Lung cancer is one of the most lethal tumors in the world with a 5-year overall survival rate of less than 20%, mainly including lung adenocarcinoma (LUAD). Tumor microenvironment (TME) has become a new research focus in the treatment of lung cancer. The TME is heterogeneous in composition and consists of cellular components, growth factors, proteases, and extracellular matrix. The various cellular components exert a different role in apoptosis, metastasis, or proliferation of lung cancer cells through different pathways, thus contributing to the treatment of adenocarcinoma and potentially facilitating novel therapeutic methods. This review summarizes the research progress on different cellular components with cell-cell interactions in the TME of LUAD, along with their corresponding drug candidates, suggesting that targeting cellular components in the TME of LUAD holds great promise for future theraputic development.
Humans ; Tumor Microenvironment/drug effects* ; Adenocarcinoma of Lung/drug therapy* ; Lung Neoplasms/pathology* ; Adenocarcinoma/metabolism* ; Animals ; Apoptosis/physiology*

BACKGROUND: Ferroptosis-related genes play a crucial role in regulating intracellular iron homeostasis and lipid peroxidation, and they are involved in the regulation of tumor growth and drug resistance. The expression of ferroptosis-related genes in tumor tissues can be used to predict patients' future survival times, aiding doctors and patients in anticipating disease progression. Based on the sequencing data of lung adenocarcinoma (LUAD) patients from The Cancer Genome Atlas (TCGA) database, this study identified genes involved in the regulation of ferroptosis, constructed a prognostic model, and evaluated the predictive performance of the model. METHODS: A total of 1467 ferroptosis-related genes were obtained from the GeneCards database. Gene expression profiles and clinical data from 541 LUAD patients were collected from the TCGA database. The expression data of all ferroptosis-related genes were extracted, and differentially expressed genes were identified using R software. Survival analysis was performed on these genes to screen for those with prognostic value. Subsequently, a prognostic risk scoring model for ferroptosis-related genes was constructed using LASSO regression model. Each LUAD patient sample was scored, and the patients were divided into high-risk and low-risk groups based on the median score. Receiver operating characteristic (ROC) curves were plotted, and the area under the curve (AUC) was calculated. Kaplan-Meier survival curves were generated to assess model performance, followed by validation in an external dataset. Finally, univariate and multivariate Cox regression analyses were conducted to evaluate the independent prognostic value and clinical relevance of the model. RESULTS: Through survival analysis, 121 ferroptosis-related genes associated with prognosis were initially identified. Based on this, a LUAD prognostic risk scoring model was constructed using 12 ferroptosis-related genes (ALG3, C1QTNF6, CCT6A, GLS2, KRT6A, LDHA, NUPR1, OGFRP1, PCSK9, TRIM6, IGF2BP1 and MIR31HG). The results indicated that patients in the high-risk group had significantly shorter survival time than those in the low-risk group (P<0.001), and the model demonstrated good predictive performance in both the training set (1-yr AUC=0.721) and the external validation set (1-yr AUC=0.768). Risk scores were significantly associated with the prognosis of LUAD patients in both univariate and multivariate Cox regression analyses (P<0.001), suggesting that this score is an important prognostic factor for LUAD patients. CONCLUSIONS This study successfully established a LUAD risk scoring model composed of 12 ferroptosis-related genes. In the future, this model is expected to be used in conjunction with the tumor-node-metastasis (TNM) staging system for prognostic predictions in LUAD patients.
Humans ; Ferroptosis/genetics* ; Prognosis ; Adenocarcinoma of Lung/pathology* ; Lung Neoplasms/pathology* ; Male ; Female ; Gene Expression Regulation, Neoplastic ; Middle Aged ; ROC Curve

