bims-meluca 2025-02-02 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2025–02–02
eight papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab, L’Institut d’Investigació Biomèdica de Bellvitge

[Translated article] Relationship between lactate dehydrogenase and survival in patients with non-small-cell lung cancer receiving immunotherapy.
The association between body composition and overall survival in patients with advanced non-small cell lung cancer.
Molecular and therapeutic insight into ER Stress signaling in NSCLC.
Effects of MIR-451 on LKB1-AMPK Signal Pathway and Oxidative Stress Index in Lung Cancer.
Association of Obesity and Skeletal Muscle with Postoperative Survival in Non-Small Cell Lung Cancer.
Tumor Metabolism as a Factor Affecting Diversity in Cancer Cachexia.
Body composition alterations in patients with lung cancer.
Brown adipose tissue is associated with reduced weight loss and risk of cancer cachexia: A retrospective cohort study.

Farm Hosp. 2025 Jan 29. pii: S1130-6343(24)00190-9. [Epub ahead of print]

[Translated article] Relationship between lactate dehydrogenase and survival in patients with non-small-cell lung cancer receiving immunotherapy.

Claudia Rosique-Aznar, Alejandro Valcuende-Rosique, Dolores Rosique-Robles, Agustín Sánchez-Alcaraz.

   OBJECTIVE: The expression level of programmed death ligand 1 (PD-L1) is the only approved biomarker for predicting response to immunotherapy, yet its efficacy is not always consistent. Lactate dehydrogenase (LDH) has been associated with tumor aggressiveness and poorer prognosis across various cancer types and may serve as a useful biomarker for monitoring treatment response. The objective of this study is to analyze the relationship between LDH levels prior to the start of treatment with immune checkpoint inhibitors (ICIs) and clinical outcomes in patients with non-small cell lung cancer (NSCLC).
METHOD: A retrospective study was conducted including patients diagnosed with NSCLC who were treated with at least 3 cycles of immunotherapy. Data on demographics, clinical and pathological characteristics, treatment received, pretreatment LDH levels, and clinical outcomes such as treatment response and overall survival (OS) were analyzed.
RESULTS: A total of 181 patients diagnosed with NSCLC were included. Elevated pretreatment LDH levels (>244 U/L) were associated with significantly reduced OS. The median survival was 548 days in patients with LDH ≤ 244 U/L, compared to 332 days in those with LDH > 244 U/L (P = .037). Among men, OS was greater in the LDH ≤ 244 U/L group (623 days) versus 332 days in the LDH > 244 U/L group (P = 0.043). In patients with metastatic disease, OS was higher in those with LDH ≤ 244 U/L (474 days) compared to 249 days in those with LDH > 244 U/L (P = .023). In patients receiving both immunotherapy and chemotherapy, OS was greater in those with LDH ≤ 244 U/L (623 days) compared to 281 days in the LDH > 244 U/L group (P = .042).
CONCLUSIONS: High levels of LDH prior to the start of treatment with ICIs are associated with lower treatment efficacy and a worse prognosis of the disease, especially in male, metastatic patients with a PD-L1 expression level <1%.

Keywords:  Biomarcadores; Biomarkers; Cáncer de pulmón no microcítico; Immunotherapy; Inmunoterapia; Lactate dehydrogenase; Lactato deshidrogenasa; Non-small cell lung cancer; Supervivencia; Survival

DOI:  https://doi.org/10.1016/j.farma.2024.11.007
Sci Rep. 2025 Jan 24. 15(1): 3109

The association between body composition and overall survival in patients with advanced non-small cell lung cancer.

Liang Fu, Haiming Ding, Liupei Mo, Xiaoyu Pan, Lijuan Feng, Shenglian Wen, Qiaoqing Lan, Liling Long.

