Immune infiltration may predict survival and have clinical significance in lung cancer. However, immune signatures derived from immune profiling based on bulk tumor transcriptomes have not been ...systematically established in lung adenocarcinoma. We aimed to construct an immune cell infiltrating score, using a new algorithm for evaluating immune infiltration, to improve the prognostic model of lung adenocarcinoma.
Public datasets of lung adenocarcinoma from the Gene Expression Omnibus and The Cancer Genome Atlas were adopted as the training and validation cohorts. Fractions of different immune cell subtypes in each sample were estimated using the CIBERSORT algorithm. The immune infiltrating score was further developed by a least absolute shrinkage and selection operator regression model. The prognostic value and clinical relationship of the model was then further explored.
An immune infiltrating score model was established on the basis of the immune cells in the training cohort. A high score was associated with significantly worse survival in patients with lung adenocarcinoma (P < 0.001). The prognostic value of the score was confirmed in the validation cohort. The immune infiltrating score could improve the accuracy of predictions of survival when combined with the staging system. Furthermore, the score was potentially associated with patient smoking status and histologic subtype of lung adenocarcinoma. Its possible association with the efficacy of adjuvant chemotherapy was not statistically significant.
The immune cell infiltrating score has prognostic significance in predicting overall survival in patients with lung adenocarcinoma.
Most cancer cells have fundamentally different metabolic characteristics, particularly much higher glycolysis rates than normal tissues, which support the increased demand for biosynthesis and ...promote tumor progression. We found that transforming growth factor (TGF)-β plays a dual function in regulating glycolysis and cell proliferation in non-small cell lung cancer.
We used the PET/MRI imaging system to observe the glucose metabolism of subcutaneous tumors in nude mice. Energy metabolism of non-small cell lung cancer cell lines detected by the Seahorse XFe96 cell outflow analyzer. Co-immunoprecipitation assays were used to detect the binding of Smads and HIF-1α. Western blotting and qRT-PCR were used to detect the regulatory effects of TGF-β and HIF-1α on c-MYC, PKM1/2, and cell cycle-related genes.
We discovered that TGF-β could inhibit glycolysis under normoxia while significantly promoting tumor cells' glycolysis under hypoxia in vitro and in vivo. The binding of hypoxia-inducible factor (HIF)-1α to the MH2 domain of phosphorylated Smad3 switched TGF-β function to glycolysis by changing Smad partners under hypoxia. The Smad-p107-E2F4/5 complex that initially inhibited c-Myc expression was transformed into a Smad-HIF-1α complex that promoted the expression of c-Myc. The increased expression of c-Myc promoted alternative splicing of PKM to PKM2, resulting in the metabolic reprogramming of tumor cells. In addition, the TGF-β/Smad signal lost its effect on cell cycle regulatory protein p15/p21. Furthermore, high expression of c-Myc inhibited p15/p21 and promoted the proliferation of tumor cells under hypoxia.
Our results indicated that HIF-1α functions as a critical factor in the dual role of TGF-β in tumor cells, and may be used as a biomarker or therapeutic target for TGF-β mediated cancer progression.
Our study aimed to validate pathologic findings of ground-glass nodules (GGOs) of different consolidation tumor ratios (CTRs), and to explore whether GGOs could be stratified according to CTR with an ...increment of 0.25 based on its prognostic role.
We retrospectively evaluated patients with clinical stage IA GGOs who underwent curative resection between 2011 and 2016. The patients were divided into 4 groups according to CTR step by 0.25. Cumulative survival rates were calculated by the Kaplan-Meier method. Univariate and multivariate Cox regression analyses were conducted to obtain the risk factors on relapse-free survival (RFS). The surv_function of the R package survminer was used to determine the optimal cutoff value. Receiver operating characteristic (ROC) analysis was generated to validate optimal cutoff points of factors.
