bims-meluca 2023-03-12 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2023–03–12
seven papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab, L’Institut d’Investigació Biomèdica de Bellvitge

Controlling Nutritional Status (CONUT) score is a prognostic marker in III-IV NSCLC patients receiving first-line chemotherapy.
A Novel Combination of Sotorasib and Metformin Enhances Cytotoxicity and Apoptosis in KRAS-Mutated Non-Small Cell Lung Cancer Cell Lines through MAPK and P70S6K Inhibition.
Epidemiology, risk factors and impact of cachexia on patient outcome: Results from the Japanese Lung Cancer Registry Study.
Serum cytokine levels and other associated factors as possible immunotherapeutic targets and prognostic indicators for lung cancer.
GLUT10 is a novel immune regulator involved in lung cancer immune cell infiltration and predicts worse survival when transcriptionally downregulated.
The prognostic value of the combination of body composition and systemic inflammation in patients with cancer cachexia.
A novel cuproptosis-related lncRNA signature to predict prognosis and immune landscape of lung adenocarcinoma.

BMC Cancer. 2023 Mar 09. 23(1): 225

Controlling Nutritional Status (CONUT) score is a prognostic marker in III-IV NSCLC patients receiving first-line chemotherapy.

Yi Zhang, Fei-Fei Kong, Zheng-Qiu Zhu, Hai-Xia Shan.

   BACKGROUND: To investigate the prognostic impact of the controlling nutritional status (CONUT) score in non-small-cell lung cancer (NSCLC) patients receiving first-line chemotherapy.
METHODS: We retrospectively reviewed 278 consecutive patients undergoing chemotherapy for stage III-IV NSCLC between May 2012 and July 2020. CONUT score was calculated by incorporating serum albumin, total cholesterol, and total lymphocyte count. The patients were divided into two groups: CONUT ≥ 3 and CONUT < 3, according to receiver operating characteristic (ROC) analysis. The associations of CONUT with clinicopathological factors and survival were evaluated.
RESULTS: A high CONUT score was significantly associated with older age(P = 0.003), worse ECOG-PS(P = 0.018), advanced clinical stage(P = 0.006), higher systematic inflammation index (SII) (P < 0.001)and lower prognostic nutritional index (PNI) (P < 0.001).The high CONUT group had a significantly shorter progression-free survival(PFS) and overall survival(OS) than the low CONUT group. In the univariate analysis, higher SII, higher CONUT, advanced clinical stage and lower PNI were associated with worse PFS (Pall < 0.05). Worse ECOG-PS, higher SII, higher CONUT, advanced clinical stage and lower PNI were associated with worse OS (Pall < 0.05). In multivariate analysis, CONUT(HR, 2.487; 95%CI 1.818 ~ 3.403; P < 0.001) was independently associated with PFS, while PNI(HR, 0.676; 95%CI 0.494 ~ 0.927; P = 0.015) and CONUT(HR, 2.186; 95%CI 1.591 ~ 3.002; P < 0.001)were independently associated with OS. In ROC analysis, CONUT had a higher area under the ROC curve (AUC) for the prediction of 24-month PFS and OS than the SII or PNI. When the time-dependent AUC curve was used to predict PFS and OS, CONUT tended to maintain its predictive accuracy for long-term prognosis at a significantly higher level for an extended period after chemotherapy when compared with the other markers tested. The CONUT score showed better accuracy of predicting OS (C-index: 0.711) and PFS(C-index: 0.753).
CONCLUSION: CONUT score is an independent prognostic indicator of poor outcomes for patients with stage III-IV NSCLC and is superior to the SII and PNI in terms of prognostic ability.

Keywords:  CONUT score; Chemotherapy; Non‑small-cell lung cancer; PNI; Prognostic factor; SII

DOI:  https://doi.org/10.1186/s12885-023-10682-z
Int J Mol Sci. 2023 Feb 22. pii: 4331. [Epub ahead of print]24(5):

A Novel Combination of Sotorasib and Metformin Enhances Cytotoxicity and Apoptosis in KRAS-Mutated Non-Small Cell Lung Cancer Cell Lines through MAPK and P70S6K Inhibition.

Pedro Barrios-Bernal, José Lucio-Lozada, Maritza Ramos-Ramírez, Norma Hernández-Pedro, Oscar Arrieta.

