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RATIONALE: Recent studies indicate that tumor-associated macrophages (MΦ) with an M2 phenotype can influence cancer progression and metastasis, but the regulatory pathways remain poorly characterized. OBJECTIVES: This study investigated the role of tumor-associated MΦ in lung cancer. METHODS: Coculturing of MΦ with mouse Lewis lung carcinoma (LLC1) and 10 different human lung cancer cell lines (adenocarcinoma, squamous cell carcinoma, and large cell carcinoma) caused up-regulation of CCR2/CCL2 and CX3CR1/CX3CL1 in both the cancer cells and the MΦ. MEASUREMENTS AND MAIN RESULTS: In the MΦ-tumor cell system, IL-10 drove CCR2 and CX3CR1 up-regulation, whereas CCL1, granulocyte colony-stimulating factor, and MIP1α were required for the up-regulation of CCL2 and CX3CL1. Downstream phenotypic effects included enhanced LLC1 proliferation and migration and MΦ M2 polarization. In vivo, MΦ depletion (clodronate, MΦ Fas-induced apoptosis mice) and genetic ablation of CCR2 and CX3CR1 all inhibited LLC1 tumor growth and metastasis, shifted tumor-associated MΦ toward M1 polarization, suppressed tumor vessel growth, and enhanced survival (metastasis model). Furthermore, mice treated with CCR2 antagonist mimicked genetic ablation of CCR2, showing reduced tumor growth and metastasis. In human lung cancer samples, tumor MΦ infiltration and CCR2 expression correlated with tumor stage and metastasis. CONCLUSIONS: Tumor-associated MΦ play a central role in lung cancer growth and metastasis, with bidirectional cross-talk between MΦ and cancer cells via CCR2 and CX3CR1 signaling as a central underlying mechanism. These findings suggest that the therapeutic strategy of blocking CCR2 and CX3CR1 may prove beneficial for halting lung cancer progression.
Assuntos
Adenocarcinoma/metabolismo , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Grandes/metabolismo , Carcinoma de Células Escamosas/metabolismo , Neoplasias Pulmonares/metabolismo , Macrófagos/metabolismo , Adenocarcinoma/patologia , Animais , Receptor 1 de Quimiocina CX3C , Carcinoma de Células Grandes/patologia , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Quimiocina CCL2/metabolismo , Quimiocina CX3CL1/metabolismo , Humanos , Neoplasias Pulmonares/patologia , Camundongos , Metástase Neoplásica , Estadiamento de Neoplasias , Receptor Cross-Talk , Receptores CCR2/metabolismo , Receptores de Quimiocinas/metabolismo , Regulação para CimaRESUMO
Lung cancer is frequently complicated by pulmonary infections which may impair prognosis of this disease. Therefore, we investigated the effect of bacterial lipopolysaccharides (LPS) on tumor proliferation in vitro in the non-small cell lung cancer (NSCLC) cell line A549, ex vivo in a tissue culture model using human NSCLC specimens and in vivo in the A549 adenocarcinoma mouse model. LPS induced a time- and dose-dependent increase in proliferation of A549 cells as quantified by MTS activity and cell counting. In parallel, an increased expression of the proliferation marker Ki-67 and cyclooxygenase (COX)-2 was detected both in A549 cells and in ex vivo human NSCLC tissue. Large amounts of COX-2-derived prostaglandin (PG)E(2) were secreted from LPS-stimulated A549 cells. Pharmacological interventions revealed that the proliferative effect of LPS was dependent on CD14 and Toll-like receptor (TLR)4. Moreover, blocking of the epidermal growth factor receptor (EGFR) also decreased LPS-induced proliferation of A549 cells. Inhibition of COX-2 activity in A549 cells severely attenuated both PGE(2) release and proliferation in response to LPS. Synthesis of PGE(2) was also reduced by inhibiting CD14, TLR4 and EGFR in A549 cells. The proliferative effect of LPS on A549 cells could be reproduced in the A549 adenocarcinoma mouse model with enhancement of tumor growth and Ki-67 expression in implanted tumors. In summary, LPS induces proliferation of NSCLC cells in vitro, ex vivo in human NSCLC specimen and in vivo in a mouse model of NSCLC. Pulmonary infection may thus directly induce tumor progression in NSCLC.