bims-meluca 2021-11-28 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2021–11–28
seven papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab, L’Institut d’Investigació Biomèdica de Bellvitge and Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge

Low-Dose Metformin as a Monotherapy Does Not Reduce Non-Small-Cell Lung Cancer Tumor Burden in Mice.
Blockade of Cellular Energy Metabolism through 6-Aminonicotinamide Reduces Proliferation of Non-Small Lung Cancer Cells by Inducing Endoplasmic Reticulum Stress.
Impact of Sodium Dichloroacetate Alone and in Combination Therapies on Lung Tumor Growth and Metastasis.
Untargeted Lipidomics of Non-Small Cell Lung Carcinoma Demonstrates Differentially Abundant Lipid Classes in Cancer vs. Non-Cancer Tissue.
Body Mass Index, Weight Loss, and Mortality Risk in Advanced-Stage Non-Small Cell Lung Cancer Patients: A Focus on EGFR Mutation.
Update Overview of the Role of Angiopoietins in Lung Cancer.
Angiogenesis inhibition in lung cancer: emerging novel strategies.

Biomedicines. 2021 Nov 14. pii: 1685. [Epub ahead of print]9(11):

Low-Dose Metformin as a Monotherapy Does Not Reduce Non-Small-Cell Lung Cancer Tumor Burden in Mice.

Nicole L Stott Bond, Didier Dréau, Ian Marriott, Jeanette M Bennett, Michael J Turner, Susan T Arthur, Joseph S Marino.

  Non-small-cell lung cancer (NSCLC) makes up 80-85% of lung cancer diagnoses. Lung cancer patients undergo surgical procedures, chemotherapy, and/or radiation. Chemotherapy and radiation can induce deleterious systemic side effects, particularly within skeletal muscle. To determine whether metformin reduces NSCLC tumor burden while maintaining skeletal muscle health, C57BL/6J mice were injected with Lewis lung cancer (LL/2), containing a bioluminescent reporter for in vivo tracking, into the left lung. Control and metformin (250 mg/kg) groups received treatments twice weekly. Skeletal muscle was analyzed for changes in genes and proteins related to inflammation, muscle mass, and metabolism. The LL/2 model effectively mimics lung cancer growth and tumor burden. The in vivo data indicate that metformin as administered was not associated with significant improvement in tumor burden in this immunocompetent NSCLC model. Additionally, metformin was not associated with significant changes in key tumor cell division and inflammation markers, or improved skeletal muscle health. Metformin treatment, while exhibiting anti-neoplastic characteristics in many cancers, appears not to be an appropriate monotherapy for NSCLC tumor growth in vivo. Future studies should pursue co-treatment modalities, with metformin as a potentially supportive drug rather than a monotherapy to mitigate cancer progression.

Keywords:  Lewis lung model; cachexia; lung cancer; skeletal muscle

DOI:  https://doi.org/10.3390/biomedicines9111685
Biology (Basel). 2021 Oct 22. pii: 1088. [Epub ahead of print]10(11):

Blockade of Cellular Energy Metabolism through 6-Aminonicotinamide Reduces Proliferation of Non-Small Lung Cancer Cells by Inducing Endoplasmic Reticulum Stress.

Neha Kaushik, Nagendra Kumar Kaushik, Eun Ha Choi, June Hyun Kim.

  The pentose phosphate pathway (PPP) is the most common pathway in most cancer cells and stimulates antioxidant defense mechanisms and synthesis of biomolecule precursors. It is believed that cancer cells persistently ameliorate glucose flux into the PPP to maintain their anabolic requirements and adjust oxidative stress. TCGA analyses have indicated the upregulation of enzymes involved in PPP in lung cancer. Hence, the present study aimed to determine whether the pharmacological blockade of glucose 6-phosphate dehydrogenase (G6PD), the primary and rate-limiting enzyme involved in PPP, using 6-aminonicotinamide (6-AN), could induce antiproliferative activity in two lung cancer cell lines. Exposure to 6-AN suppressed lactate production and glucose consumption, modified the mitochondrial potential and redox balance, and thereby induced the endoplasmic reticulum (ER) stress to reduce lung cancer cell proliferation and govern cellular apoptosis. Collectively, this is the first study in which PPP blockade by 6-AN causes reactive oxygen species (ROS)-mediated apoptosis by ER stress in lung cancer cells. Further preclinical studies will be conducted to validate the biological applicability of these findings.

Keywords:  endoplasmic reticulum stress; lung cancer; metabolic inhibitor; mitochondrial activity

DOI:  https://doi.org/10.3390/biology10111088
Int J Mol Sci. 2021 Nov 21. pii: 12553. [Epub ahead of print]22(22):

Impact of Sodium Dichloroacetate Alone and in Combination Therapies on Lung Tumor Growth and Metastasis.