A total of 862 patients (608 women; median age, 59y) were included, with 442 patients in group A (CTR ≤ 0.25), 210 patients in group B (0.25<CTR ≤ 0.5), 173 patients in group C (0.5<CTR ≤ 0.75), and 37 patients in group D (0.75<CTR<1). The rate of adenocarcinoma
(AIS) or minimally invasive adenocarcinoma (MIA) in group A (70.6%) was much higher than other three groups (p<0.001). Multivariable Cox regression revealed that CTR (HR, 1.865; 95%CI, 1.312-2.650;
= 0.001) and lymph node metastasis (HR, 10.407; 95%CI, 1.957-55.343;
= 0.006) were independent prognostic factors for recurrence free survival. In addition, CTR was the only risk factor for the presence of micropapillary or solid pattern (OR=133.9, 95%CI:32.2-556.2,
<0.001) and lymph node metastasis (OR=292498.8, 95%CI:1.2-7.4×10
,
=0.047). Paired comparison showed that rate of presence of micropapillary or solid pattern was highest in group D, followed by group C and group A/B (p<0.001). Lymph node metastasis occurred in group D only (
=0.002).
CTR is an independent prognostic factor for clinical stage IA lung adenocarcinoma manifesting as GGO in CT scan. Radiologic cutoffs of CTR 0.50 and 0.75 were able to subdivide patients with different prognosis.
Background. Lung adenocarcinoma is one of the most commonly diagnosed malignancies worldwide. Macrophage plays crucial roles in the tumor microenvironment, but its autocrine network and ...communications with tumor cell are still unclear. Methods. We acquired single-cell RNA sequencing (scRNA-seq) (n=30) and bulk RNA sequencing (n=1480) samples of lung adenocarcinoma patients from previous literatures and publicly available databases. Various cell subtypes were identified, including macrophages. Differentially expressed ligand-receptor gene pairs were obtained to explore cell-to-cell communications between macrophages and tumor cells. Furthermore, a machine-learning predictive model based on ligand-receptor interactions was built and validated. Results. A total of 159,219 single cells (18,248 tumor cells and 29,520 macrophages) were selected in this study. We identified significantly correlated autocrine ligand-receptor gene pairs in tumor cells and macrophages, respectively. Furthermore, we explored the cell-to-cell communications between macrophages and tumor cells and detected significantly correlated ligand-receptor signaling pairs. We determined that some of the hub gene pairs were associated with patient prognosis and constructed a machine-learning model based on the intercellular interaction network. Conclusion. We revealed significant cell-to-cell communications (both autocrine and paracrine network) within macrophages and tumor cells in lung adenocarcinoma. Hub genes with prognostic significance in the network were also identified.
Background
Lung adenocarcinoma (LUAD) patients with different American Joint Committee on Cancer stages have different overall 5‐year survival rates. The tumor microenvironment (TME) and intra‐tumor ...heterogeneity (ITH) have been shown to play a crucial role in the occurrence and development of tumors. However, the TME and ITH in different lesions of LUAD have not been extensively explored.
Methods
We present a 204,157‐cell catalog of the TME transcriptome in 29 lung samples to systematically explore the TME and ITH in the different stages of LUAD. Traditional RNA sequencing data and complete clinical information were downloaded from publicly available databases.
Results
Based on these high‐quality cells, we constructed a single‐cell network underlying cellular and molecular features of normal lung, early LUAD, and advanced LUAD cells. In contrast with early malignant cells, we noticed that advanced malignant cells had a remarkably more complex TME and higher ITH level. We also found that compared with other immune cells, more differences in CD8+/CTL T cells, regulatory T cells, and follicular B cells were evident between early and advanced LUAD. Additionally, cell‐cell communication analyses, revealed great diversity between different lesions of LUAD at the single‐cell level. Flow cytometry and qRT‐PCR were used to validate our results.