  Novel inhibitors of KRAS with G12C mutation (sotorasib) have demonstrated short-lasting responses due to resistance mediated by the AKT-mTOR-P70S6K pathway. In this context, metformin is a promising candidate to break this resistance by inhibiting mTOR and P70S6K. Therefore, this project aimed to explore the effects of the combination of sotorasib and metformin on cytotoxicity, apoptosis, and the activity of the MAPK and mTOR pathways. We created dose-effect curves to determine the IC50 concentration of sotorasib, and IC10 of metformin in three lung cancer cell lines; A549 (KRAS G12S), H522 (wild-type KRAS), and H23 (KRAS G12C). Cellular cytotoxicity was evaluated by an MTT assay, apoptosis induction through flow cytometry, and MAPK and mTOR pathways were assessed by Western blot. Our results showed a sensitizing effect of metformin on sotorasib effect in cells with KRAS mutations and a slight sensitizing effect in cells without K-RAS mutations. Furthermore, we observed a synergic effect on cytotoxicity and apoptosis induction, as well as a notable inhibition of the MAPK and AKT-mTOR pathways after treatment with the combination, predominantly in KRAS-mutated cells (H23 and A549). The combination of metformin with sotorasib synergistically enhanced cytotoxicity and apoptosis induction in lung cancer cells, regardless of KRAS mutational status.

Keywords:  AKT; KRAS; MAPK; P70S6K; lung cancer; metformin; sotorasib

DOI:  https://doi.org/10.3390/ijms24054331
J Cachexia Sarcopenia Muscle. 2023 Mar 10.

Epidemiology, risk factors and impact of cachexia on patient outcome: Results from the Japanese Lung Cancer Registry Study.

Takehito Shukuya, Kazuhisa Takahashi, Yasushi Shintani, Keita Miura, Ikuo Sekine, Koichi Takayama, Akira Inoue, Isamu Okamoto, Katsuyuki Kiura, Tomoya Kawaguchi, Nobuyuki Yamamoto, Etsuo Miyaoka, Ichiro Yoshino, Hiroshi Date.

   BACKGROUND: Cancer cachexia is a syndrome that does not fully recover with nutritional support and causes appetite loss and body weight loss. It worsens a patient's quality of life and prognosis. In this study, the epidemiology of cachexia in lung cancer, its risk factors and its impact on chemotherapy response rate and prognosis were examined using the national database of the Japan Lung Cancer Society. Understanding these things related to cancer cachexia is important as a starting point in overcoming cancer cachexia in patients with lung cancer.
METHODS: In 2012, 12 320 patients from 314 institutions in Japan were registered in a nationwide registry database (Japanese Lung Cancer Registry Study). Of these, data on body weight loss within 6 months were available for 8489 patients. We defined the patients with body weight loss ≥ 5% within 6 months, which is one of the three criteria listed in the 2011 international consensus definition of cancer cachexia, as cachectic in this study.
RESULTS: Approximately 20.4% of the 8489 patients had cancer cachexia. Sex, age, smoking history, emphysema, performance status, superior vena cava syndrome, clinical stage, site of metastasis, histology, epidermal growth factor receptor (EGFR) mutation status, primary treatment method and serum albumin levels were significantly different between patients with and without cachexia. Logistic analyses showed that smoking history, emphysema, clinical stage, site of metastasis, histology, EGFR mutation, serum calcium and albumin levels were significantly associated with cancer cachexia. The response to initial therapy, including chemotherapy, chemoradiotherapy or radiotherapy, was significantly poorer in the patients with cachexia than in those without cachexia (response rate: 49.7% vs. 41.5%, P < 0.001). Overall survival was significantly shorter in the patients with cachexia than in those without cachexia in both univariate and multivariable analyses (1-year survival rate: 60.7% vs. 37.6%, Cox proportional hazards model, hazard ratio: 1.369, 95% confidence interval: 1.274-1.470, P < 0.001).
CONCLUSIONS: Cancer cachexia was seen in approximately one fifth of the lung cancer patients and was related to some baseline patient characteristics. It was also associated with a poor response to initial treatment, resulting in poor prognosis. The results of our study may be useful for early identification and intervention in patients with cachexia, which may improve their response to treatment and their prognosis.

Keywords:  body weight loss; cancer cachexia; chemotherapy; lung cancer; risk factor; survival

DOI:  https://doi.org/10.1002/jcsm.13216
Front Oncol. 2023 ;13 1064616

Serum cytokine levels and other associated factors as possible immunotherapeutic targets and prognostic indicators for lung cancer.

Yinghao Zhao, Shengnan Jia, Kun Zhang, Lian Zhang.

