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Ca(2+) acts as a universal and versatile second messenger in the regulation of a myriad of biological processes, including cell proliferation, differentiation, migration and apoptosis. Store-operated Ca(2+) entry (SOCE) mediated by ORAI and the stromal interaction molecule (STIM) constitutes one of the major routes of calcium entry in nonexcitable cells, in which the depletion of intracellular Ca(2+) stores triggers activation of the endoplasmic reticulum (ER)-resident Ca(2+) sensor protein STIM to gate and open the ORAI Ca(2+) channels in the plasma membrane (PM). Accumulating evidence indicates that SOCE plays critical roles in cancer cell proliferation, metastasis and tumor neovascularization, as well as in antitumor immunity. We summarize herein the recent advances in our understanding of the function of SOCE in various types of tumor cells, vascular endothelial cells and cells of the immune system. Finally, the therapeutic potential of SOCE inhibitors in the treatment of cancer is also discussed.
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Canales de Calcio/metabolismo , Calcio/metabolismo , Neoplasias/metabolismo , Neoplasias/patología , Animales , HumanosRESUMEN
The alternative activation of M2 macrophages in the lungs has been implicated as a causative agent in pulmonary fibrosis; however, the mechanisms underlying M2 polarization are poorly characterized. In this study, we investigated the role of the ubiquitously expressed Src homology domain-containing tyrosine phosphatase Shp2 in this process. Shp2 inactivation augmented IL-4-mediated M2 polarization in vitro, suggesting that Shp2 regulates macrophage skewing and prevents a bias toward the M2 phenotype. Conditional removal of Shp2 in monocytes/macrophages with lysozyme M promoter-driven Cre recombinase caused an IL-4-mediated shift toward M2 polarization. Additionally, an increase in arginase activity was detected in Shp2(∆/∆) mice after i.p. injection of chitin, whereas Shp2-deficient macrophages showed enhanced M2 polarization and protection against schistosome egg-induced schistosomiasis. Furthermore, mutants were more sensitive than control mice to bleomycin-induced inflammation and pulmonary fibrosis. Shp2 was associated with IL-4Rα and inhibited JAK1/STAT6 signaling through its phosphatase activity; loss of Shp2 promoted the association of JAK1 with IL-4Rα, which enhanced IL-4-mediated JAK1/STAT6 activation that resulted in M2 skewing. Taken together, these findings define a role for Shp2 in alveolar macrophages and reveal that Shp2 is required to inhibit the progression of M2-associated pulmonary fibrosis.
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Activación de Macrófagos/inmunología , Proteína Tirosina Fosfatasa no Receptora Tipo 11/inmunología , Fibrosis Pulmonar/inmunología , Schistosoma japonicum/inmunología , Esquistosomiasis Japónica/inmunología , Animales , Arginasa/biosíntesis , Bleomicina/efectos adversos , Bleomicina/farmacología , Líquido del Lavado Bronquioalveolar/citología , Líquido del Lavado Bronquioalveolar/inmunología , Células Cultivadas , Quitina/farmacología , Inflamación/inducido químicamente , Interleucina-13/biosíntesis , Interleucina-4/biosíntesis , Interleucina-4/inmunología , Interleucina-5/biosíntesis , Janus Quinasa 1/biosíntesis , Pulmón/inmunología , Pulmón/patología , Activación de Macrófagos/genética , Macrófagos Alveolares/inmunología , Ratones , Ratones Noqueados , Proteína Tirosina Fosfatasa no Receptora Tipo 11/genética , Fibrosis Pulmonar/inducido químicamente , Interferencia de ARN , ARN Interferente Pequeño , Receptores de Superficie Celular/inmunología , Factor de Transcripción STAT6/biosíntesis , Esquistosomiasis Japónica/parasitología , Transducción de Señal/genética , Transducción de Señal/inmunologíaRESUMEN