Conclusion
Our results revealed the cellular diversity and molecular complexity of cell lineages in different stages of LUAD. We believe our research, which serves as a basic framework and valuable resource, can facilitate exploration of the pathogenesis of LUAD and identify novel therapeutic targets in the future.
Our study comprehensively studied the tumor microenvironment (TME)and intra‐tumor heterogeneity (ITH) in different stages of LUAD by both scRNA‐seq and bulk RNA‐seq analyses.
Based on these high‐quality cells derived from different tissues, our results revealed the cellular diversity and molecular complexity of cell lineages in different stages of LUAD.
This study, which serves as a basic framework and valuable resource, can facilitate exploration of the pathogenesis of LUAD and identify novel therapeutic targets in the future.
EGF receptor (EGFR) tyrosine kinase inhibitors (TKIs) have achieved clinical success in lung adenocarcinoma (LUAD). However, tumors often show profound but transient initial response and then gain ...resistance. We identify transcription factor ZNF263 as being significantly decreased in osimertinib-resistant or drug-tolerant persister LUAD cells and clinical residual tumors. ZNF263 overexpression improves the initial response of cells and delays the formation of persister cells with osimertinib treatment. We further show that ZNF263 binds and recruits DNMT1 to the EGFR gene promoter, suppressing EGFR transcription with DNA hypermethylation. ZNF263 interacts with nuclear EGFR, impairing the EGFR-STAT5 interaction to enhance AURKA expression. Overexpressing ZNF263 also makes tumor cells with wild-type EGFR expression or refractory EGFR mutations more susceptible to EGFR inhibition. More importantly, lentivirus or adeno-associated virus (AAV)-mediated ZNF263 overexpression synergistically suppresses tumor growth and regrowth with osimertinib treatment in xenograft animal models. These findings suggest that enhancing ZNF263 may achieve complete response in LUAD with EGFR-targeted therapies.
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•Loss of ZNF263 expression occurs in EGFR TKI-residual lung adenocarcinoma•ZNF263 overexpression combats tumor cell survival and resistance to EGFR inhibition•ZNF263 suppresses the EGFR expression and disrupts the nuclear function of EGFR•AAV-ZNF263 is promising for achieving durable response to EGFR-targeted therapies
Liang et al. show that ZNF263 expression is decreased in response to EGFR inhibition in lung adenocarcinoma. ZNF263 expression decrease contributes to cell persistence and resistance by enhancing EGFR expression and its nuclear activity. The authors show that overexpressing ZNF263 in tumors may achieve complete response with EGFR-targeted therapies.
Purpose: We aimed to verify the prognosis of epidermal growth factor receptor (EGFR) mutation of clinical (c)-stage IA lung adenocarcinoma with the ground-glass opacity (GGO) component.Methods: We ...evaluated 226 cases of surgically resected c-stage IA lung adenocarcinoma with GGO component. Endpoints were overall survival (OS) and recurrence-free survival (RFS). Kaplan–Meier analysis and the log-rank test were used to estimate the survival differences. Prognostic factors were assessed using the univariable and multivariable Cox proportional hazards model.Results: Among the 226 cases, 177 cases harbored the EGFR-mutant adenocarcinoma with the GGO component. The mean duration of follow-up time was 54.4 ± 1.2 months. The 5-year OS and RFS did not differ significantly between the EGFR-mutant and wild-type groups (5-year OS 100% vs. 94.3%, hazard ratio HR 0.276, P = 0.168; 5-year RFS 94.7% vs. 95.7%, HR 0.873, P = 0.864). Multivariable Cox hazard model revealed that radiologically solid component size (P = 0.010) and pathological node-positive (P = 0.036) were significant predictors of an inferior RFS.Conclusion: EGFR-mutant was not a prognostic factor of OS and RFS for c-stage IA lung adenocarcinoma with the GGO component. Radiologically solid component size and pathological lymph node status were independent prognostic factors of worse RFS.