BACKGROUND: Lung adenocarcinoma is an important pathohistologic subtype of non-small cell lung cancer (NSCLC). Invasive non-mucinous pulmonary adenocarcinomas (INMA) tend to have a poor prognosis due to their significant heterogeneity and diverse histologic components. Establishing a histologic grading system for INMA is crucial for evaluating its malignancy. In 2021, the International Association for the Study of Lung Cancer (IASLC) proposed that a new histological grading system could better stratify the prognosis of INMA patients. The aim of this study was to establish a visualized nomogram model to predict INMA IASLC grading preoperatively by means of dual-energy computed tomography (DECT), fractal dimension (FD), clinical features and conventional CT parameters. METHODS: A total of 112 patients with INMA who underwent preoperative DECT were retrospectively enrolled from March 2021 to January 2025. Patients were categorized into low-intermediate grade and high grade groups based on IASLC grading. The clinical characteristics and conventional CT parameters, including baseline features, biochemical markers, and serum tumor markers, were collected. DECT-derived parameters, including iodine concentration (IC), effective atomic number (eff-Z), and normalized IC (NIC), were collected and determined as NIC ratio (NICr) and fractal dimension (FD). Univariate analysis was employed to compare differences in conventional characteristics and DECT parameters between the two groups. Variables demonstrating statistical significance were subsequently incorporated into a multivariate Logistic regression analysis. A nomogram model integrating clinical data, conventional CT parameters, and DECT parameters was developed to identify independent predictors for IASLC grading of INMA. The discriminatory performance of the model was evaluated using receiver operating characteristic (ROC) curve analysis. RESULTS: Multivariate analysis identified smoking history [odds ratio (OR)=2.848, P=0.041], lobulation sign (OR=2.163, P=0.004), air bronchogram (OR=7.833, P=0.005), eff-Z in arterial phase (OR=4.266, P<0.001), and IC in arterial phase (OR=1.290, P=0.012) as independent and significant predictors for IASLC grading of INMA. The nomogram model constructed based on these indicators demonstrated optimal predictive performance, achieving an area under the curve (AUC) of 0.804 (95%CI: 0.725-0.883), with specificity and sensitivity of 85.3% and 65.7%, respectively. CONCLUSIONS The nomogram model based on clinical features, imaging features and spectral CT parameters have a large potential for application in the preoperative noninvasive assessment of INMA IASLC grading.
Humans ; Nomograms ; Female ; Male ; Middle Aged ; Tomography, X-Ray Computed/methods* ; Lung Neoplasms/pathology* ; Aged ; Retrospective Studies ; Adenocarcinoma of Lung/pathology* ; Neoplasm Grading ; Adult

BACKGROUND: Lung cancer currently ranks first globally in both incidence and mortality. Pemetrexed (PMX) serves as a first-line treatment for lung adenocarcinoma (LUAD), but the patients often develop drug resistance during therapy. Milk exosome (mEXO) have the advantages of low immunogenicity, high tissue affinity, and low cost, and mEXO itself has anti-tumor effects. Hyaluronan (HA) naturally bind to CD44, a receptor which is highly expressed in LUAD tissues. This study aims to construct hyaluronan-modified milk exosome (HA-mEXO) and preliminarily investigate their molecular mechanisms for reversing PMX resistance through cellular experiments. METHODS: Exosomes were extracted from milk using high-speed centrifugation, and HA-mEXO was constructed. PMX-resistant A549 and PC-9 cell lines were treated with mEXO and HA-mEXO, respectively. CCK-8 assays, colony formation assays, Transwell assays, and flow cytometry were performed to evaluate proliferation, colony formation, migration, invasion, and apoptosis phenotypes in the treated resistant cell lines. Finally, transcriptomic sequencing, analysis, and cellular functional recovery experiments were conducted to investigate the mechanism by which HA-mEXO reverses PMX resistance in LUAD cells. RESULTS: The expression of CD44 in A549 and PC-9 LUAD drug-resistant cell lines was significantly higher than that in parental cells, and the uptake rate of HA-mEXO by drug-resistant cell lines was significantly higher than that of mEXO. Compared to the mEXO group, HA-mEXO-treated A549 and PC-9 resistant cells exhibited significantly reduced half maximal inhibitory concentration (IC50) values for PMX, markedly diminished clonogenic, migratory, and invasive capabilities, and a significantly increased proportion of apoptotic cells. Western blot analysis revealed that, compared to parental cells, A549 and PC-9 drug-resistant cells exhibited downregulated ZNF516 expression and upregulated ABCC5 expression. Immunofluorescence analysis revealed that HA-mEXO treatment downregulated ABCC5 expression in A549 and PC-9 drug-resistant cells compared to the PBS group, whereas co-treatment with HA-mEXO and ZNF516 knockdown showed no significant change in ABCC5 expression. CONCLUSIONS HA-mEXO carrying ZNF516 suppress ABCC5 expression, thereby enhancing the sensitivity of A549 and PC-9 LAUD drug-resistant cells to PMX.
Humans ; Hyaluronic Acid/chemistry* ; Drug Resistance, Neoplasm/drug effects* ; Exosomes/chemistry* ; Adenocarcinoma of Lung/genetics* ; Pemetrexed/pharmacology* ; Animals ; Lung Neoplasms/pathology* ; Milk/chemistry* ; Cell Proliferation/drug effects* ; Apoptosis/drug effects* ; Cell Line, Tumor ; Hyaluronan Receptors/metabolism*

