice were subjected to renal ischemia and subsequent reperfusion followed by the analysis of blood urea nitrogen (BUN) and serum creatinine (SCr) levels, the severity of histological changes, HO1 and vascular cell adhesion molecule1 (VCAM1) protein expression, the mRNA expression of inflammatory factors and the effects of VCAM1 blockade. The results of the present study demonstrated that the upregulated expression levels of VCAM1 in HO1+/ mice during IRI increased the extent of renal tissue damage and activated the inflammatory response. These effects were subsequently reversed following infusion with an antiVCAM1 antibody. In addition, the upregulated expression of VCAM1 in mouse glomerulus vascular endothelial cells isolated from HO1+/ mice increased the adhesion and migration of neutrophils, effects which were also reversed upon incubation with an antiVCAM1 antibody. These results indicated that HO1 knockdown may upregulate the expression of VCAM1 during renal IRI, resulting in increased neutrophil recruitment and the activation of the inflammatory response, thereby exacerbating renal IRI. The present study thus highlights the regulatory mechanisms of HO1 in renal IRI and provides a potential target for the clinical treatment of IRI following renal transplantation.
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Heme Oxigenase-1/genética , Nefropatias/genética , Proteínas de Membrana/genética , Neutrófilos/imunologia , Traumatismo por Reperfusão/genética , Regulação para Cima/genética , Molécula 1 de Adesão de Célula Vascular/genética , Animais , Nitrogênio da Ureia Sanguínea , Creatinina/sangue , Creatinina/imunologia , Heme Oxigenase-1/imunologia , Inflamação/sangue , Inflamação/genética , Inflamação/imunologia , Rim/imunologia , Rim/patologia , Nefropatias/imunologia , Masculino , Proteínas de Membrana/imunologia , Camundongos , Traumatismo por Reperfusão/imunologia , Regulação para Cima/imunologia , Molécula 1 de Adesão de Célula Vascular/imunologiaRESUMO
Cancer cells need to generate large amounts of glutathione (GSH) to buffer oxidative stress during tumor development. A rate-limiting step for GSH biosynthesis is cystine uptake via a cystine/glutamate antiporter Xc-. Xc- is a sodium-independent antiporter passively driven by concentration gradients from extracellular cystine and intracellular glutamate across the cell membrane. Increased uptake of cystine via Xc- in cancer cells increases the level of extracellular glutamate, which would subsequently restrain cystine uptake via Xc-. Cancer cells must therefore evolve a mechanism to overcome this negative feedback regulation. In this study, we report that glutamate transporters, in particular SLC1A1, are tightly intertwined with cystine uptake and GSH biosynthesis in lung cancer cells. Dysregulated SLC1A1, a sodium-dependent glutamate carrier, actively recycled extracellular glutamate into cells, which enhanced the efficiency of cystine uptake via Xc- and GSH biosynthesis as measured by stable isotope-assisted metabolomics. Conversely, depletion of glutamate transporter SLC1A1 increased extracellular glutamate, which inhibited cystine uptake, blocked GSH synthesis, and induced oxidative stress-mediated cell death or growth inhibition. Moreover, glutamate transporters were frequently upregulated in tissue samples of patients with non-small cell lung cancer. Taken together, active uptake of glutamate via SLC1A1 propels cystine uptake via Xc- for GSH biosynthesis in lung tumorigenesis. SIGNIFICANCE: Cellular GSH in cancer cells is not only determined by upregulated Xc- but also by dysregulated glutamate transporters, which provide additional targets for therapeutic intervention.