  Nutritional status is associated with prognosis in a variety of cancers. Studies analyzing the association between the measurements of skeletal muscle and adipose tissue obtained from Computerized Tomography (CT) images at the time of diagnosis of advanced non-small cell lung cancer (NSCLC) and overall survival (OS) are relatively few. Data from 425 patients diagnosed with advanced NSCLC between January 2016 and December 2017 were retrospectively analyzed, with an average follow-up of 15.3 months. To outline the patient's chest CT plain image at the time of diagnosis,skeletal muscle and subcutaneous fat at the level of both thoracic vertebrae were quantified in terms of mass and quantity by the pectoral muscle index (PMI), pectoral muscle density (PMD), subcutaneous fat index (SFI), subcutaneous fat density (SFD), paravertebral muscle index (PVMI), and paravertebral muscle density (PVMD). The SFI value in the female survival group is significantly lower than that in the death group (P = 0.049), and the PVMI value in the overall survival group is significantly lower than that in the death group (P < 0.001). After adjusting for clinical variables such as gender, smoking status, clinical staging, degree of differentiation, and radiotherapy history, the multivariable Cox regression analysis showed that an increase in SFI significantly improves the overall survival rate of patients (Hazard Ratio [HR] = 1.410, 95% Confidence Interval [CI]: 1.042-1.908, P = 0.026). Conversely, a decrease in PVMD is significantly associated with improved overall survival and prognosis (HR = 0.762, 95% CI: 0.579-0.982, P = 0.048). No association was found between body mass index (BMI) and chest muscle status indicators and overall survival (P > 0.05). CT-measured body composition parameters provide precise prognostic information and are superior to BMI; an increased OS rate in advanced NSCLC is associated with a greater SFI and a lower PVMD.

Keywords:  Body composition; NSCLC; Overall Survival; Skeletal muscle; Subcutaneous fat

DOI:  https://doi.org/10.1038/s41598-025-87073-w
J Drug Target. 2025 Jan 30. 1-18

Molecular and therapeutic insight into ER Stress signaling in NSCLC.

Aastha Jadhav, Arjun Menon, Kush Gupta, Neeru Singh.

  Endoplasmic Reticulum (ER) stress is intricately involved in cancer development, progression and response to chemotherapy. ER stress related genes might play an important role in predicting the prognosis in lung adenocarcinoma patients and may be manipulated to improve the treatment outcome and overall survival rate. In this review, we analyzed the contribution of the three major ER stress pathways-IRE1, ATF6, and PERK-in lung cancer pathogenesis via modulation of tumor microenvironment (TME) and processes as metastasis, angiogenesis, apoptosis and N-glycosylation. Furthermore, we discuss the regulatory role of microRNAs in fine-tuning ER stress pathways in Non-Small Cell Lung Cancer (NSCLC). Our review also highlights various promising strategies to overcome chemoresistance by targeting ER stress pathways, offering new therapeutic opportunities.

Keywords:  ATF6; Chemoresistance; ER stress; IRE1; Non-Small Cell Lung Cancer (NSCLC); PERK; miRNA

DOI:  https://doi.org/10.1080/1061186X.2025.2461105
Ann Clin Lab Sci. 2024 Nov;54(6): 774-781

Effects of MIR-451 on LKB1-AMPK Signal Pathway and Oxidative Stress Index in Lung Cancer.

Zhuxiu Jiang, Yao Zhong, Jiahao Chen, Xiang Guo, Jingjing Wang, Zhibo Xu.

OBJECTIVE: To understand the influence of MIR-451 on LKB1-AMPK signal pathway and oxidative stress index in lung cancer mice.
METHODS: 40 rats were divided into four groups: ZC group (no lung cancer model), model group (lung cancer model), intervention group (rats with MiR-451 agomir injected), and NC group (rats with MiR-451 agomir control injected), 10 mice/group. The levels of MDA (malondialdehyde) and SOD (superoxide dismutase) in the four groups were detected, as well as the overall weights of the lungs and spleens. Lung tissue pathological changes were assessed by HE and LKB1-AMPK protein level and mRNA by Western blot and PCR.
RESULTS: Compared to ZC group, the MDA levels in model and NC group were higher (p<0.05). In comparison with model and NC groups, the MDA level in intervention group was lower (p<0.05), while SOD was inversely associated with MDA levels. The lung and spleen indexes were similar in the NC and model groups (p>0.05). The lung index was lower and spleen index was higher in intervention group than in the other two groups (p<0.05). LKB1 and AMPK protein levels in model and NC groups were significantly elevated over the ZC group (P<0.05), and the LKB1 and AMPK protein levels of intervention group were the highest (P<0.05); LKB1 and AMPK mRNA levels of model and NC group were minor than ZC and intervention group (P<0.05).
CONCLUSION: MiR-451 agonist shows a favorable response in a lung cancer model, reducing MDA levels and increasing SOD levels and improving lung weight as well as increasing LKB1-AMPK protein and mRNA expression.