Ground-glass nodule (GGN) lung cancer often progresses slowly in clinical and there are few clinical studies on long-term follow-up of patients with operable GGN lung cancer treated with stereotactic body radiation therapy (SBRT). We present a successful case of GGN lung cancer treated with SBRT, but a new GGN was found in the lung adjacent to the SBRT target during follow-up. The nodule progressed rapidly and was confirmed as lung adenocarcinoma by surgical resection. No significant risk factors and related driving genes were found in molecular pathological findings and genetic tests. It deserves further study whether new GGN is related to the SBRT. This case suggests that the follow-up after SBRT should be vigilant against the occurrence of new rapidly progressive lung cancer in the target area and adjacent lung tissue.
.
Humans ; Lung Neoplasms/pathology* ; Radiosurgery ; Retrospective Studies ; Adenocarcinoma of Lung/surgery* ; Lung/pathology*

BACKGROUND: Lung cancer prevails and induces high mortality around the world. This study provided real-world information on the evolution of clinicopathological profiles and survival outcomes of lung cancer, and provided survival information within stage I subtypes. METHODS: Patients pathologically confirmed with lung cancer between January 2009 and December 2018 were identified with complete clinicopathological information, molecular testing results, and follow-up data. Shifts in clinical characteristics were evaluated using χ2 tests. Overall survival (OS) was calculated through the Kaplan-Meier method. RESULTS: A total of 26,226 eligible lung cancer patients were included, among whom 62.55% were male and 52.89% were smokers. Non-smokers and elderly patients took increasingly larger proportions in the whole patient population. The proportion of adenocarcinoma increased from 51.63% to 71.80%, while that of squamous carcinoma decreased from 28.43% to 17.60%. Gene mutations including EGFR (52.14%), KRAS (12.14%), and ALK (8.12%) were observed. Female, younger, non-smoking, adenocarcinoma patients and those with mutated EGFR had better survival prognoses. Importantly, this study validated that early detection of early-stage lung cancer patients had contributed to pronounced survival benefits during the decade. Patients with stage I lung cancer, accounted for an increasingly considerable proportion, increasing from 15.28% to 40.25%, coinciding with the surgery rate increasing from 38.14% to 54.25%. Overall, period survival analyses found that 42.69% of patients survived 5 years, and stage I patients had a 5-year OS of 84.20%. Compared with that in 2009-2013, the prognosis of stage I patients in 2014-2018 was dramatically better, with 5-year OS increasing from 73.26% to 87.68%. Regarding the specific survival benefits among stage I patients, the 5-year survival rates were 95.28%, 93.25%, 82.08%, and 74.50% for stage IA1, IA2, IA3, and IB, respectively, far more promising than previous reports. CONCLUSIONS Crucial clinical and pathological changes have been observed in the past decade. Notably, the increased incidence of stage I lung cancer coincided with an improved prognosis, indicating actual benefits of early detection and management of lung cancer.
Humans ; Male ; Female ; Aged ; Lung Neoplasms/genetics* ; Adenocarcinoma/pathology* ; Prognosis ; Survival Rate ; Mutation ; ErbB Receptors/genetics* ; Neoplasm Staging ; Retrospective Studies

Objective: To investigate the clinicopathological features, treatment and prognosis of patients with RET fusion positive non-small cell lung cancer (NSCLC). Methods: A total of 1 089 NSCLCs were retrieved at Affiliated Hospital of Jiangnan University from August 2018 to April 2020. In all cases, multiple gene fusion detection kits (fluorescent PCR method) were used to detect the gene status of RET, EGFR, ALK, ROS1, KRAS, BRAF and HER2; and immunohistochemical method was used to detect the expression of PD-L1 and mismatch repair related proteins. The correlation between RET-fusion and patients' age, gender, smoking history, tumor stage, grade, pathologic type, and PD-L1, mismatch repair related protein expression was analyzed. Results: There were 22 cases (2.02%) detected with RET fusion-positive in 1 089 NSCLC patients, in which 11 males and 11 females; and the median age was 63.5 years. There were 20 adenocarcinomas, including 11 acinar predominant adenocarcinoma (APA), five solid predominant adenocarcinoma (SPA) and four lepidic predominant adenocarcinoma (LPA); There were one case each of squamous cell carcinoma (non-keratinizing type) and sarcomatoid carcinoma (pleomorphic carcinoma). There were 6 and 16 patients with RET fusion-positive who were in stage Ⅰ-Ⅱ and Ⅲ-Ⅳ respectively, and 16 cases with lymph node metastasis, 11 cases with distant metastasis. Among RET fusion-positive cases, one was detected with HER2 co-mutation. The tumor proportion score of PD-L1≥1% in patients with RET fusion positive lung cancer was 54.5% (12/22). Defects in mismatch repair protein expression were not found in patients with RET fusion positive NSCLC. Four patients with RET fusions positive (two cases of APA and two cases of SPA) received pratinib-targeted therapy, and two showed benefits from this targeted therapy. Conclusions: The histological subtypes of RET fusions positive NSCLC are more likely to be APA or SPA. RET fusion-positive NSCLC patients are associated with advanced clinical stage, lymph node metastases, and they may benefit from targeted therapy with RET-specific inhibitors.
Male ; Female ; Humans ; Middle Aged ; Carcinoma, Non-Small-Cell Lung/pathology* ; Lung Neoplasms/pathology* ; B7-H1 Antigen/genetics* ; Protein-Tyrosine Kinases/genetics* ; Proto-Oncogene Proteins c-ret/metabolism* ; Proto-Oncogene Proteins/genetics* ; Adenocarcinoma/pathology* ; Carcinoma, Squamous Cell/genetics* ; Mutation