  Lung cancer is one of the most prevalent cancer types and the leading cause of cancer-related deaths worldwide. Non-small cell lung cancer (NSCLC) accounts for 80-85% of all cancer incidences. Lung cancer therapy and prognosis largely depend on the disease's degree at the diagnosis time. Cytokines are soluble polypeptides that contribute to cell-to-cell communication, acting paracrine or autocrine on neighboring or distant cells. Cytokines are essential for developing neoplastic growth, but they are also known to operate as biological inducers following cancer therapy. Early indications are that inflammatory cytokines such as IL-6 and IL-8 play a predictive role in lung cancer. Nevertheless, the biological significance of cytokine levels in lung cancer has not yet been investigated. This review aimed to assess the existing literature on serum cytokine levels and additional factors as potential immunotherapeutic targets and lung cancer prognostic indicators. Changes in serum cytokine levels have been identified as immunological biomarkers for lung cancer and predict the effectiveness of targeted immunotherapy.

Keywords:  biomarkers; lung cancer; prognosis; serum cytokines; targeted immunotherapy

DOI:  https://doi.org/10.3389/fonc.2023.1064616
Heliyon. 2023 Mar;9(3): e13836

GLUT10 is a novel immune regulator involved in lung cancer immune cell infiltration and predicts worse survival when transcriptionally downregulated.

Lijuan Jian, Qi Wu, Xinping Min, Bowen Li, Min Zhang, Zhiyong Wu, Xiaoping Hu, Zongli Ren, Zhiwei Wang, Zhipeng Hu.

   Background: Glucose transporter 10 (GLUT10) is encoded by the SLC2A10 gene. Our recent investigations have shown that GLUT10 is not only involved in glucose metabolism but also involved in the body's immune response to cancer cells. However, the role of GLUT10 in tumor prognosis and in tumor immunity has not been reported.
Methods: We knocked down SLC2A10 and performed transcriptome sequencing to analyse the biological function of GLUT10 and found that GLUT10 may be involved in immune signaling. Then, we studied the expression level of SLC2A10 in cancers by the Oncomine database and Tumor Immune Estimation Resource (TIMER) site. We also evaluated the prognostic potential of SLC2A10 in different cancers using the Kaplan‒Meier plotter database and PrognoScan online software. The correlations between SLC2A10 expression and immune infiltrates were analysed by TIMER. In addition, correlations between SLC2A10 expression and gene marker sets of immune infiltrates were analysed by TIMER and Gene Expression Profiling Interactive Analysis (GEPIA). Immunofluorescence staining of cyclooxygenase-2 (COX-2) and GLUT10 in lung cancer tissue and adjacent tissue was performed to confirm our findings from the database research.
Results: Knocking down SLC2A10 widely activated immune and inflammatory signaling. SLC2A10 was abnormally expressed in several tumors. The expression level of SLC2A10 was closely correlated with cancer prognosis. Low SLC2A10 expression was related to poorer prognosis and increased malignancy of lung cancer. Lung cancer patients with low expression of SLC2A10 have a much shorter median survival time than patients with high expression of SLC2A10. SLC2A10 expression is closely related to the infiltration of different types of immune cells, particularly macrophages. Both database research and lung cancer sample research revealed that GLUT10 might modulate immune cell infiltration via the COX-2 pathway.
Conclusions: By transcriptome experiments, database studies, and human sample studies, we found that GLUT10 is a new immune signaling molecule involved in tumor immunity, especially in the immune cell infiltration of lung adenocarcinoma (LUAD). GLUT10 may modulate the immune cell infiltration of LUAD via the COX-2 pathway.

Keywords:  GLUT10; Immune infiltration; Immune molecule; Lung cancer; Prognosis; Tumor immunity

DOI:  https://doi.org/10.1016/j.heliyon.2023.e13836
J Cachexia Sarcopenia Muscle. 2023 Mar 05.

The prognostic value of the combination of body composition and systemic inflammation in patients with cancer cachexia.

Hai-Lun Xie, Guo-Tian Ruan, Lishuang Wei, Qi Zhang, Yi-Zhong Ge, Meng-Meng Song, Xi Zhang, Shi-Qi Lin, Xiao-Yue Liu, Xiao-Wei Zhang, Xiang-Rui Li, Kang-Ping Zhang, Chun-Lei Hu, Ming Yang, Meng Tang, Chun-Hua Song, Ming-Hua Cong, Min Weng, Zeng-Ning Li, Wei Li, Kun-Hua Wang, Han-Ping Shi.