Keywords: LKB1-AMPK; Lung cancer; MiR-451; oxidative stress
Radiology. 2025 Jan;314(1): e241507

Association of Obesity and Skeletal Muscle with Postoperative Survival in Non-Small Cell Lung Cancer.

Ji Hyun Lee, Danbee Kang, Junghee Lee, Yeong Jeong Jeon, Seong Yong Park, Jong Ho Cho, Yong Soo Choi, Jhingook Kim, Young Mog Shim, Sunga Kong, Hong Kwan Kim, Juhee Cho.

Background A comprehensive assessment of skeletal muscle health is crucial to understanding the association between improved clinical outcomes and obesity as defined by body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) in lung cancer, but limited studies have been conducted on this topic. Purpose To investigate the association between BMI-defined obesity and survival in patients with non-small cell lung cancer who underwent curative resection, with a specific focus on the status of skeletal muscle assessed at CT. Materials and Methods This retrospective study investigated Korean patients with non-small cell lung cancer who underwent curative resection between January 2008 and December 2019. Patients were classified into nonobese (BMI <25) or obese (BMI ≥25) groups. Skeletal muscle status was assessed at CT at the level of the third lumbar vertebrae. Low skeletal muscle mass (LSMM) was defined as the sex-specific lowest quartile. Cox regression analysis was used to evaluate the associations of BMI and muscle status with overall survival. Results A total of 7076 patients (mean age, 62.5 years ± 9.7 [SD]; 4081 male) were included, of whom 2512 (35.5%) had a BMI greater than or equal to 25 (obese group). In the setting of absent LSMM and myosteatosis, patients in the obese group had longer overall survival compared with patients in the nonobese group (hazard ratio [HR], 0.77; 95% CI: 0.66, 0.90; P = .001). The associations between obesity and lower mortality were observed only in male patients (HR, 0.72; 95% CI: 0.60, 0.85; P < .001) and patients who had ever smoked (HR, 0.71; 95% CI: 0.60, 0.85; P < .001) who were without LSMM and myosteatosis, with effect differing according to sex and smoking status (P value range, <.001 to .02 for interaction). Conclusion Obesity is associated with improved overall survival in patients with non-small cell lung cancer after curative resection when skeletal muscle mass and radiodensity are preserved. © RSNA, 2025 Supplemental material is available for this article. See also the editorial by Vannier in this issue.

DOI: https://doi.org/10.1148/radiol.241507
Am J Physiol Cell Physiol. 2025 Jan 27.

Tumor Metabolism as a Factor Affecting Diversity in Cancer Cachexia.

Oliver F Bathe.

  Cancer cachexia is a multifaceted metabolic syndrome characterized by muscle wasting, fat redistribution, and metabolic dysregulation, commonly associated with advanced cancer but sometimes also evident in early-stage disease. More subtle body composition changes have also been reported in association with cancer, including sarcopenia, myosteatosis, and increased fat radiodensity. Emerging evidence reveals that body composition changes including sarcopenia, myosteatosis, and increased fat radiodensity, arise from distinct biological mechanisms and significantly impact survival outcomes. Importantly, these features often occur independently, with their combined presence exacerbating poor prognoses. Tumor plays a pivotal role in driving these host changes, either by acting as a metabolic parasite or by releasing mediators that disrupt normal tissue function. This review explores the diversity of tumor metabolism. It highlights the potential for tumor-specific metabolic phenotypes to influence systemic effects, including fat redistribution and sarcopenia. Addressing this tumorhost metabolic interplay requires personalized approaches that disrupt tumor metabolism while preserving host health. Promising strategies include targeted pharmacologic interventions and anti-cachexia agents like GDF-15 inhibitors. Nutritional modifications such as ketogenic diets and omega-3 fatty acid supplementation also merit further investigation. In addition to preserving muscle, these therapies will need to be evaluated for their capability to improve survival and quality of life. This review underscores the need for further research into tumor-driven metabolic effects on the host and the development of integrative treatment strategies to address the interconnected challenges of cancer progression and cachexia.

Keywords:  cachexia; cancer; host response; metabolism; tumor microenvironment

DOI:  https://doi.org/10.1152/ajpcell.00677.2024
Am J Physiol Cell Physiol. 2025 Jan 31.

Body composition alterations in patients with lung cancer.

Deena B Snoke, Gary S Atwood, Emma R Bellefleur, Alice M Stokes, Michael J Toth.