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Cistina/metabolismo , Transportador 3 de Aminoácido Excitatório/metabolismo , Ácido Glutâmico/metabolismo , Glutationa/biossíntese , Neoplasias Pulmonares/metabolismo , Animais , Antiporters/metabolismo , Morte Celular , Linhagem Celular Tumoral , Glutamina/deficiência , Neoplasias Pulmonares/etiologia , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Nus , Estresse Oxidativo , Receptores Acoplados a Proteínas G , Estresse Fisiológico , Regulação para CimaRESUMO
Lung squamous cell carcinomas (SCCs) are highly aggressive tumors, and there is currently no effective targeted therapy owing to the lack of specific mutation targets. Compared with lung adenocarcinoma (ADCs), lung SCCs reportedly utilized higher levels of glucose metabolism to meet the anabolic and catabolic needs required to sustain rapid tumor growth. Hexokinase 2 (HK2) is an enzyme that catalyzes the rate-limit and first committed step in glucose metabolism. Here, we investigated the expression and effect of HK2 in lung SCCs. We found a significantly higher HK2 expression in lung SCCs, but not lung ADC or normal tissues. HK2 depletion or inhibition decreased the glycolysis and tumor growth via activating AMPK signaling pathway, which downregulated mTORC1 activity. Furthermore, we found an increased oxygen respiration rate compensating for HK2 depletion. Thus, metformin treatment showed combinatorial therapeutic value, which resulted in greater induction of lung SCC apoptosis in vitro and in vivo. Our study suggests that HK2 depletion in combination with metformin might be a novel effective strategy for lung SCCs therapy.
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Cancer cells that succeed in forming metastasis need to be reprogrammed to evade immune surveillance and survive in a new microenvironment. This is facilitated by metastatic niches that are either postformed through reciprocal signaling between tumor cells and local stromal cells or preformed as premetastatic niches before tumor cell arrival. IL6/STAT3 signaling is aberrantly activated in lung tumorigenesis and metastasis, however, the roles and mechanisms of action of IL6 remain controversial. Here, we showed that blockade of intrinsic STAT3 signaling in lung tumor cells suppressed lung metastasis in immune-competent syngeneic mice, but not in immune-deficient nude mice. Consistently, repression of STAT3 signaling in tumor cells made them susceptible to T-cell-mediated cytotoxicity. Thus, STAT3-mediated immunosuppression is crucial for metastasis. Noticeably, lung metastasis was greatly increased in Gprc5a-knockout (ko; 5a -/-) mice compared with wild-type mice, which correlated with upregulated IL6 in the tumor microenvironment. Depletion of IL6 via combined deletion of Il6 and Gprc5a genes almost completely eliminated lung metastasis in Gprc5a-ko/Il6-ko (5a -/-;Il6 -/-) mice. Mechanistically, dysregulated IL6 reprogrammed the STAT3 pathway in metastatic tumor cells, and induced recruitment of myeloid-derived suppressor cells and polarized macrophages to evade host immunity. Consistently, IHC staining showed that activated STAT3 correlated with repressed infiltration of CD8+ T cells in non-small cell lung cancer. Therefore, IL6/STAT3 signaling is crucial for orchestrating premetastatic niche formation and immunosuppression in lung.Significance: IL6 plays important roles not only in cell autonomous propensity for metastasis, but also in establishing the metastatic niche.
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Carcinoma Pulmonar de Lewis/patologia , Carcinoma Pulmonar de Células não Pequenas/imunologia , Interleucina-6/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/imunologia , Animais , Linfócitos T CD8-Positivos/imunologia , Carcinogênese/imunologia , Carcinogênese/patologia , Carcinoma Pulmonar de Lewis/imunologia , Carcinoma Pulmonar de Células não Pequenas/secundário , Linhagem Celular Tumoral , Reprogramação Celular/genética , Reprogramação Celular/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Pulmão/citologia , Pulmão/imunologia , Pulmão/patologia , Linfócitos do Interstício Tumoral/imunologia , Macrófagos/imunologia , Camundongos , Camundongos Knockout , Camundongos Nus , Células Supressoras Mieloides/imunologia , Cultura Primária de Células , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Fator de Transcrição STAT3/imunologia , Evasão Tumoral/genética , Microambiente Tumoral/genética , Microambiente Tumoral/imunologiaRESUMO
Chronic inflammation has been linked to promotion of tumorigenesis and metastasis in lung. However, due to lack of a relevant animal model for characterization, the underlying mechanism remains elusive. Lung tumor suppressor gene Gprc5a-knockout (ko) mice are susceptible to lung inflammation, tumorigenesis and metastasis, which resembles the pathological features in human patients. Here, we showed that PTGES/PGE2 signaling was highly associated with lung tumorigenesis and metastasis in Gprc5a-ko mice. Interestingly, Ptges-knockout in mouse lung tumor cells, although reduced their stemness and EMT-like features, still formed tumors and lung metastasis in immune-deficient nude mice, but not in immune-competent mice. This suggests that the major role of PTGES/PGE2 signaling in tumorigenicity and lung metastasis is through immunosuppression. Mechanistically, PTGES/PGE2 signaling intrinsically endows tumor cells resistant to T-cell cytotoxicity, and induces cytokines extrinsically for MDSC recruitment, which is crucial for suppression of T-cell immunity. Importantly, targeting PGE2 signaling in Gprc5a-ko mice by PTGES inhibitor suppressed MDSC recruitment, restored T cells, and significantly repressed lung metastasis. Thus, PTGES/PGE2 signaling links immunosuppression and metastasis in an inflammatory lung microenvironment of Gprc5a-ko mouse model.