PURPOSE: Our study aimed to evaluate the impact of concomitant medications on the response and survival of patients with advanced digestive tract cancer receiving an immunotherapy-antiangiogenesis combination. METHODS: We conducted a three-center observational retrospective study of patients with advanced digestive tract cancer who received programmed death-1 (PD-1) inhibitors plus antiangiogenic agents between March 2019 and July 2022 in China. The patients had one of the three types of primary tumors: hepatocellular carcinoma (HCC), colorectal cancer (CRC), and gastric cancer (GC). RESULTS: The study included 352 patients. The most frequently prescribed co-medications were nonsteroidal anti-inflammatory drugs (NSAIDs) (46.3%), proton pump inhibitors (PPIs) (38.0%), systemic antibiotics (33.8%), and corticosteroids (30.1%). Probiotics had a direct correlation with a higher objective response rate (ORR) (OR 2.4, 95% CI 1.2 to 4.7, p = 0.013). Patients who received PPIs for gastritis/gastroesophageal reflux disease (GERD) (HR 0.7, 95% CI 0.5 to 1.0, p = 0.045), anticoagulants (HR 0.5, 95% CI 0.3 to 0.9, p = 0.009), and probiotics (HR 0.7, 95% CI 0.5 to 1.0, p = 0.034) had longer progression-free survival (PFS). Patients who received PPIs for gastritis/GERD (HR 0.6, 95% CI 0.4 to 0.9; p = 0.009) had longer overall survival (OS), while patients receiving opioids (HR 1.5, 95% CI 1.1 to 2.0, p = 0.010) had a significantly higher risk of death. CONCLUSION: Patients with advanced digestive tract cancer who were administered PPIs for gastritis/GERD indication, anticoagulants, or probiotics in combination with PD-1 inhibitors and antiangiogenic agents experienced improved clinical outcomes. However, opioid administration was linked to reduced OS in patients receiving combined therapy.
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Background: Cancer of unknown primary (CUP) is a class of metastatic malignant tumors whose primary location cannot be determined. The diagnosis and treatment of CUP are a considerable challenge for clinicians. Herein, we report a CUP case whose corresponding primary tumor sites were successfully identified, and the patient received proper treatment. Case report: In February 2022, a 74-year-old woman was admitted to the Medical Oncology Department at Sir Run Run Shaw Hospital for new lung and intestinal tumors after more than 9 years of breast cancer surgery. After laparoscopically assisted right hemicolectomy, pathology revealed mucinous adenocarcinoma; the pathological stage was pT2N0M0. Results from needle biopsies of lung masses suggested poorly differentiated cancer, ER (-), PR (-), and HER2 (-), which combined with the clinical history, did not rule out metastatic breast cancer. A surgical pathology sample was needed to determine the origin of the tumor tissue, but the patient's chest structure showed no indications for surgery. Analysis of the tumor's traceable gene expression profile prompted breast cancer, and analysis of next-generation amplification sequencing (NGS) did not obtain a potential drug target. We developed a treatment plan based on comprehensive immunohistochemistry, a gene expression profile, and NGS analysis. The treatment plan was formulated using paclitaxel albumin and capecitabine in combination with radiotherapy. The efficacy evaluation was the partial response (PR) after four cycles of chemotherapy and two cycles combined with radiotherapy. Conclusion: This case highlighted the importance of identifying accurate primary tumor location for patients to benefit from treatment, which will provide a reference for the treatment decisions of CUP tumors in the future.
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Immunotherapy and antiangiogenic therapy have shown promising clinical activity in patients with advanced biliary tract cancer (BTC) in clinical trials. As the combination of these two treatments for BTC is not well studied in the real world, the present study retrospectively analyzed the clinical outcomes of patients with unresectable BTC who received immunotherapy-antiangiogenesis combination therapy in a real-world setting. A three-center, retrospective study was performed on patients with unresectable BTC who received a combination of programmed death 1 inhibitor and antiangiogenic agent between March 26, 2019 and November 1, 2021 in China. In total, 68 patients were enrolled in the cohort. The objective response rate and disease control rate were 13.2 and 75.0%, respectively. The median time to progression, progression-free survival and overall survival were 8.2, 5.5 and 10.7 months, respectively. Adverse events of all grades occurred in 58 patients (85.3%). In conclusion, the present study demonstrated that immunotherapy-antiangiogenesis combination therapy may be considered a therapeutic option for patients with unresectable BTC. Further prospective investigations are needed.