  Most patients with lung cancer experience cancer cachexia (CC), a syndrome of skeletal muscle and adipose tissue wasting. Knowledge of body composition changes in patients is limited, however, because most studies have been cross-sectional, comparing patients with non-cancer controls or patients with and without CC. Few studies, in contrast, have evaluated body composition in patients with lung cancer over time. This review examines our current understanding of longitudinal body composition changes in patients with lung cancer and identifies modifying factors contributing to variation in muscle and adipose tissue wasting, focusing on biological sex. We identified 32 studies conducting longitudinal measurements of body composition by computed tomography, bioelectrical impedance, dual x-ray absorptiometry or total body nitrogen, with a total of n=3,951 patients (35% female). All studies evaluated changes following diagnosis while patients were receiving treatment. Most studies reporting muscle-specific outcomes show decreased skeletal muscle mass, with more pronounced muscle wasting in males and male-enriched populations. In a small number of studies reporting muscle density, the majority show increased myosteatosis. Adiposity changes are less frequently reported, although wasting appears more prevalent in late-stage disease. Further studies are needed to define adipose changes along the lung cancer continuum. Our review emphasizes the need for balanced recruitment based on biological sex and sex-based analyses. Additionally, consensus reporting of relevant patient data and outcomes in future studies will allow for meta-analysis and assist in the development of effective treatments for lung CC.

Keywords:  adiposity; biological sex; cachexia; muscle wasting; myosteatosis

DOI:  https://doi.org/10.1152/ajpcell.01048.2024
Clin Nutr. 2024 Dec 30. pii: S0261-5614(24)00469-2. [Epub ahead of print]45 262-269

Brown adipose tissue is associated with reduced weight loss and risk of cancer cachexia: A retrospective cohort study.

Grigorios Panagiotou, Demsina Babazadeh, Dario F Mazza, Soheila Azghadi, Joseph M Cawood, Aaron S Rosenberg, Fumiaki Imamura, Nita G Forouhi, Abhijit J Chaudhari, Yasser G Abdelhafez, Ramsey D Badawi, Maria Chondronikola.

   BACKGROUND & AIMS: Brown adipose tissue (BAT) has been mainly investigated as a potential target against cardiometabolic disease, but it has also been linked to cancer-related outcomes. Although preclinical data support that BAT and the thermogenic adipocytes in white adipose tissue may play an adverse role in the pathogenesis of cancer cachexia, results from studies in patients have reported inconsistent results. The purpose of this study was to examine the interrelationship between presence of detectable BAT, changes in body weight, and cachexia in patients with cancer. We hypothesized that evidence of BAT at cancer diagnosis would be associated with greater weight loss and risk of cancer cachexia up to a year after cancer diagnosis.
METHODS: We conducted a retrospective cohort study in treatment-naïve patients with detectable BAT (BAT+, n = 57) and without evidence of BAT (BAT-, n = 73) on 2-deoxy-2-[18F]fluoro-d-glucose positron emission tomography-computed tomography (18F-FDG-PET-CT) imaging performed for cancer staging (2004-2020). Patients' clinical, demographic, and anthropometric characteristics were extracted from their electronic medical record for up to a year after diagnosis. The two groups were a priori matched for demographic, anthropometric, and disease-related characteristics at diagnosis, as well as for season and outdoor temperature on the day of the PET-CT scan. Cancer cachexia was defined as weight loss greater than 5 % or 2 % if body mass index was lower than 20 kg/m2. Poisson regression models were fitted to estimate the relative risk (RR) for developing cancer cachexia over the 1-year follow-up among BAT+ compared to BAT- patients.
RESULTS: The BAT+ group experienced a lower magnitude of weight loss compared with the BAT- group during the 1-year follow-up (p = 0.014 for interaction between BAT status and time). The risk for cancer cachexia was 44 % lower in the BAT+ than the BAT- group, adjusted for age, sex, outdoor temperature on the day of the 18F-FDG-PET-CT imaging, cancer site and stage (RR: 0.56, 95 % CI: 0.32 to 0.97).
CONCLUSION: Contrary to our original hypothesis, evidence of BAT assessed by 18F-FDG-PET-CT imaging at cancer diagnosis was associated with greater body weight maintenance and lower risk for developing cancer cachexia up to one year after diagnosis. Larger, prospective studies and mechanistic experiments are needed to expand and identify the causal factors of our observations.

Keywords:  Brown adipose tissue; Cachexia; Cancer; Muscle; Obesity

DOI:  https://doi.org/10.1016/j.clnu.2024.12.028