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/patologia , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Receptores ErbB/metabolismo , Lipopolissacarídeos/imunologia , Neoplasias Pulmonares/patologia , Proteínas de Membrana/metabolismo , Animais , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Inibidores de Ciclo-Oxigenase/farmacologia , Dinoprostona/análise , Dinoprostona/metabolismo , Modelos Animais de Doenças , Receptores ErbB/antagonistas & inibidores , Humanos , Indometacina/farmacologia , Antígeno Ki-67/biossíntese , Receptores de Lipopolissacarídeos/metabolismo , Lipopolissacarídeos/farmacologia , Neoplasias Pulmonares/metabolismo , Proteínas de Membrana/antagonistas & inibidores , Camundongos , Nitrobenzenos/farmacologia , Sulfonamidas/farmacologia , Receptor 4 Toll-Like/antagonistas & inibidores , Receptor 4 Toll-Like/metabolismoRESUMO
The radium lutetium (RALU) study evaluated the feasibility of sequential α- and ß-emitter use in patients with bone-predominant metastatic castration-resistant prostate cancer. Methods: This preplanned interim retrospective analysis investigated safety and survival outcomes with 177Lu-PSMA in patients treated with prior 223Ra. Results: Forty-nine patients were evaluated. Patients received a median of 6 223Ra injections; 59% of patients received at least 4 177Lu-PSMA cycles. Most (69%) patients received at least 4 life-prolonging therapies before 177Lu-PSMA. Common Terminology Criteria for Adverse Events grade 3-4 treatment-emergent adverse events during 177Lu-PSMA therapy and a 30-d follow-up period included anemia (18%) and thrombocytopenia (2%). Median overall survival was 12.6 mo (95% CI, 8.8-16.1 mo) and 31.4 mo (95% CI, 25.7-37.6 mo) from starting 177Lu-PSMA or 223Ra, respectively. Conclusion: 177Lu-PSMA treatment was well tolerated in patients who had received prior 223Ra. 223Ra use before 177Lu-PSMA is feasible and can be considered for future assessment of the optimal treatment sequence.
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Neoplasias de Próstata Resistentes à Castração , Rádio (Elemento) , Masculino , Humanos , Lutécio/efeitos adversos , Rádio (Elemento)/efeitos adversos , Resultado do Tratamento , Estudos Retrospectivos , Próstata/patologia , Antígeno Prostático Específico , Dipeptídeos/efeitos adversos , Compostos Heterocíclicos com 1 Anel/efeitos adversosRESUMO
223Ra-dichloride (223Ra) and 177Lu-prostate-specific membrane antigen (PSMA) are approved treatments for metastatic castration-resistant prostate cancer (mCRPC). The safety and effectiveness of sequential use of 223Ra and 177Lu-PSMA in patients with mCRPC are not well described. This study aimed to evaluate 177Lu-PSMA safety and efficacy in patients with mCRPC previously treated with 223Ra. Methods: The radiumâlutetium (RALU) study was a multicenter, retrospective, medical chart review. Participants had received at least 1 223Ra dose and, in any subsequent therapy line, at least 1 177Lu-PSMA dose. Primary endpoints included the incidence of adverse events (AEs), serious AEs, grade 3-4 hematologic AEs, and abnormal laboratory values. Secondary endpoints included overall survival, time to next treatment/death, and change from baseline in serum prostate-specific antigen and alkaline phosphatase levels. Results: Data were from 133 patients. Before 177Lu-PSMA therapy, 56% (75/133) of patients received at least 4 life-prolonging therapies; all patients received 223Ra (73% received 5-6 injections). Overall, 27% (36/133) of patients received at least 5 177Lu-PSMA infusions. Any-grade treatment-emergent AEs were reported in 79% (105/133) of patients and serious AEs in 30% (40/133). The most frequent grade 3-4 laboratory abnormalities were anemia (30%, 40/133) and thrombocytopenia (13%, 17/133). Median overall survival was 13.2 mo (95% CI, 10.5-15.6 mo) from the start of 177Lu-PSMA. Conclusion: In this real-world setting, 223Ra followed by 177Lu-PSMA therapy in heavily pretreated patients with mCRPC was clinically feasible, with no indication of impairment of 177Lu-PSMA safety or effectiveness.