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Colorectal cancer has a poor prognosis and is prone to recurrence and metastasis. DPP7, a prolyl peptidase, is reported to regulate lymphocyte quiescence. However, the correlation of DPP7 with prognosis in CRC remains unclear. With publicly available cohorts, the Wilcoxon rank-sum test and logistic regression were employed to analyze the relationship between DPP7 expression and the clinicopathological features of CRC patients. Specific pathways of differentially expressed genes were determined through biofunctional analysis and gene set enrichment analysis (GSEA). qPCR and immunohistochemical staining were used to determine DPP7 expression levels in surgical specimens. The public dataset and analysis of the biospecimens of CRC patients revealed that DPP7, in the CRC samples, was expressed significantly higher than in non-tumor tissues. Moreover, increased DPP7 was significantly associated with a higher N stage, lymphatic invasion, and shorter overall survival. Functionally, DPP7 is involved in neuroactive ligand-receptor interaction and olfactory transduction signaling. We identified a series of targeted drugs and small-molecule drugs with responses to DPP7. To conclude, DPP7 is a valuable diagnostic and prognostic biomarker for CRC and considered as a new therapeutic target.
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Studies have shown that epigenetic enzymes such as histone deacetylase (HDAC) are closely related to cancers and that several HDAC inhibitors exert antitumor effects. Studies have further suggested that class IIa HDAC inhibitors are related to immune functions, including immune responses and the expression of chemokines and complement pathway components. TMP195, a selective class IIa HDAC inhibitor, has been reported to be effective against breast cancer. However, the role and mechanism of TMP195 in colorectal cancer remain unknown. In this study, we found that TMP195 significantly reduced the tumor burden in two mouse models of colitis-associated colorectal cancer (CAC) and subcutaneous tumor. Mechanistically, TMP195 decreased the proportion of total macrophages but increased the proportion of M1 macrophages by promoting polarization, resulting in the increased release of inflammatory cytokines. TMP195 had no direct effect on the proliferation of colorectal cancer cells, and its antitumor effect on the colorectal cancer disappeared when macrophages were partly depleted by clodronate liposomes. In addition, TMP195 enhanced the efficacy of PD-1 blockade. The present study revealed that the combination of TMP195 and PD-1 blockade may provide a therapeutic strategy for colorectal cancer.
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Neoplasias Colorrectales , Inhibidores de Histona Desacetilasas , Ratones , Animales , Inhibidores de Histona Desacetilasas/farmacología , Receptor de Muerte Celular Programada 1/metabolismo , Ácido Clodrónico/metabolismo , Ácido Clodrónico/farmacología , Liposomas/metabolismo , Liposomas/farmacología , Macrófagos/metabolismo , Histona Desacetilasas/metabolismo , Citocinas/metabolismo , Neoplasias Colorrectales/metabolismo , Línea Celular TumoralRESUMEN
The crucial role of CD4+ and CD8+ T cells in shaping and controlling immune responses during immune disease and cancer development has been well established and used to achieve marked clinical benefits. CD3+CD4-CD8- double-negative (DN) T cells, although constituting a rare subset of peripheral T cells, are gaining interest for their roles in inflammation, immune disease and cancer. Herein, we comprehensively review the origin, distribution and functions of this unique T cell subgroup. First, we focused on characterizing multifunctional DN T cells in various immune responses. DN regulatory T cells have the capacity to prevent graft-versus-host disease and have therapeutic value for autoimmune disease. T helper-like DN T cells protect against or promote inflammation and virus infection depending on the specific settings and promote certain autoimmune disease. Notably, we clarified the role of DN tumor-infiltrating lymphocytes and outlined the potential for malignant proliferation of DN T cells. Finally, we reviewed the recent advances in the applications of DN T cell-based therapy for cancer. In conclusion, a better understanding of the heterogeneity and functions of DN T cells may help to develop DN T cells as a potential therapeutic tool for inflammation, immune disorders and cancer.