Aya Al-Azawi, Shahrazad Sulaiman, Kholoud Arafat, Javed Yasin, Abderrahim Nemmar, Samir Attoub.

  Metabolic reprogramming has been recognized as an essential emerging cancer hallmark. Dichloroacetate (DCA), an inhibitor of pyruvate dehydrogenase kinase (PDK), has been reported to have anti-cancer effects by reversing tumor-associated glycolysis. This study was performed to explore the anti-cancer potential of DCA in lung cancer alone and in combination with chemo- and targeted therapies using two non-small cell lung cancer (NSCLC) cell lines, namely, A549 and LNM35. DCA markedly caused a concentration- and time-dependent decrease in the viability and colony growth of A549 and LNM35 cells in vitro. DCA also reduced the growth of tumor xenografts in both a chick embryo chorioallantoic membrane and nude mice models in vivo. Furthermore, DCA decreased the angiogenic capacity of human umbilical vein endothelial cells in vitro. On the other hand, DCA did not inhibit the in vitro cellular migration and invasion and the in vivo incidence and growth of axillary lymph nodes metastases in nude mice. Treatment with DCA did not show any toxicity in chick embryos and nude mice. Finally, we demonstrated that DCA significantly enhanced the anti-cancer effect of cisplatin in LNM35. In addition, the combination of DCA with gefitinib or erlotinib leads to additive effects on the inhibition of LNM35 colony growth after seven days of treatment and to synergistic effects on the inhibition of A549 colony growth after 14 days of treatment. Collectively, this study demonstrates that DCA is a safe and promising therapeutic agent for lung cancer.

Keywords:  angiogenesis; dichloroacetate; erlotinib; gefitinib; lung cancer; pyruvate dehydrogenase kinase inhibitor; tumor growth

DOI:  https://doi.org/10.3390/ijms222212553
Metabolites. 2021 Oct 28. pii: 740. [Epub ahead of print]11(11):

Untargeted Lipidomics of Non-Small Cell Lung Carcinoma Demonstrates Differentially Abundant Lipid Classes in Cancer vs. Non-Cancer Tissue.

Joshua M Mitchell, Robert M Flight, Hunter N B Moseley.

  Lung cancer remains the leading cause of cancer death worldwide and non-small cell lung carcinoma (NSCLC) represents 85% of newly diagnosed lung cancers. In this study, we utilized our untargeted assignment tool Small Molecule Isotope Resolved Formula Enumerator (SMIRFE) and ultra-high-resolution Fourier transform mass spectrometry to examine lipid profile differences between paired cancerous and non-cancerous lung tissue samples from 86 patients with suspected stage I or IIA primary NSCLC. Correlation and co-occurrence analysis revealed significant lipid profile differences between cancer and non-cancer samples. Further analysis of machine-learned lipid categories for the differentially abundant molecular formulas identified a high abundance sterol, high abundance and high m/z sphingolipid, and low abundance glycerophospholipid metabolic phenotype across the NSCLC samples. At the class level, higher abundances of sterol esters and lower abundances of cardiolipins were observed suggesting altered stearoyl-CoA desaturase 1 (SCD1) or acetyl-CoA acetyltransferase (ACAT1) activity and altered human cardiolipin synthase 1 or lysocardiolipin acyltransferase activity respectively, the latter of which is known to confer apoptotic resistance. The presence of a shared metabolic phenotype across a variety of genetically distinct NSCLC subtypes suggests that this phenotype is necessary for NSCLC development and may result from multiple distinct genetic lesions. Thus, targeting the shared affected pathways may be beneficial for a variety of genetically distinct NSCLC subtypes.

Keywords:  Fourier-transform mass spectrometry; SMIRFE; lipidomics; non-small cell lung carcinoma

DOI:  https://doi.org/10.3390/metabo11110740
Nutrients. 2021 Oct 24. pii: 3761. [Epub ahead of print]13(11):

Body Mass Index, Weight Loss, and Mortality Risk in Advanced-Stage Non-Small Cell Lung Cancer Patients: A Focus on EGFR Mutation.

Yu-Mu Chen, Chien-Hao Lai, Chiung-Yu Lin, Yi-Hsuan Tsai, Ya-Chun Chang, Hung-Chen Chen, Chia-Cheng Tseng, Huang-Chih Chang, Kuo-Tung Huang, Yung-Che Chen, Wen-Feng Fang, Chin-Chou Wang, Tung-Ying Chao, Meng-Chih Lin.

