bims-meluca 2022-05-01 papers

J Thorac Cardiovasc Surg. 2022 Mar 10. pii: S0022-5223(22)00241-0. [Epub ahead of print]

Identification of patient characteristics associated with survival benefit from metformin treatment in patients with stage I non-small cell lung cancer.

Peter L Elkin, Sarah Mullin, Sheldon Tetewsky, Skyler D Resendez, Wilmon McCray, Joseph Barbi, Sai Yendamuri.

BACKGROUND: Non-small cell lung cancer (NSCLC) continues to be a major cause of cancer deaths. Previous investigation has suggested that metformin use can contribute to improved outcomes in NSCLC patients. However, this association is not uniform in all analyzed cohorts, implying that patient characteristics might lead to disparate results. Identification of patient characteristics that affect the association of metformin use with clinical benefit might clarify the drug's effect on lung cancer outcomes and lead to more rational design of clinical trials of metformin's utility as an intervention. In this study, we examined the association of metformin use with long-term mortality benefit in patients with NSCLC and the possible modulation of this benefit by body mass index (BMI) and smoking status, controlling for other clinical covariates.
METHODS: This was a retrospective cohort study in which we analyzed data from the Veterans Affairs (VA) Tumor Registry in the United States. Data from all patients with stage I NSCLC from 2000 to 2016 were extracted from a national database, the Corporate Data Warehouse that captures data from all patients, primarily male, who underwent treatment through the VA health system in the United States. Metformin use was measured according to metformin prescriptions dispensed to patients in the VA health system. The association of metformin use with overall survival (OS) after diagnosis of stage I NSCLC was examined. Patients were further stratified according to BMI and smoking status (previous vs current) to examine the association of metformin use with OS across these strata.
RESULTS: Metformin use was associated with improved survival in patients with stage I NSCLC (average hazard ratio, 0.82; P < .001). An interaction between the effect of metformin use and BMI on OS was observed (χ2 = 3268.42; P < .001) with a greater benefit of metformin use observed in patients as BMI increased. Similarly, an interaction between smoking status and metformin use on OS was also observed (χ2 = 2997.05; P < .001) with a greater benefit of metformin use observed in previous smokers compared with current smokers.
CONCLUSIONS: In this large retrospective study, we showed that a survival benefit is enjoyed by users of metformin in a robust stage I NSCLC patient population treated in the VA health system. Metformin use was associated with an 18% improved OS. This association was stronger in patients with a higher BMI and in previous smokers. These observations deserve further mechanistic study and can help rational design of clinical trials with metformin in patients with lung cancer.

Keywords: lung cancer; metformin; obesity; outcomes

DOI: https://doi.org/10.1016/j.jtcvs.2022.02.046

Front Oncol. 2022 ;12 848483

Choline Kinase Alpha2 Promotes Lipid Droplet Lipolysis in Non-Small-Cell Lung Carcinoma.

Rongxuan Zhu, Yannan Yang, Fei Shao, Juhong Wang, Yibo Gao, Jie He, Zhimin Lu.

Background: Rapid tumor growth inevitably results in energy stress, including deficiency of glutamine, a critical amino acid for tumor cell proliferation. However, whether glutamine deficiency allows tumor cells to use lipid droplets as an energy resource and the mechanism underlying this potential regulation remain unclear.
Methods: We purified lipid droplets from H322 and H358 human non-small-cell lung cancer (NSCLC) cells under glutamine deprivation conditions and performed immunoblotting to determine the binding of choline kinase (CHK) α2 to lipid droplets. Immunofluorescence was used to quantify lipid droplet numbers and sizes. Immunoprecipitation and immunoblotting were performed to examine AMPK activation and CHKα2 phosphorylation. Cellular fatty acid levels, mitochondrial acetyl coenzyme A and ATP production, and cell apoptosis and proliferation were measured. Immunohistochemical analyses were performed to determine the expression levels of ACC pS79 and CHKα2 pS279 in tumor specimens from NSCLC patients. The prognostic value of ACC pS79 and CHKα2 pS279 was assessed using the Kaplan-Meier method and Cox regression models.
Results: Glutamine deficiency induces AMPK-mediated CHKα2 S279 phosphorylation, which promotes the binding of CHKα2 to lipid droplets, resulting in recruitment of cytosolic lipase ATGL and autophagosomes and subsequent lipolysis of lipid droplets to sustain tumor cell survival and proliferation. In addition, the levels of ACC pS79 and CHKα S279 were much higher in human NSCLC specimens than in their adjacent normal tissues and positively correlated with each other. Notably, ACC pS79 and CHKα pS279 expression levels alone were associated with poor prognosis of NSCLC patients, and combined values of both phosphorylation levels were correlated with worse prognosis of the patients.
Conclusion: CHKα2 plays a critical role in lipolysis of lipid droplets in NSCLC. ACC pS79 and CHKα2 pS279 alone or in combination can be used as prognostic markers in NSCLC.

Keywords: choline kinase; lipid metabolism; non-small-cell lung cancer; phosphorylation; prognostic biomarker

DOI: https://doi.org/10.3389/fonc.2022.848483

Front Biosci (Landmark Ed). 2022 Apr 18. 27(4): 129

Optimising Outcomes in Non Small Cell Lung Cancer: Targeting Cancer Cachexia.

Iain Phillips, Mark Stares, Lindsay Allan, Judith Sayers, Richard Skipworth, Barry Laird.