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Enfermedades Autoinmunes , Enfermedad Injerto contra Huésped , Neoplasias , Enfermedades Autoinmunes/terapia , Antígenos CD8 , Linfocitos T CD8-positivos , Humanos , Inflamación , Neoplasias/terapiaRESUMEN
BACKGROUND: Immunotherapy-antiangiogenesis combination therapy has achieved excellent survival outcomes in hepatocellular carcinoma (HCC) in clinical trials. However, the combination therapy for HCC outside clinical trials is not well studied, and predictive factors are lacking. Here, we retrospectively analyzed the efficacy and safety of immunotherapy-antiangiogenesis combination therapy in unresectable HCC patients in a real-world setting. METHODS: We conducted a four-center, retrospective study of unresectable HCC patients who received the combination of programmed death 1 (PD-1) inhibitor and antiangiogenic agent between April 2018 and July 2021 in China. RESULTS: In total, 136 patients were enrolled in the cohort. The objective response rate (ORR) and disease control rate (DCR) were 38.0% and 81.8%, respectively. The median time to progression (TTP), progression-free survival (PFS), and overall survival (OS) were 7.2, 7.3, and 19.6 months, respectively. The multivariate analysis indicated that ECOG performance status score (PS) 2 was a significantly independent negative factor of ORR. Moreover, ECOG PS 2, peritoneum metastasis and previous immunotherapy were found to be independent negative predictors of PFS. A shorter OS was associated with ECOG PS 2, peritoneum metastasis, the presence of previous immunotherapy, Child-Pugh stage B, and high alpha-fetoprotein (AFP) concentration. One hundred and twenty-five patients (91.9%) reported adverse events (AEs) with any grade. CONCLUSION: We elucidated the efficacy and safety of immunotherapy-antiangiogenesis combination therapy and identified potential predictors for response and survival in a real-world cohort of patients with unresectable HCC.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Inhibidores de la Angiogénesis/efectos adversos , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/patología , Humanos , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Neoplasias Hepáticas/patología , Receptor de Muerte Celular Programada 1 , Estudios Retrospectivos , alfa-FetoproteínasRESUMEN
Objective: We sought to investigate the prognostic significance of body composition and weight change during the first 6 months of adjuvant chemotherapy after R0 resection and develop novel nomograms to accurately predict relapse-free survival (RFS) and overall survival (OS). Methods: This retrospective study included 190 patients who underwent curative radical gastrectomy for gastric cancer and received adjuvant chemotherapy. The changes in weight and body composition including skeletal muscle index (SMI), subcutaneous adipose tissue (SAT), and visceral adipose tissue (VAT) were analyzed for 6 months. LASSO Cox regression and multivariate Cox regression were conducted to evaluate other clinical characteristics, which were used to construct a nomogram for the prediction of 3- and 5-year RFS and OS. The constructed nomogram was subjected to 1,000 resamples bootstrap for internal validation. The Concordance index (C-index) and time-dependent receiver operating characteristic (t-ROC) curves were used to evaluate and compare the discriminative abilities of the new nomograms, non-nutritional nomograms, and pTNM stage. Results: The median follow-up duration was 42.0 (25.2-55.1) months. Factors included in the newly-built nomogram for RFS were pT stage, pN stage, tumor site, tumor size, nerve invasion or not, surgery type, and change of L3SMI, while factors included in the nomogram for OS were pT stage, pN stage, tumor size, nerve invasion or not, surgery type, and change of L3SMI. The C-index and t-ROC indicated that our newly-built nomograms had greater potential to accurately predict prognosis than the non-nutritional nomograms and pTNM stage system. Besides, oral nutritional supplements can reduce the degree of weight and L3SMI loss. Conclusion: Change in skeletal muscle mass during adjuvant chemotherapy can be incorporated into predictive prognostic nomograms for RFS and OS in GC patients after radical resection. Dynamic changes in body composition and weight during adjuvant chemotherapy contribute to the early detection of poor outcomes.
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Arsenic trioxide (ATO), an ancient traditional Chinese medicine, has been successfully used as a therapeutic agent for leukemia. Drug resistance and toxicity are major concerns with the treatment. MicroRNAs (miRNAs) are endogenous small non-coding RNA molecules that might modulate cellular sensitivity to anticancer drugs. miRNA-21 (miR-21) is one of the most prominent miRNAs involved in various aspects of human cancers. However, miR-21 has been rarely characterized in chronic myelogenous leukemia (CML). Here, we used a specific anti-miR-21 oligonucleotide (AMO-miR-21) to sensitize K562 cells to ATO by degradation of miR-21. The results showed that both AMO-miR-21 and ATO caused growth inhibition, apoptosis, and G1-phase arrest in K562 cells. Meanwhile, AMO-miR-21 significantly promoted ATO-mediated growth inhibition and apotosis without affecting the G1 phase. Apoptotic cells were confirmed morphologically with Giemsa's staining. Furthermore, dual-luciferase reporter vector, containing two tandem miR-21 binding sites from PDCD4 3'UTR, validated that PDCD4 was directly regulated by miR-21. Therefore, AMO-miR-21 sensitized leukemic K562 cells to ATO by inducing apoptosis partially due to its up-regulation of PDCD4 protein level. The combination of ATO and AMO-miR-21 present therapeutic potential for CML.