   BACKGROUND: Changes in body composition and systemic inflammation are important characteristics of cancer cachexia. This multi-centre retrospective study aimed to explore the prognostic value of the combination of body composition and systemic inflammation in patients with cancer cachexia.
METHODS: The modified advanced lung cancer inflammation index (mALI), which combines body composition and systemic inflammation, was defined as appendicular skeletal muscle index (ASMI) × serum albumin/neutrophil-lymphocyte ratio. The ASMI was estimated according to a previously validated anthropometric equation. Restricted cubic splines were used to evaluate the relationship between mALI and all-cause mortality in patients with cancer cachexia. Kaplan-Meier analysis and Cox proportional hazard regression analysis were used to evaluate the prognostic value of mALI in cancer cachexia. A receiver operator characteristic curve was used to compare the effectiveness of mALI and nutritional inflammatory indicators in predicting all-cause mortality in patients with cancer cachexia.
RESULTS: A total of 2438 patients with cancer cachexia were enrolled, including 1431 males and 1007 females. The sex-specific optimal cut-off values of mALI for males and females were 7.12 and 6.52, respectively. There was a non-linear relationship between mALI and all-cause mortality in patients with cancer cachexia. Low mALI was significantly associated with poor nutritional status, high tumour burden, and high inflammation. Patients with low mALI had significantly lower overall survival (OS) than those with high mALI (39.5% vs. 65.5%, P < 0.001). In the male population, OS was significantly lower in the low mALI group than in the high group (34.3% vs. 59.2%, P < 0.001). Similar results were also observed in the female population (46.3% vs. 75.0%, P < 0.001). mALI was an independent prognostic factor for patients with cancer cachexia (hazard ratio [HR] = 0.974, 95% confidence interval [CI] = 0.959-0.990, P = 0.001). For every standard deviation [SD] increase in mALI, the risk of poor prognosis for patients with cancer cachexia was reduced by 2.9% (HR = 0.971, 95%CI = 0.943-0.964, P < 0.001) in males and 8.9% (HR = 0.911, 95%CI = 0.893-0.930, P < 0.001) in females. mALI is an effective complement to the traditional Tumour, Lymph Nodes, Metastasis (TNM) staging system for prognosis evaluation and a promising nutritional inflammatory indicator with a better prognostic effect than the most commonly used clinical nutritional inflammatory indicators.
CONCLUSIONS: Low mALI is associated with poor survival in both male and female patients with cancer cachexia and is a practical and valuable prognostic assessment tool.

Keywords:  Body composition; Cancer cachexia; Prognostic; Systemic inflammation

DOI:  https://doi.org/10.1002/jcsm.13205
Transl Lung Cancer Res. 2023 Feb 28. 12(2): 230-246

A novel cuproptosis-related lncRNA signature to predict prognosis and immune landscape of lung adenocarcinoma.

Xinyi Wang, Hui Jing, Hecheng Li.

   Background: Cuproptosis, a recently discovered type of programmed cell death (PCD), paves a new avenue for cancer treatment. It has been revealed that PCD-related lncRNAs play a critical role in various biological processes of lung adenocarcinoma (LUAD). However, the role of cuproptosis-related lncRNA (CuRLs) remains unclear. This study aimed to identify and validate a CuRLs-based signature for the prognostic prediction of patients with LUAD.
Methods: RNA sequencing data and clinical information of LUAD were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Pearson correlation analysis was used to identify CuRLs. Univariate Cox regression analysis, Least Absolute Shrinkage and Selection Operator (LASSO) Cox regression, and stepwise multivariate Cox analysis were applied to construct a novel prognostic CuRLs signature. A nomogram was developed for the prediction of patient survival outcomes. Gene set variation analysis (GSVA), gene set enrichment analysis (GSEA), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were utilized to explore potential functions underlying the CuRLs signature. Patients were divided into low- and high-risk groups. Several algorithms, such as tumor immune estimation resource (TIMER), cell-type identification by estimating relative subsets of RNA transcripts (CIBERSORT), and QuanTIseq, were combined to comprehensively investigate the differences in immune landscape between different risk groups. Sensitivity to common anticancer drugs was analyzed using the pRRophetic algorithm.
Results: We constructed a novel prognostic signature based on 10 CuRLs, including CARD8-AS1, RUNDC3A-AS1, TMPO-AS1, MIR31HG, SEPSECS-AS1, DLGAP1-AS1, LINC01137, ZSCAN16-AS1, APTR, and ELOA-AS1. This 10-CuRLs risk signature showed great diagnostic accuracy combined with traditional clinical risk factors, and a nomogram was constructed for potential clinical translation. The tumor immune microenvironment was significantly different between different risk groups. Among drugs commonly used in the treatment of lung cancer, the sensitivity of cisplatin, docetaxel, gemcitabine, gefitinib, and paclitaxel was higher in low-risk patients, and patients in the low-risk group may benefit more from imatinib.
Conclusions: These results revealed the outstanding contribution of the CuRLs signature to the evaluation of prognosis and treatment modalities for patients with LUAD. The differences in characteristics between different risk groups provide an opportunity for better patient stratification and to explore novel drugs in different risk groups.

Keywords:  Lung adenocarcinoma; cuproptosis; immune landscape; lncRNA; prognostic prediction

DOI:  https://doi.org/10.21037/tlcr-22-500