Reliable and noninvasive biomarkers for the early diagnosis of non‐small‐cell lung cancer (NSCLC) are an unmet need. This study aimed to screen and validate potential urinary biomarkers for the early ...diagnosis of NSCLC. Using protein mass spectrometry, urinary MDH2 was found to be abundant both in patients with lung cancer and lung cancer model mice compared with controls. Urine samples obtained as retrospective and prospective cohorts including 1091 NSCLC patients and 736 healthy controls were measured using ELISA. Patients with stage I NSCLC had higher urinary MDH2 compared with healthy controls. The area under the receiver‐operating characteristic curve (AUC) for the urinary MDH2 was 0.7679 and 0.7234 in retrospective and prospective cohorts to distinguish stage I cases from controls. Urinary MDH2 levels correlated with gender and smoking history. MDH2 expression levels were elevated in lung cancer tissues. MDH2 knockdown using shRNA inhibited the proliferation of lung cancer cells. Our study demonstrated that urinary MDH2 concentration was higher in early‐stage NSCLC patients compared with that in controls and that MDH2 could serve as a potential biomarker for early detection of NSCLC.
Malate dehydrogenase 2 was significantly elevated both in urine and in cancer tissues of NSCLC patients. The level of MDH2 in urine could serve as an assistant biomarker for the early diagnosis of NSCLC.
The need for tumor postoperative treatments aimed at recurrence prevention and tissue regeneration have raised wide considerations in the context of the design and functionalization of implants. ...Herein, an injectable hydrogel system encapsulated with anti-tumor, anti-oxidant dual functional nanoparticles has been developed in order to prevent tumor relapse after surgery and promote wound repair. The utilization of biocompatible gelatin methacryloyl (GelMA) was geared towards localized therapeutic intervention. Zeolitic imidazolate framework-8@ceric oxide (ZIF-8@CeO2, ZC) nanoparticles (NPs) were purposefully devised for their proficiency as reactive oxygen species (ROS) scavengers. Furthermore, injectable GelMA hydrogels loaded with ZC NPs carrying doxorubicin (ZC-DOX@GEL) were tailored as multifunctional postoperative implants, ensuring the efficacious eradication of residual tumor cells and alleviation of oxidative stress. In vitro and in vivo experiments were conducted to substantiate the efficacy in cancer cell elimination and the prevention of tumor recurrence through the synergistic chemotherapy approach employed with ZC-DOX@GEL. The acceleration of tissue regeneration and in vitro ROS scavenging attributes of ZC@GEL were corroborated using rat models of wound healing. The results underscore the potential of the multifaceted hydrogels presented herein for their promising application in tumor postoperative treatments.
Abstract
Background
Long non-coding RNAs (lncRNAs) are critical regulators in lung adenocarcinoma (LUAD). M2-type tumor-associated macrophages (TAMs) also play oncogenic roles in LUAD. However, the ...involvement of lncRNAs in TAM activation is still largely unknown.
Methods
The expressions of LARRPM, LINC00240 and CSF1 were determined by RT-qPCR. The regulation of LINC00240 and CSF1 by LARRPM was investigated by RNA–protein pull-down, RNA immunoprecipitation, chromatin immunoprecipitation and bisulfite DNA sequencing. In vitro and in vivo gain- and loss-of-function assays were performed to investigate the roles of LARRPM.
Results
The lncRNA LARRPM was expressed at low levels in LUAD tissues and cells. The low expression of LARRPM was correlated with advanced stage and poor survival of patients with LUAD. Functional experiments revealed that LARRPM suppressed LUAD cell proliferation, migration and invasion, and promoted apoptosis. LARRPM also repressed macrophage M2 polarization and infiltration. Taken together, LARRPM significantly restricted LUAD progression in vivo. Mechanistically, LARRPM bound and recruited DNA demethylase TET1 to the promoter of its anti-sense strand gene
LINC00240
, leading to a decrease in DNA methylation level of the
LINC00240
promoter and transcriptional activation of
LINC00240
. Functional rescue assays suggested that the lncRNA LINC00240 was responsible for the roles of LARRPM in the malignant behavior of LUAD cells. LARRPM decreased the binding of TET1 to the
CSF1
promoter, resulting in increased DNA methylation of the
CSF1
promoter and transcriptional repression of
CSF1
, which is responsible for the roles of LARRPM in macrophage M2 polarization and infiltration. The TAMs educated by LUAD cells exerted oncogenic roles, which was negatively regulated by LARRPM expressed in LUAD cells.