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Antineoplásicos/farmacología , Arsenicales/uso terapéutico , Leucemia Mielógena Crónica BCR-ABL Positiva/terapia , MicroARNs/farmacología , Oligonucleótidos/farmacología , Óxidos/uso terapéutico , Apoptosis , Proteínas Reguladoras de la Apoptosis/genética , Proteínas Reguladoras de la Apoptosis/metabolismo , Trióxido de Arsénico , Ciclo Celular/genética , Fase G1/genética , Humanos , Células K562 , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , Regulación hacia ArribaRESUMEN
BACKGROUND: The synergistic effects of immunotherapy and antiangiogenic therapy in advanced non-small cell lung cancer (NSCLC) have been reported in both preclinical and clinical trials. Herein, we evaluated the preliminary efficacy and safety of combined immunotherapy and antiangiogenic therapy in patients with previously treated advanced NSCLC in a real-world setting. METHODS: We conducted a 2-center, retrospective study of previously treated advanced NSCLC patients who received any anti-programmed death-1 antibody combined with antiangiogenic agent between May 2018 and March 2020. RESULTS: In total, 57 patients were included in this study, and the objective response rate and disease control rate were 19.3% and 63.2%, respectively. The median progression-free survival (PFS) was 4.2 months (95% confidence interval [CI]: 3.2-5.2 months). Bone metastases (odds ratio [OR] not available; P < .01) and ≥ 3 treatment lines (OR 6.8; 95% CI: 1.6-29.6; P < .05) were independent negative predictors of objective response. Additionally, liver metastases (hazard ratio [HR] 3.7; 95% CI: 1.6-8.5; P < 0.01), poor performance status score (PS) (HR 3.4; 95% CI: 1.6-7.5; P < 0.01) and ≥ 3 treatment lines (HR 3.5; 95% CI: 1.7-7.4; P < 0.01) were found to be negative predictors of PFS. Eighty-nine percent of the patients experienced an adverse event. CONCLUSIONS: Metastatic sites (bone and liver), ≥3 treatment lines and poor PS were potential negative predictors of the efficacy of immunotherapy combined with antiangiogenic therapy for treating NSCLC. Further investigations and randomized controlled trials are needed.
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Inhibidores de la Angiogénesis/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inmunoterapia , Neoplasias Pulmonares/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Inhibidores de la Angiogénesis/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Carcinoma de Pulmón de Células no Pequeñas/secundario , China , Femenino , Humanos , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Inmunoterapia/efectos adversos , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Proyectos Piloto , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Supervivencia sin Progresión , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Factores de TiempoRESUMEN
BACKGROUND: Though immune checkpoint blockade (ICB) against PD-1 has shown success in the treatment of lung cancer, not all patients respond. We have previously shown that adoptive transfer of double negative T (DNT) cells expanded from healthy donors can target leukemia but their role in treating established lung cancer is not clear. Here we explore the role of human DNT cells in targeting late-stage established lung cancer either alone or in combination with Nivolumab (anti-PD-1 antibody) and describe underlying mechanisms. METHODS: DNT cells from resected lung cancer tissue of patients were analyzed by flow cytometry to determine their infiltration and PD-1 expression. Expansion capacity and anti-tumor function of lung cancer patient and healthy donor DNT cells were compared. Late-stage lung cancer xenograft models were developed to determine the anti-tumor effect of DNT cells alone or in combination with anti-PD-1 antibody, and the level of tumor-infiltrating DNT cells was quantified by histology and characterized by flow cytometry. RESULTS: Patient-derived tumor infiltrating lymphocytes contained a lower frequency of DNT cells with a higher expression of PD-1 relative to normal lung tissue. Ex vivo expanded patient- and healthy donor-derived DNT cells showed similar levels of cytotoxicity against lung cancer cells in vitro. Healthy donor-derived DNT cells significantly inhibited the growth of late-stage lung cancer xenografts, which was further augmented by anti-PD-1 through increased DNT cell tumor infiltration. CONCLUSION: This study supports the use of DNT cells for adoptive cellular therapy against lung cancer either alone or in combination with anti-PD-1.