Epithelial neutrophil-activating peptide-78 (CXCL5), a member of the subgroup of CXC-type chemokine family, is an inflammatory factor involved in the progression of lung cancer, but the underlying ...mechanism remains unclear. In this study, we investigated the effects of CXCL5 on proliferation and migration in non-small cell lung cancer (NSCLC) using tissue microarrays from NSCLC patients and H460 cells transfected with a CXCL5-interfered lentivirus vector or stimulated with recombinant CXCL5. We observed that the expression of CXCL5 was significantly higher in lung cancer cell lines, and high CXCL5 was associated with high chemokine (C-X-C motif) receptor 2 expression and was significantly associated with poor differentiation. The high expression of CXCL5 was associated with poor NSCLC prognosis and was an independent predictive factor. Furthermore, downregulation of CXCL5 in H460 cells significantly reduced proliferation and migration. Recombinant CXCL5 promoted H460 cell proliferation and movement by activating MAPK/ERK1/2 and PI3K/AKT signaling. Our study elucidates the important role of CXCL5 in the progression and prognosis of NSCLC. These findings suggested that CXCL5 might be a potential biomarker and novel therapeutic target for lung cancer.
Hosting more than two-thirds of the global high-speed train network, and growing at an unprecedented rate, China has become an interesting location for studying this infrastructure. In this paper, ...the authors begin by introducing some particularities related to the high-speed travel experience, in order to provide a general understanding of how it affects people’s perceptions of time and space. This is followed by an explanation of some peculiarities that have defined the Chinese case as unique. Grounded on theories that assert the interlaced connection between modernity and phenomenology, in this paper the authors explore the connection between the conditions that defined modernity in China and the phenomenology of travel using high-speed trains. The problematic initial approach to Chinese modernity – through the Great Leap Forward and the Cultural Revolution – impacted later decisions regarding the new infrastructure, rendering high-speed train journeys in China unique. After the end of the Cultural Revolution in 1976, when China recovered a sense of normality and togetherness, modernity was globally staged out. Two years later, China commenced the development of its high-speed rail (HSR) network and the beginning of the reform era, as part of its statements of a reframed modernity. This paper explores how the singularities of the Chinese modernity have affected the development of the High-speed train network, defining a particular phenomenology of the trip.
Objective
The extent of mediastinal lymphadenectomy for clinical stage I non-small-cell lung cancer (NSCLC) remains controversial. This study explored the value of selective mediastinal ...lymphadenectomy from the clinical viewpoint.
Methods
From 2005 to 2008, a total of 403 patients diagnosed clinically as having stage I NSCLC underwent lobectomy and mediastinal lymph node dissection. Among them, 309 underwent complete mediastinal lymphadenectomy, and the other 94 underwent selective mediastinal lymphadenectomy. We compared the perioperative parameters and overall survival statistics for the two groups retrospectively.
Results
The two groups had no significant differences in sex, pathology, tumor location, or preoperative staging. The selective mediastinal lymphadenectomy group had an older average age, with a much higher rate of patients >70 years of age (
p
= 0.016). Also, the patients were apt to undergo thoracoscopic lobectomy (
p
= 0.044). This group had shorter operating times and less intraoperative bleeding. No significant differences in total drainage volume, length of hospital stay, or complication rates were found between the two groups. The mean follow-up periods were 35.8 ± 13.7 vs. 34.6 ± 17.2 months. Local and distant recurrence rates were 25.6 % vs. 30.9 %, respectively (
p
= 0.560). The 3-year and 5-year overall survival rates were 83.0 % and 74.6 % vs. 75.1 % and 68.5 %, respectively (
p
= 0.216).
Conclusions
For patients with clinical stage I NSCLC, selective mediastinal lymphadenectomy can reduce the trauma caused by the procedure, especially for elderly patients and those with co-morbidities. Survival was acceptable and was no worse than that after complete mediastinal lymphadenectomy. Our results need to be confirmed by prospective randomized controlled studies.
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