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Neoplasias de Próstata Resistentes à Castração , Rádio (Elemento) , Masculino , Humanos , Lutécio/uso terapêutico , Rádio (Elemento)/efeitos adversos , Resultado do Tratamento , Estudos Retrospectivos , Próstata/patologia , Compostos Radiofarmacêuticos/uso terapêutico , Antígeno Prostático Específico , Dipeptídeos/efeitos adversos , Compostos Heterocíclicos com 1 Anel/efeitos adversosRESUMO
Radium-223 dichloride (223Ra) is an α-emitter approved for the treatment of metastatic castration-resistant prostate cancer (mCRPC) with bone metastases, but without visceral involvement. Despite being a life-prolonging therapy (LPT), 223Ra remains underutilized. A large body of real-world evidence (RWE) for 223Ra has been published in the decade since the pivotal phase 3 ALSYMPCA study, a period during which the treatment landscape has continued to evolve. How to optimize 223Ra use, including how to integrate it into the mCRPC management pathway amongst other current LPTs (i.e., with respect to timing and concurrent, layered, or sequential use), is therefore of considerable interest. RWE studies lack the conventional restraints of clinical trials and can therefore help to build an understanding of how treatments may be best used in routine practice. Here we review RWE studies investigating the efficacy and safety of 223Ra in mCRPC [including in sequence with the recently approved 177-Lutetium conjugated to the ligand prostate-specific membrane antigen (177Lu-PSMA)], as well as response marker development, imaging techniques, and current clinical practice recommendations.
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Immune microenvironment plays a critical role in lung cancer control versus progression and metastasis. In this investigation, we explored the effect of tumor-infiltrating lymphocyte subpopulations on lung cancer biology by studying in vitro cocultures, in vivo mouse models, and human lung cancer tissue. Lymphocyte conditioned media (CM) induced epithelial-mesenchymal transition (EMT) and migration in both primary human lung cancer cells and cell lines. Correspondingly, major accumulation of Th9 and Th17 cells was detected in human lung cancer tissue and correlated with poor survival. Coculturing lung cancer cells with Th9/Th17 cells or exposing them to the respective CM induced EMT in cancer cells and modulated the expression profile of genes implicated in EMT and metastasis. These features were reproduced by the signatory cytokines IL-9 and IL-17, with gene regulatory profiles evoked by these cytokines partly overlapping and partly complementary. Coinjection of Th9/Th17 cells with tumor cells in WT, Rag1-/-, Il9r-/-, and Il17ra-/- mice altered tumor growth and metastasis. Accordingly, inhibition of IL-9 or IL-17 cytokines by neutralizing antibodies decreased EMT and slowed lung cancer progression and metastasis. In conclusion, Th9 and Th17 lymphocytes induce lung cancer cell EMT, thereby promoting migration and metastatic spreading and offering potentially novel therapeutic strategies.
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Movimento Celular/imunologia , Transição Epitelial-Mesenquimal/imunologia , Neoplasias Pulmonares/imunologia , Células Th17/imunologia , Microambiente Tumoral/imunologia , Células A549 , Animais , Humanos , Interleucina-17/imunologia , Interleucina-9/imunologia , Neoplasias Pulmonares/patologia , Camundongos , Metástase Neoplásica , Células Th17/patologiaRESUMO
Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal parenchymal lung disease with limited therapeutic options, with fibroblast-to-myofibroblast transdifferentiation and hyperproliferation playing a major role. Investigating ex vivo-cultured (myo)fibroblasts from human IPF lungs as well as fibroblasts isolated from bleomycin-challenged mice, Forkhead box O3 (FoxO3) transcription factor was found to be less expressed, hyperphosphorylated, and nuclear-excluded relative to non-diseased controls. Downregulation and/or hyperphosphorylation of FoxO3 was reproduced by exposure of normal human lung fibroblasts to various pro-fibrotic growth factors and cytokines (FCS, PDGF, IGF1, TGF-ß1). Moreover, selective knockdown of FoxO3 in the normal human lung fibroblasts reproduced the transdifferentiation and hyperproliferation phenotype. Importantly, mice with global- (Foxo3-/-) or fibroblast-specific (Foxo3f.b-/-) FoxO3 knockout displayed enhanced susceptibility to bleomycin challenge, with augmented fibrosis, loss of lung function, and increased mortality. Activation of FoxO3 with UCN-01, a staurosporine derivative currently investigated in clinical cancer trials, reverted the IPF myofibroblast phenotype in vitro and blocked the bleomycin-induced lung fibrosis in vivo These studies implicate FoxO3 as a critical integrator of pro-fibrotic signaling in lung fibrosis and pharmacological reconstitution of FoxO3 as a novel treatment strategy.