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Carcinoma de Pulmón de Células no Pequeñas/terapia , Tratamiento Basado en Trasplante de Células y Tejidos , Inmunoterapia , Receptor de Muerte Celular Programada 1/inmunología , Linfocitos T/inmunología , Animales , Antígeno B7-H1/inmunología , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Carcinoma de Pulmón de Células no Pequeñas/patología , Modelos Animales de Enfermedad , Citometría de Flujo , Humanos , Pulmón/efectos de los fármacos , Pulmón/inmunología , Pulmón/patología , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/patología , Ratones , Nivolumab/administración & dosificación , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Linfocitos T/trasplante , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: The advents of novel immunotherapies have revolutionized the treatment of cancer. Adoptive cellular therapies using chimeric antigen receptor T (CAR-T) cells have achieved remarkable clinical responses in B cell leukemia and lymphoma but the effect on solid tumors including lung cancer is limited. Here we present data on the therapeutic potential of allogeneic CD3+CD4-CD8- double negative T (DNT) cells as a new cellular therapy for the treatment of lung cancer and underlying mechanisms. METHODS: DNTs were enriched and expanded ex vivo from healthy donors and phenotyped by flow cytometry. Functionally, their cytotoxicity was determined against primary and established non-small-cell lung cancer (NSCLC) cell lines in vitro or through in vivo adoptive transfer into xenograft models. Mechanistic analysis was performed using blocking antibodies against various cell surface and soluble markers. Furthermore, the role of IL-15 on DNT function was determined. RESULTS: We demonstrated that ex vivo expanded DNTs can effectively lyse various human NSCLC cells in vitro and inhibit tumor growth in xenograft models. Expanded DNTs have a cytotoxic phenotype, as they express NKp30, NKG2D, DNAM-1, membrane TRAIL (mTRAIL), perforin and granzyme B, and secrete IFNγ and soluble TRAIL (sTRAIL). DNT-mediated cytotoxicity was dependent on a combination of tumor-expressed ligands for NKG2D, DNAM-1, NKp30 and/or receptors for TRAIL, which differ among different NSCLC cell lines. Furthermore, stimulation of DNTs with IL-15 increased expression of effector molecules on DNTs, their TRAIL production and cytotoxicity against NSCLC in vitro and in vivo. CONCLUSION: Healthy donor-derived DNTs can target NSCLC in vitro and in vivo. DNTs recognize tumors via innate receptors which can be up-regulated by IL-15. DNTs have the potential to be used as a novel adoptive cell therapy for lung cancer either alone or in combination with IL-15.
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Carcinoma de Pulmón de Células no Pequeñas/terapia , Inmunoterapia Adoptiva , Interleucina-15/uso terapéutico , Neoplasias Pulmonares/terapia , Linfocitos T/trasplante , Animales , Línea Celular Tumoral , Terapia Combinada , Humanos , Interleucina-15/farmacología , Ligandos , Masculino , RatonesRESUMEN
Autophagy is an evolutionarily conserved catabolic process that eliminates harmful components through lysosomal degradation. In addition to its role in maintaining cellular homeostasis, autophagy is critical to pathological processes, such as inflammation and cancer. Colitis-associated colorectal cancer (CAC) is a specific type of colorectal cancer that develops from long-standing colitis in inflammatory bowel disease (IBD) patients. Accumulating evidence indicates that autophagy of microenvironmental cells plays different but vital roles during tumorigenesis and CAC development. Herein, after summarizing the recent advances in understanding the role of autophagy in regulating the tumor microenvironment during different CAC stages, we draw the following conclusions: autophagy in intestinal epithelial cells inhibits colitis and CAC initiation but promotes CAC progression; autophagy in macrophages inhibits colitis, but its function on CAC is currently unclear; autophagy in neutrophils and cancer-associated fibroblasts (CAFs) promotes both colitis and CAC; autophagy in dendritic cells (DCs) and T cells represses both colitis and CAC; autophagy in natural killer cells (NKs) inhibits colitis, but promotes CAC; and autophagy in endothelial cells plays a controversial role in colitis and CAC. Understanding the role of autophagy in specific compartments of the tumor microenvironment during different stages of CAC may provide insight into malignant transformation, tumor progression, and combination therapy strategies for CAC.