Conclusions
LARRPM restricts LUAD progression through repressing both LUAD cell and macrophages. These data shed new insights into the regulation of LUAD progression by lncRNAs and provide data on the potential utility of LARRPM as a target for LUAD treatment.
Background
Pazopanib is an approved multitarget anticancer agent for soft tissue sarcoma (STS) and renal cell carcinoma (RCC), which is also under clinical investigation for other malignancies, ...including small cell lung cancer (SCLC). However, the potential anti‐SCLC mechanisms of pazopanib remain unclear.
Methods
Cell viability was evaluated by CCK‐8, apoptotic cell detection was conducted using annexin V/PI staining followed by flow cytometry, and Western blot analysis was used to detect the apoptotic‐related molecules and ER‐stress pathway effectors. The intracellular reactive oxygen species (ROS) level was determined by DCFH‐HA staining followed by flow cytometry. An NCI‐H446 xenograft model was established to evaluate pazopanib on tumor suppression in vivo. Immunohistochemistry (IHC) was used to assess the proliferative activity of xenograft in NCI‐H446 cell‐bearing NOD‐SCID mice.
Results
Pazopanib dose‐ and time‐dependently inhibited SCLC cell proliferation induced significant apoptosis in SCLC cell lines, increased cleaved‐caspase3 and Bax, and decreased Bcl‐2. Moreover, the PERK‐related ER‐stress pathway was potently activated by pazopanib treatment, inhibiting ER‐stress by salubrinal significantly reversing pazopanib‐mediated apoptosis in SCLC cell lines. Furthermore, pazopanib‐induced intracellular ROS levels increased, while inhibiting ROS by NAC significantly reversed pazopanib‐induced apoptosis in SCLC cells. In addition, pazopanib significantly suppressed NCI‐H446 xenograft growth and decreased Ki67 positive cells in the tumor.
Conclusion
Our findings indicate that pazopanib induces SCLC cell apoptosis through the ER‐stress process via upregulation of ROS levels. Further investigation of relevant biomarkers to accurately select patients for benefit from pazopanib should be further investigated.
Administration of pazopanib upregulates ROS, causing endoplasmic reticulum stress, which finally promotes apoptosis in small cell lung cancer cells.
Calcifying fibrous tumor of the pleura (CFTP) is a rare benign tumor of the thoracic cavity. Due to the low incidence of CFPT, it is prone to be misdiagnosed because intraoperative analysis of frozen ...section is a challenge for pathologists. At present, it is difficult to distinguish this tumor from other benign thoracic tumors based on radiographic features. Therefore, surgical resection is the best method for definite diagnosis and treatment.
Tumor-associated macrophages (TAMs) are a major component of leukocyte infiltration in the tumor microenvironment. Osteopontin is related to tumor metastasis and proliferation. Osteopontin is ...expressed not only by tumor cells but also by TAMs. The purpose of the current study was to assess the prognostic significance of osteopontin expressed by TAMs (TOPN) in patients with non-small cell lung cancer.
Tissue microarray was used to detect the expression of TOPN, TAMs, and microvascular density in 159 patients with non-small cell lung cancer undergoing complete pulmonary resection in our hospital between 2003 and 2006. The correlations between TOPN, TAMs, and clinicopathologic data were analyzed with χ(2) tests. Quantitation of TAMs or TOPN and microvascular density analyses was performed using Bonferroni correction and the Student's t test. The prognostic value of TOPN was evaluated by univariate Kaplan-Meier survival analysis and multivariate Cox proportional hazard model analysis.