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Dinoprostona/metabolismo , Neoplasias Pulmonares/imunologia , Prostaglandina-E Sintases/metabolismo , Receptores Acoplados a Proteínas G/genética , Evasão Tumoral/genética , 4-Butirolactona/análogos & derivados , 4-Butirolactona/farmacologia , 4-Butirolactona/uso terapêutico , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Carcinogênese/efeitos dos fármacos , Carcinogênese/genética , Carcinogênese/imunologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Células HEK293 , Humanos , Pulmão/imunologia , Pulmão/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Knockout , Camundongos Nus , Células Supressoras Mieloides/efeitos dos fármacos , Células Supressoras Mieloides/imunologia , Células Supressoras Mieloides/metabolismo , Pneumonia/genética , Pneumonia/imunologia , Pneumonia/patologia , Cultura Primária de Células , Prostaglandina-E Sintases/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Tiofenos/farmacologia , Tiofenos/uso terapêutico , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologiaRESUMO
Iron is an essential trace element in the human body, and its deficiency or excess induces diverse biological processes. Iron dysregulation is closely associated with the initiation and development of several malignant tumors, including lung cancer. Emerging evidence suggests a particularly important role for iron in lung cancer. Moreover, iron plays a prominent part in multiple forms of cell death, making it important for the development of potential strategies for lung cancer therapy. Here we review the function and characteristics of iron and new therapeutic opportunities in lung cancer.
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Ferro/metabolismo , Neoplasias Pulmonares/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Sobrevivência Celular/efeitos dos fármacos , Redes Reguladoras de Genes/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/tratamento farmacológicoRESUMO
AIMS: Lung cancer remains the leading cause of cancer incidence and mortality. Although cigarette smoke is regarded as a high risk factor for lung tumor initiation, the role of the lung tumor suppressor GPRC5A in smoking-induced lung cancer is unclear. MAIN METHODS: We obtained two lung cancer cohorts from the TCGA and GEO databases. Bioinformatics analysis showed differential gene expression in the cohorts. Quantitative real-time PCR, Western Blot and Gprc5a-/- mice uncovered the relationship between cigarette smoke and lung cancer in the GPRC5A deletion system in vitro and in vivo. KEY FINDINGS: Bioinformatics analysis showed that the smoking lung cancer patients with low expression of GPRC5A had poor overall survival compared to the patients with high GPRC5A expression. Further analysis revealed that cancer-related stemness pathways such as the Hippo signaling pathway were induced in smoking patients with low GPRC5A expression. Additionally, we detected enriched expression of WNT5A and DLX5 in normal human lung epithelial 16HBE cells and human lung cancer H1299 cells in vitro. A relationship between cigarette smoke extract (NNK) and lung tumor initiation was observed in Gprc5a-/- mice. SIGNIFICANCE: The lung tumor suppressor gene GPRC5A played a protective role in cigarette smoke-induced lung tumor initiation, providing a target for the prevention of lung cancer development and monitoring of prognosis.