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Macrophages are highly plastic cells, which serve as sentinels of the host immune system due to their ability to recognize and respond to microbial products rapidly and dynamically. Appropriate regulation of macrophage activation is essential for pathogen clearance or preventing autoimmune diseases. However, regularly used endpoint assays for analyzing macrophage functions have the limitations of being static and non-high throughput. In this study, we introduced a real-time and convenient method based on changes in cellular impedance that are detected by microelectronic biosensors. This new method can record the time/dose-dependent cell response profiles (TCRPs) of macrophages in real time and generates physiologically relevant data. The TCRPs generated from classically interferon-γ/lipopolysaccharide-activated macrophages showed considerable consistency with the data generated from standard endpoint assays. We further explored this approach by using it for global screening of a library of protein tyrosine kinase/phosphatase (PTK/PTP) inhibitors to investigate their impact on macrophage activation. Collectively, our findings suggest that the cellular impedance-based assay provides a promising approach for dynamically monitoring macrophage functions in a convenient and high-throughput manner.
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Activación de Macrófagos , Animales , Antraquinonas/farmacología , Análisis por Conglomerados , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/análisis , Inhibidores Enzimáticos/farmacología , Interferón gamma/metabolismo , Cinética , Lipopolisacáridos , Activación de Macrófagos/efectos de los fármacos , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Ratones , Fenotipo , Fosforilación/efectos de los fármacos , Células RAW 264.7 , Factores de TiempoRESUMEN
Store-operated Ca(2+) entry (SOCE) inhibitors are emerging as an attractive new generation of anti-cancer drugs. Here, we report that SKF-96365, an SOCE inhibitor, exhibits potent anti-neoplastic activity by inducing cell-cycle arrest and apoptosis in colorectal cancer cells. In the meantime, SKF-96365 also induces cytoprotective autophagy to delay apoptosis by preventing the release of cytochrome c (cyt c) from the mitochondria into the cytoplasm. Mechanistically, SKF-96365 treatment inhibited the calcium/calmodulin-dependent protein kinase IIγ (CaMKIIγ)/AKT signaling cascade in vitro and in vivo. Overexpression of CaMKIIγ or AKT abolished the effects of SKF-96365 on cancer cells, suggesting a critical role of the CaMKIIγ/AKT signaling pathway in SFK-96365-induced biological effects. Moreover, Hydroxychloroquine (HCQ), an FDA-approved drug used to inhibit autophagy, could significantly augment the anti-cancer effect of SFK-96365 in a mouse xenograft model. To our best knowledge, this is the first report to demonstrate that calcium/CaMKIIγ/AKT signaling can regulate apoptosis and autophagy simultaneously in cancer cells, and the combination of the SOCE inhibitor SKF-96365 with autophagy inhibitors represents a promising strategy for treating patients with colorectal cancer.
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Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Bloqueadores de los Canales de Calcio/farmacología , Señalización del Calcio/efectos de los fármacos , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Neoplasias Colorrectales/tratamiento farmacológico , Imidazoles/farmacología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/genética , Proliferación Celular/efectos de los fármacos , Neoplasias Colorrectales/enzimología , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Citocromos c/metabolismo , Relación Dosis-Respuesta a Droga , Femenino , Células HCT116 , Células HT29 , Humanos , Hidroxicloroquina/farmacología , Ratones Endogámicos BALB C , Ratones Desnudos , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Proteínas Proto-Oncogénicas c-akt/genética , Serina-Treonina Quinasas TOR/metabolismo , Factores de Tiempo , Transfección , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Acute lung injury (ALI) and its more severe form, acute respiratory distress syndrome (ARDS), are life-threatening diseases that are associated with high mortality rates due to treatment limitations. Neutrophils play key roles in the pathogenesis of ALI/ARDS by promoting the inflammation and injury of the alveolar microenvironment. To date, in vivo functional approaches have been limited by the inaccessibility to the alveolar sacs, which are located at the anatomical terminal of the respiratory duct in mammals. We are the first to characterize the swim bladder of the zebrafish larva, which is similar to the mammalian lung, as a real-time in vivo model for examining pulmonary neutrophil infiltration during ALI. We observed that the delivery of exogenous materials, including lipopolysaccharide (LPS), Poly IC and silica nanoparticles, by microinjection triggered significant time- and dose-dependent neutrophil recruitment into the swim bladder. Neutrophils infiltrated the LPS-injected swim bladder through the blood capillaries around the pneumatic duct or a site near the pronephric duct. An increase in the post-LPS inflammatory cytokine mRNA levels coincided with the in vivo neutrophil aggregation in the swim bladder. Microscopic examinations of the LPS-injected swim bladders further revealed in situ injuries, including epithelial distortion, endoplasmic reticulum swelling and mitochondrial injuries. Inhibitor screening assays with this model showed a reduction in neutrophil migration into the LPS-injected swim bladder in response to Shp2 inhibition. Moreover, the pharmacological suppression and targeted disruption of Shp2 in myeloid cells alleviated pulmonary inflammation in the LPS-induced ALI mouse model. Additionally, we used this model to assess pneumonia-induced neutrophil recruitment by microinjecting bronchoalveolar lavage fluid from patients into swim bladders; this injection enhanced neutrophil aggregation relative to the control. In conclusion, our findings highlight the swim bladder as a promising and powerful model for mechanistic and drug screening studies of alveolar injuries.