In the recurrence and metastasis group, microvascular density was higher than that in the control group (14.4 ± 1.06 versus 8.9 ± 1.02; p = 0.0002). In the TOPN-positive group, microvascular density was increased compared with that in the TOPN-negative group (14.3 ± 1.37 versus 10.7 ± 0.91; p = 0.0273). Osteopontin expressed by TAMs was an independent predictor for overall survival (p = 0.017) and disease-free survival (p < 0.001), especially for stage I non-small cell lung cancer. The 6-year overall and disease-free survival rates in TOPN-positive patients were 22.64% and 16.98%, respectively, which were significantly lower than those of TOPN-negative patients (50.00% and 39.62%, respectively).
Osteopontin expressed by TAMs is a valuable independent predictor of tumor recurrence and survival in patients with non-small cell lung cancer.
Osteopontin (OPN) is identified as one of the leading genes that promote the metastasis of malignant tumor through binding to CD44v6 and integrin. The purpose of the current study was to assess the ...prognostic significance of OPN and CD44v6 in patients with non-small cell lung cancer (NSCLC).
Tissue microarray was used to detect the expression of OPN and CD44v6 in 159 NSCLC patients undergoing complete pulmonary resection in our hospital between 2003 and 2006. The correlations among OPN, CD44v6, and clinicopathologic data were analyzed using χ(2) testing analysis. The prognostic values of OPN and CD44v6 were evaluated by univariate Kaplan-Meier survival analysis and multivariate Cox proportional hazard model analysis.
OPN and CD44v6 were both independent predictors for overall survival and disease-free survival. When OPN and CD44v6 were considered together, the predictive range was extended and the sensitivity was improved, especially for those patients with stage I NSCLC. The 6-year overall survival and disease-free survival rates in OPN+ or CD44v6+ patients were 49.1% and 39.6%, respectively, which were significantly lower than those of OPN-/CD44v6- patients (64.4% and 47.7%, respectively), and were higher than those of OPN+/CD44v6+ patients (16.4% and 14.8%, respectively). Stratification into OPN+/CD44v6+, OPN+ or CD44v6+, or OPN-/CD44v6- groups, based on the expression OPN and CD44v6, could efficiently predicted outcomes (p < 0.001) of NSCLC patients.
The combination of OPN and CD44v6 is a valuable independent predictor of tumor recurrence and survival in NSCLC patients.
Background
Effective biomarkers for early diagnosis of lung cancer are needed. Previous studies have indicated positive associations between abnormal circulating cytokines and the etiology of lung ...cancer.
Methods
Blood samples were obtained from 286 patients with pretreatment lung cancer and 80 healthy volunteers. Circulating cytokine levels were detected with a Luminex assay and enzyme-linked immunosorbent assay (ELISA). Urine samples were obtained from 284 patients and 122 healthy volunteers. CXC chemokine ligand 14 (CXCL14) expression in tumors and nontumor regions of lung tissues from 133 lung cancer cases was detected by immunohistochemical (IHC) staining and immunofluorescence (IF) staining of formalin fixed paraffin-embedded (FFPE) tissues.
Results
Compared with healthy volunteers, a 65.7-fold increase was observed in the level of CXCL14 in the plasma of lung cancer patients, and a 1.7-fold increase was observed in the level of CXCL14 in the urine of lung cancer patients, achieving a 0.9464 AUC (area under the curve) value and a 0.6476 AUC value for differentiating between lung cancer patients and healthy volunteers, respectively. Stromal CXCL14 expression was significantly associated with advanced pathologic stage (
P
<0.001), pathologic N stage (
P
<0.001), and recurrence and metastasis (
P
=0.014). Moreover, multivariate analysis suggested stromal CXCL14 expression as an independent predictor of DFS and OS.
Conclusions
Our study demonstrates that CXCL14 might serve as a potential diagnostic and prognostic biomarker in patients with lung cancer.