Assuntos
Carcinogênese/metabolismo , Neoplasias Pulmonares/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Fumar/metabolismo , Adenocarcinoma/metabolismo , Animais , Linhagem Celular Tumoral , Transformação Celular Neoplásica/metabolismo , Feminino , Genes Supressores de Tumor/fisiologia , Humanos , Pulmão/metabolismo , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Transdução de Sinais/fisiologiaRESUMO
Induction of cancer stem cell (CSC) characters and epithelial mesenchymal transition (EMT) features are crucial in tumor initiation, progression and metastasis. However, underlying mechanisms remain incompletely understood. Here, we showed that ENPP1 plays an important role in inducing and maintaining EMT phenotypes and CSC features in lung cancer. ENPP1 is upregulated in lung cancer cells. ENPP1-knockdown in lung cancer HCC827 cells and A549 cells resulted in suppressed colonogenic formation, anchorage-independent growth in vitro, and tumorigenicity in vivo. ENPP1-knockdown also reduced expression of CSC makers, including ABCG2, SOX2, NANOG, and CD44. Moreover, ENPP1-knockdown reversed TGFß-induced EMT phenotypes, including cell migration, E-cadherin repression and vimentin induction. Finally, upregulated ENPP1 was identified in majority of human lung tumor tissues compared to adjacent normal lung tissues. Taken together, our study demonstrates that dysregulated ENPP1 contributes to increased malignancy of human lung cancer by inducing CSC-features, and EMT-like phenotypes.
RESUMO
The mechanism by which tumor-associated macrophages (TAMs) affect cancer progression is not fully understood. This study developed a microfluidic-based co-culture device to mimic the tumor microenvironment to assess TAM effects on invasion and metastasis in NSCLC. The results showed lung carcinoma cells could cause macrophages to show the M2 (a TAM-like) phenotype, and these M2 macrophages promoted lung cancer cell EMT and invasion. Proteomic analysis by the iTRAQ quantitation strategy and GO ontology of the cancer cells indicated that αB-Crystallin (CRYAB) might be involved in this process. Further, we confirmed the role of CRYAB in cancer invasion and metastasis through cell and animal experiments, as well as human cancer tissue assessment. Overall, we demonstrated that M2 macrophages promote malignancy in lung cancer through the EMT by upregulating CRYAB expression and activating the ERK1/2/Fra-1/slug signaling pathway.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/patologia , Transição Epitelial-Mesenquimal , Macrófagos/metabolismo , Cadeia B de alfa-Cristalina/metabolismo , Animais , Linhagem Celular Tumoral , Técnicas de Cocultura , Regulação para Baixo , Técnicas de Silenciamento de Genes , Humanos , Camundongos , Camundongos Nus , Microfluídica , Invasividade Neoplásica , Metástase Neoplásica , Proteômica , Transdução de Sinais , Microambiente Tumoral , Regulação para Cima , Cadeia B de alfa-Cristalina/genéticaRESUMO
Early metastasis and local recurrence are the major causes of mortality and poor prognosis of non-small cell lung cancer (NSCLC). However, the underlying mechanisms of these processes are poorly understood. In this study, we aimed to investigate the roles of the PTGES/PGE2 pathway in lung cancer progression. We found that prostaglandin E synthase (PTGES), a key enzyme for PGE2 synthesis in the arachidonic acid pathway, was highly dysregulated in NSCLC. Dysregulated PTGES was essential for the promotion of tumor migration and metastasis of NSCLC cells. Knockdown of PTGES in lung cancer cells resulted in suppressed cell migration, which was reversed by exogenous PGE2. Consistent with this, PTGES knockdown also reduced the expression of CSC markers, tumor sphere formation, colony forming activity, tumorigenicity, and lung metastasis in vivo. Dysregulated PTGES is mainly attributed to protein stabilization by USP9X, a deubiquitination enzyme. USP9X physically interacted with PTGES and prevented it from proteasome-directed degradation via deubiquitination. Consistent with this, USP9X expression was highly correlated with PTGES expression in NSCLC tumor tissues. Taken together, our results show that the upregulated USP9X-PTGES-PGE2 axis contributes significantly to the metastatic features of NSCLC.