Asunto(s)
Lesión Pulmonar Aguda/patología , Sacos Aéreos/patología , Aire , Inflamación/patología , Neutrófilos/patología , Pez Cebra/fisiología , Sacos Aéreos/ultraestructura , Animales , Movimiento Celular , Citocinas/metabolismo , Modelos Animales de Enfermedad , Lipopolisacáridos , Ratones , Infiltración Neutrófila , Proteína Tirosina Fosfatasa no Receptora Tipo 11/deficiencia , Proteína Tirosina Fosfatasa no Receptora Tipo 11/metabolismoRESUMEN
Chronic inflammation in the intestine is a strong risk factor for colitis-associated colorectal cancer (CAC). Hydroxychloroquine (HCQ) is widely used as an anti-inflammatory drug in the treatment of immune-mediated inflammatory disorders and various tumors. However, little is known regarding the effects of HCQ on colitis-associated tumorigenesis. In this study, mice treated with HCQ showed a significant reduction in early-stage colitis following azoxymethane (AOM)/dextran sodium sulfate (DSS) administration, as well as a remarkable inhibition of colonic tumorigenesis and tumor growth at late stages of CAC. Mechanistically, the therapeutic effects of HCQ were attributed to inhibition of inflammatory responses and production of mutagenic reactive oxygen species (ROS) in immune cells and subsequent promotion of apoptosis and cell cycle arrest in tumor cells. Furthermore, we found that HCQ inhibited the production of inflammatory cytokines and ROS in response to toll-like receptor 4 (TLR4) activation in macrophages. Our data presented herein may help guide the clinical use of HCQ as a prevention and treatment strategy for CAC.
Asunto(s)
Antiinflamatorios no Esteroideos/uso terapéutico , Carcinogénesis/efectos de los fármacos , Colitis/tratamiento farmacológico , Neoplasias Colorrectales/prevención & control , Hidroxicloroquina/uso terapéutico , Animales , Proliferación Celular/efectos de los fármacos , Colitis/complicaciones , Colitis/patología , Neoplasias Colorrectales/etiología , Citocinas/metabolismo , Inflamación/prevención & control , Masculino , Ratones , Ratones Endogámicos C57BL , Células RAW 264.7 , Especies Reactivas de Oxígeno/metabolismoRESUMEN
The epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have dramatically prolonged the overall survival of non-small cell lung cancer (NSCLC) patients with EGFR-activating mutation, but the presence of primary or acquired resistance eventually leads to therapeutic failure. Thus, how to improve the efficacy and reverse the resistance to EGFR-TKIs remains a significant challenge. In this study, we found that CsA significantly augmented the anti-cancer effect of gefitinib in EGFR-TKI-sensitive and -resistant NSCLC cells. Mechanistically, CsA promoted gefitinib-induced apoptosis through inhibition of the STAT3 pathway. Similar with the function of CsA, siRNAs against STAT3 also enhanced gefitinib-induced apoptosis in multiple lung cancer cells. Xenograft studies further demonstrated that CsA promoted the anti-cancer activity of gefitinib on lung cancer cells through inhibition of STAT3. Moreover, NSCLC patients with high levels of phosphorylated STAT3 (Y705) showed a significantly poorer therapeutic response to EGFR-TKIs. This study provides preclinical evidence that the combination of CsA or a STAT3 inhibitor with EGFR-TKIs is a promising approach to improve the efficacy of EGFR-TKIs for the treatment of patients with advanced NSCLC.