Impact
CXCL14 might serve as a potential diagnostic and prognostic biomarker in patients with lung cancer.
Background
Circulating genetically abnormal cells (CACs) with specific chromosome variations have been confirmed to be present in non‐small cell lung cancer (NSCLC). However, the diagnostic ...performance of CAC detection remains unclear. This study aimed to evaluate the potential clinical application of the CAC test for the early diagnosis of NSCLC.
Methods
In this prospective study, a total of 339 participants (261 lung cancer patients and 78 healthy volunteers) were enrolled. An antigen‐independent fluorescence in situ hybridization was used to enumerate the number of CACs in peripheral blood.
Results
Patients with early‐stage NSCLC were found to have a significantly higher number of CACs than those of healthy participants (1.34 vs. 0.19; P < 0.001). The CAC test displayed an area under the receiver operating characteristic (ROC) curve of 0.76139 for discriminating stage I NSCLC from healthy participants with 67.2% sensitivity and 80.8% specificity, respectively. Compared with serum tumor markers, the sensitivity of CAC assays for distinguishing early‐stage NSCLC was higher (67.2% vs. 48.7%, P < 0.001), especially in NSCLC patients with small nodules (65.4% vs. 36.5%, P = 0.003) and ground‐glass nodules (pure GGNs: 66.7% vs. 40.9%, P = 0.003; mixed GGNs: 73.0% vs. 43.2%, P < 0.001).
Conclusions
CAC detection in early stage NSCLC was feasible. Our study showed that CACs could be used as a promising noninvasive biomarker for the early diagnosis of NSCLC.
Key points
What this study adds: This study aimed to evaluate the potential clinical application of the CAC test for the early diagnosis of NSCLC.
Significant findings of the study: CAC detection in early stage NSCLC was feasible. Our study showed that CACs could be used as a promising noninvasive biomarker for the early diagnosis of NSCLC.
Workflow of circulating genetically abnormal cells enumeration.
Circulating genetically abnormal cell detection in early stage non‐small‐cell lung cancer was feasible.
Circulating genetically abnormal cell test has good stability and adaptability for different patient populations.
Circulating genetically abnormal cells could be used as a promising noninvasive biomarker for the early diagnosis of NSCLC.
Background
The aim of this study was to investigate the relation between the metastatic lymph node ratio (LNR) and the prognosis of non-small-cell lung cancer (NSCLC).
Methods
A total of 301 patients ...with N1 or N2 NSCLC who underwent complete pulmonary resection were analyzed retrospectively. The correlations between the LNR and clinical and pathologic data were analyzed using χ
2
test analysis. The prognostic value of the LNR was calculated by univariate Kaplan–Meier survival analysis and multivariate Cox proportional hazard model analysis. The risk groups were classified by a combination of the LNR and pN stage.
Results
The LNR was correlated with age, smoking status, pathologic type, subcarinal lymph node, clinical staging, N stage (
P
< 0.05), and the number of positive lymph nodes and positive lymph node stations (
P
< 0.0001). In the univariate analysis, the LNR played an important role in predicting overall survival (OS) (
P
< 0.0001) and disease-free survival (
P
< 0.0001) by Kaplan–Meier survival analysis. In the multivariate analysis, high LNR (>18%) was an independent poor prognostic factor for OS hazard ratio (HR) 2.5034, 95% confidence interval (CI) 1.6096–3.8933,
P
< 0.0001 and DFS (HR 1.9023, 95% CI 1.2465–2.9031,
P
= 0.0031). Stratification into high-, medium-, and low-risk groups—based on high-risk factors (LNR > 18%, N2) intermediate-risk factors (LNR > 18%, N1 or LNR < 18%, N2), and low-risk factors (LNR < 18%, N1)—could efficiently predicted outcomes (
P
< 0.0001) of patients with lymph node-positive NSCLC.
Conclusions
The combination of the LNR and pN status provides a valuable help with prognosis. However, these results must be evaluated further in a large prospective randomized clinical trial.
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