Objective: To investigate the applicability of the 2021 WHO classification of thoracic tumors' new grading system for invasive pulmonary adenocarcinoma (IPA) with different clinical stages and its correlation with the characteristics of targeted genes' variation. Methods: A total of 2 467 patients with surgically resected primary IPA in Shanghai Pulmonary Hospital, Shanghai, China from September to December 2020 were retrospectively analyzed. Eligible cases were graded using the new grading system of IPA of the 2021 WHO classification of thoracic tumors. The clinicopathological data and targeted-gene abnormality were collected. The utility of new grading system of IPA in different clinical stages was investigated. The correlation of clinicopathological features and targeted-gene abnormality in different grades of IPA were compared. Results: All 2 311 cases of IPA were included. There were 2 046 cases of stage Ⅰ IPA (88.5%), 169 cases of stage Ⅱ (7.3%), and 96 cases of stage Ⅲ (4.2%). According to the new classification system of IPA, 186 cases (9.1%), 1 413 cases (69.1%) and 447 cases (21.8%) of stage-Ⅰ adenocarcinoma were classified as Grade 1, Grade 2 and Grade 3, respectively. However, there were no Grade 1 adenocarcinomas in stages Ⅱ and Ⅲ cases. Among stage-Ⅱ and Ⅲ IPA cases, there were 38 Grade 2 cases (22.5%) and 131 Grade 3 cases (77.5%), and 3 Grade 2 cases (3.1%) and 93 Grade 3 cases (96.9%), respectively. In stage-Ⅰ cases, no tumor cells spreading through airspace (STAS), vascular invasion or pleural invasion was found in Grade 1 of IPA, while the positive rates of STAS in Grade 2 and 3 IPA cases were 11.3% (159/1 413) and 73.2% (327/447), respectively. There was a significant difference among the three grades (P<0.01). Similarly, the rates of vascular and pleural invasion in Grade 3 IPA cases were 21.3% (95/447) and 75.8% (339/447), respectively, which were significantly higher than those of 1.3% (19/1 413) and 3.0% (42/1 413) in Grade 2 (P<0.01). EGFR mutational rates in Grades 1, 2 and 3 IPA were 65.7% (94/143), 76.4% (984/1 288) and 51.3% (216/421), respectively. The differences among the three grades were statistically significant (P<0.01). No fusion genes were detected in Grade 1 IPA, while the positive rates of ROS1 and ALK fusion genes in Grade 3 were 2.4% (10/421) and 8.3% (35/421), respectively, which were significantly higher than that of 0.5% (7/1 288) and 1.6% (20/1 288) in Grade 2 (P<0.01). In stage-Ⅱ cases, only EGFR mutation rate in Grade 2 adenocarcinoma (31/37, 83.8%) was higher than that in Grade 3 adenocarcinoma (71/123, 57.7%; P<0.01). However, the correlation between the new grade system of IPA and the distribution characteristics of targeted-gene variation cannot be evaluated in stage Ⅲ cases. Conclusions: The new grading system for IPA is mainly applicable to clinical stage-Ⅰ patients. Tumor grades of IPA are strongly correlated with the high-risk factors of prognosis and the distribution features of therapeutic targets. It is of great significance and clinical value to manage postoperative patients with early-stage IPA.
Humans ; Lung Neoplasms/pathology* ; Protein-Tyrosine Kinases/genetics* ; Retrospective Studies ; Proto-Oncogene Proteins/genetics* ; China ; Adenocarcinoma of Lung/pathology* ; Adenocarcinoma/pathology* ; Prognosis ; ErbB Receptors/genetics* ; World Health Organization ; Neoplasm Staging

Humans ; Lung Neoplasms/pathology* ; Adenocarcinoma of Lung/pathology* ; Neoplasm Invasiveness ; Prognosis ; Retrospective Studies ; Neoplasm Staging ; Neoplasm Recurrence, Local/pathology*

Humans ; Adenocarcinoma/pathology* ; Lung Neoplasms/pathology* ; Lung/pathology*