Lung cancer is the commonest malignancy worldwide and the leading cause of cancer death. Half of patients with lung cancer present with advanced disease. The number of systemic therapies including immunotherapy and targeted treatment are rapidly increasing. Despite this, the outcomes for many patients with locally advanced and advanced lung cancer are poor, as many patients are too unwell for treatment. One of the reasons patients with Non-Small Cell Lung Cancer are not fit for treatment is cancer cachexia, which is common (upto 75% of patients) in this group. This metabolic syndrome presents clinically as weight loss (muscle +/- fat), decreased physical function (patients less active) and anorexia on a background of systemic inflammation. Currently there is not an optimal management pathway for these patients, however, there is emerging data that multi-modal intervention including nutritional support, physical training and pharmacological therapy may have a role in treating cachexia. This review discusses assessment and intervention in cancer cachexia.

Keywords: cachexia; inflammation; lung cancer; weight loss

DOI: https://doi.org/10.31083/j.fbl2704129

Bioengineered. 2022 Apr;13(4): 11258-11268

Untargeted metabolomics profiling in a mouse model of lung cancer treated with thermal ablation.

Haoyue Pang, Kaiwen Hu, Fuyao Li, Hua Duan, Yu Chen, Yaqi Hu, Dan Wang, Min Jiang.

Thermal ablation is widely used in the treatment of lung cancer and is beneficial for the overall survival of patients in clinic. However, there is barely a priority in which ablation system should be chosen under different periods of tumor progression in lung cancer. The present study investigated different modes of thermal ablation systems in mice with transplanted Lewis lung carcinoma tumors and their various biological effects in local regions using untargeted metabolomics. The results showed that thermal ablation could significantly suppress tumor growth and the differentially expressed metabolites of tumors after ablation relative to untreated tumors concentrated on organic compounds, organic acids and derivatives, nucleosides, nucleotides, and lipids. The upregulated metabolites indicated an inflammatory reaction in the ablation groups at an early stage after ablation. Steroid hormone and tryptophan metabolism, which are associated with immune responses, were modulated after both cryoablation and hyperthermal ablation. Characteristically, the results also indicated that cryoablation suppressed glucose oxidation and carbohydrate metabolism of tumor, while hyperthermal ablation suppressed lipid metabolism of tumor. In conclusion, thermal ablation could inhibit tumor growth under either freezing or heating modes with characteristic different biological effects on tumors.

Keywords: Thermal ablation; cryoablation; hyperthermal ablation; lung cancer; metabolomics

DOI: https://doi.org/10.1080/21655979.2022.2065742

PeerJ. 2022 ;10 e13272

Changes in serum amino acid levels in non-small cell lung cancer: a case-control study in Chinese population.

Ke Liu, Jiaoyuan Li, Tingting Long, Yi Wang, Tongxin Yin, Jieyi Long, Ying Shen, Liming Cheng.

Background: Previous studies have shown the alteration of amino acid (AA) profile in patients with non-small cell lung cancer (NSCLC). However, there is little data regarding AA profile in NSCLC in Chinese population. The aim of this study was to evaluate AA profile in Chinese NSCLC patients, explore its utility in sample classification and further discuss its related metabolic pathways.
Methods: The concentrations of 22 AAs in serum samples from 200 patients with NSCLC and 202 healthy controls were determined by liquid chromatography-tandem mass spectrometer (LC-MS/MS). AA levels in different tumor stages and histological types were also discussed. The performance of AA panel in classifying the cases and controls was evaluated in the training data set and validation data set based on the receiver operating characteristic (ROC) curve, and the important metabolic pathways were identified.
Results: The concentrations of tryptophan (Trp), phenylalanine (Phe), isoleucine (Ile), glycine (Gly), serine (Ser), aspartic acid (Asp), asparagine (Asn), cystein (Cys), glutamic acid (Glu), ornithine (Orn) and citrulline (Cit) were significantly altered in NSCLC patients compared with controls (all P-FDR < 0.05). Among these, four AAs including Asp, Cys, Glu and Orn were substantially up-regulated in NSCLC patients (FC ≥ 1.2). AA levels were significantly altered in patients with late-stage NSCLC, but not in those with early-stage when comparing with healthy controls. In terms of histological type, these AAs were altered in both adenocarcinoma and squamous cell carcinoma. For discrimination of NSCLC from controls, the area under the ROC curve (AUC) was 0.80 (95% CI [0.74-0.85]) in the training data set and 0.79 (95%CI [0.71-0.87]) in the validation data set. The AUCs for early-stage and late-stage NSCLC were 0.75 (95% CI [0.68-0.81]) and 0.86 (95% CI [0.82-0.91]), respectively. Moreover, the model showed a better performance in the classification of squamous cell carcinoma (AUC = 0.90, 95% CI [0.85-0.95]) than adenocarcinoma (AUC = 0.77, 95% CI [0.71-0.82]) from controls. Three important metabolic pathways were involved in the alteration of AA profile, including Gly, Ser and Thr metabolism; Ala, Asp and Glu metabolism; and Arg biosynthesis.
Conclusions: The levels of several AAs in serum were altered in Chinese NSCLC patients. These altered AAs may be utilized to classify the cases from the controls. Gly, Ser and Thr metabolism; Ala, Asp and Glu metabolism and Arg biosynthesis pathways may play roles in metabolism of the NSCLC patient.

Keywords: Amino acids; Liquid chromatography-tandem mass spectrometer; Metabolomics; Non-small cell lung cancer

DOI: https://doi.org/10.7717/peerj.13272