  Body mass index (BMI) influences the prognosis of patients with non-small cell lung cancer (NSCLC), including both early-stage and late-stage NSCLC patients that are undergoing chemotherapies. However, earlier research on the relationship between BMI and survival in patients taking epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) yielded contradictory results. These publications either had a limited number of patients or were getting TKIs in various lines of therapy, which might explain why the outcomes were contradictory. As a result, we undertook retrospective study to examine the effect of BMI on survival outcomes in patients with advanced EGFR mutant NSCLC receiving first-line EGFR-TKIs. We also compared the findings to those with wild-type EGFR. Between November 2010 and March 2014, 513 patients with advanced NSCLC were enrolled in the study. According to the adjusted BMI cut-off point for Asia, 35 out of 513 (6.8%) patients were underweight (BMI < 18.5 kg/m2), whereas 197 (38.4%) were overweight (BMI > 24 kg/m2). Overweight patients with wild-type EGFR exhibited longer progression-free survival (4.6 vs. 2.1 months, p = 0.003) and overall survival (OS) (8.9 vs. 4.3 months, p = 0.003) than underweight patients. Overweight patients with EGFR mutations had a longer OS than normal-weight patients (23.0 vs. 20.2 months, p = 0.025). Bodyweight reduction was related to a shorter OS in both the mutant EGFR patients (17.1 vs. 30.5 months, p < 0.001) and the wild-type EGFR patients (7.8 vs. 18.7 months, p < 0.001). In conclusion, advanced stages NSCLC patients with a lower BMI and early weight loss had a worse outcome that was independent of EGFR mutation status.

Keywords:  body mass index; non-small cell lung cancer; tyrosine kinase inhibitor; weight loss

DOI:  https://doi.org/10.3390/nu13113761
Medicina (Kaunas). 2021 Nov 01. pii: 1191. [Epub ahead of print]57(11):

Update Overview of the Role of Angiopoietins in Lung Cancer.

Dimitris Tsakogiannis, Asimina Nikolakopoulou, Flora Zagouri, Grigorios Stratakos, Konstantinos Syrigos, Eleni Zografos, Nikolaos Koulouris, Garyfalia Bletsa.

  Angiogenesis is a biological process that involves the formation of new blood vessels from the existing vasculature, and it plays a fundamental role in the development and progression of several types of cancer, including lung cancer. The angiopoietin/Tie2 ligand/receptor system orchestrates vascular integrity. In particular, Angiopoietin-1 activates the endothelial cell (EC)-specific receptor tyrosine kinase,Tie2,which is essential for preserving endothelial quiescence. On the other hand, Angiopoietin-2 acts as an inhibitor of the Angiopoietin-1/Tie2 signaling pathways, thus facilitating the destabilization of quiescent endothelium in cases of inflammation and cancer. Clinical studies have proven that high levels of Angiopoietin-2 indicate the development of non-small-cell lung carcinomas (NSCLC), while high levels of Angiopoietin-2 are strongly related to tumor angiogenesis, lymphangiogenesis, metastasis, and poor prognosis. Interestingly, the association of Angiopoietin-2 levels with the type of surgical approach makes Angiopoietin-2 a valuable factor in selecting the most suitable therapeutic strategy for lung cancer patients. The role of the Angiopoietin-1 and Angiopoietin-4 levels in NSCLC development requires further investigation. The present review focuses on the clinical impact of the Angiopoietin-1, Angiopoietin-2, and Angiopoietin-4 levels in patients diagnosed with NSCLC, emphasizing the interaction between them, and how they affect the development, progression, and metastasis of lung disease. Finally, it estimates the role of angiopoietins levels in the effective therapy of lung cancer patients.

Keywords:  Ang-1; Ang-2; Ang-3; Ang-4; angiogenesis; angiopoietins; lung cancer; non-small-cell lung cancer

DOI:  https://doi.org/10.3390/medicina57111191
Curr Opin Oncol. 2021 Nov 22.

Angiogenesis inhibition in lung cancer: emerging novel strategies.

Chiara Lazzari, Alessandra Bulotta, Giuseppe Damiano, Aurora Mirabile, Mariagrazia Viganó, Giulia Veronesi, Vanesa Gregorc.

PURPOSE OF REVIEW: In the current review, we will explore the molecular bases that have determined the design of clinical trials exploring the efficacy of antivascular agents in combination with chemotherapy, immune check point inhibitors and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in patients with advanced nonsmall cell lung cancer.
RECENT FINDINGS: Recent clinical trials have demonstrated the synergistic effect of antivascular agents with immune checkpoint inhibitors and EGFR-TKIs, despite no molecular marker has been identified yet to select patients.
SUMMARY: Lung cancer remains one of the first causes of cancer-related death. However, thanks to the development of stratified molecular medicine and the introduction of immune checkpoint inhibitors, patients' survival has significantly improved. Due to the critical role of pro-angiogenic factors in cancer progression, antivascular agents targeting the vascular endothelial growth factor (VEGF) and its receptor (VEGFR) have been developed. Their efficacy has been explored in combination with chemotherapy, and immune checkpoint inhibitors, with promising but not definitive conclusions about their impact on prolonging patients' survival.

DOI: https://doi.org/10.1097/CCO.0000000000000807