bims-meluca 2021-03-07 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2021–03–07
nine 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

Cystine supplementation rebalances the redox homeostasis of microenvironment in non-small cell lung cancer cells and reverses their resistance to docetaxel.
p62-Induced Cancer-Associated Fibroblast Activation via the Nrf2-ATF6 Pathway Promotes Lung Tumorigenesis.
ESM1/HIF‑1α pathway modulates chronic intermittent hypoxia‑induced non‑small‑cell lung cancer proliferation, stemness and epithelial‑mesenchymal transition.
Blocking Aerobic Glycolysis by Targeting Pyruvate Dehydrogenase Kinase in Combination with EGFR TKI and Ionizing Radiation Increases Therapeutic Effect in Non-Small Cell Lung Cancer Cells.
Preoperative prognostic nutritional index level is associated with tumour-infiltrating lymphocyte status in patients with surgically resected lung squamous cell carcinoma.
Identified lung adenocarcinoma metabolic phenotypes and their association with tumor immune microenvironment.
Hypoxia Induces Overexpression of CCL28 to Recruit Treg Cells to Enhance Angiogenesis in Lung Adenocarcinoma.
High lymphocyte population-related predictive factors for a long-term response in non-small cell lung cancer patients treated with pemetrexed: a retrospective observational study.
Pre-Existing Diabetes Limits Survival Rate After Immune Checkpoint Inhibitor Treatment for Advanced Lung Cancer: A Retrospective Study in Japan.

Acta Pharmacol Sin. 2021 Mar 03.

Cystine supplementation rebalances the redox homeostasis of microenvironment in non-small cell lung cancer cells and reverses their resistance to docetaxel.

Si-Jia Li, Bei Cao, Zhen-Yao Lu, Run-Bin Sun, Su-Han Guo, Yuan Xie, Ji-Ye Aa, Guang-Ji Wang.

  Continuous docetaxel (DTX) treatment of non-small cell lung cancer induces development of drug resistance, but the mechanism is poorly understood. In this study we performed metabolomics analysis to characterize the metabolic patterns of sensitive and resistant A549 non-small cell lung cancer cells (A549/DTX cells). We showed that the sensitive and resistant A549 cells exhibited distinct metabolic phenotypes: the resistant cells were characterized by an altered microenvironment of redox homeostasis with reduced glutathione and elevated reactive oxygen species (ROS). DTX induction reprogrammed the metabolic phenotype of the sensitive cells, which acquired a phenotype similar to that of the resistant cells: it reduced cystine influx, inhibited glutathione biosynthesis, increased ROS and decreased glutathione/glutathione disulfide (GSH/GSSG); the genes involved in glutathione biosynthesis were dramatically depressed. Addition of the ROS-inducing agent Rosup (25, 50 μg/mL) significantly increased P-glycoprotein expression and reduced intracellular DTX in the sensitive A549 cells, which ultimately acquired a phenotype similar to that of the resistant cells. Supplementation of cystine (1.0 mM) significantly increased GSH synthesis, rebalanced the redox homeostasis of A549/DTX cells, and reversed DTX-induced upregulation of P-glycoprotein, and it markedly improved the effects of DTX and inhibited the growth of A549/DTX in vitro and in vivo. These results suggest that microenvironmental redox homeostasis plays a key role in the acquired resistance of A549 cancer cells to DTX. The enhancement of GSH synthesis by supplementary cystine is a promising strategy to reverse the resistance of tumor cells and has potential for translation in the clinic.

Keywords:  NAC; P-glycoprotein; Rosup; cystine; docetaxel; drug resistance; metabolomics; microenvironment; non-small cell lung cancer cells; redox homeostasis

DOI:  https://doi.org/10.1038/s41401-020-00610-3
Cancers (Basel). 2021 Feb 18. pii: 864. [Epub ahead of print]13(4):

p62-Induced Cancer-Associated Fibroblast Activation via the Nrf2-ATF6 Pathway Promotes Lung Tumorigenesis.

Ji In Kang, Dong Hyun Kim, Ki Woon Sung, Sang Mi Shim, Hyunjoo Cha-Molstad, Nak Kyun Soung, Kyung Ho Lee, Joonsung Hwang, Hee Gu Lee, Yong Tae Kwon, Bo Yeon Kim.

  Cancer-associated fibroblasts (CAFs) are important in tumor progression. The autophagy adaptor protein, p62/SQSTM1/Sequestosome-1, is up-regulated in tumors, but down-regulated in CAFs in the early stages of lung adenocarcinoma. We investigated whether p62-induced autophagy might control CAF activation. Under CAF-inducing conditions, like hypoxia or cancer cell co-cultures, p62 ablation or autophagy inhibition with hydroxychloroquine (HCQ) impaired CAF activation and reduced transforming growth factor beta (TGFβ) production, which impeded tumor growth. During CAF activation, p62-induced autophagy up-regulated the expression of the anti-oxidant signaling protein, nuclear factor erythroid 2-related factor 2 (Nrf2), and the ER-stress response regulator, activating transcription factor 6 (ATF6). Genetically or pharmacologically inhibiting the Nrf2-ATF6 pathway totally blocked CAF activation and tumor progression. These results demonstrate that p62 is a key modulator of primary lung adenocarcinoma progression. Thus, targeting the p62-Nrf2 autophagy signaling pathway might be a novel, stroma-focused, cancer prevention and/or treatment strategy.

Keywords:  activating transcription factor 6; cancer-associated fibroblast; lung adenocarcinoma; nuclear factor erythroid 2-related factor 2; p62/SQSTM1/Sequestosome-1; selective autophagy; tumor microenvironment

DOI:  https://doi.org/10.3390/cancers13040864
Oncol Rep. 2021 Mar;45(3): 1226-1234

ESM1/HIF‑1α pathway modulates chronic intermittent hypoxia‑induced non‑small‑cell lung cancer proliferation, stemness and epithelial‑mesenchymal transition.

Xin Gu, Jie Zhang, Yuheng Shi, Haiji Shen, Yao Li, Yanyan Chen, Li Liang.

Obstructive sleep apnea (OSA) is a sleep‑related disorder characterized by chronic intermittent hypoxia (CIH). Previous studies have found that intermittent hypoxia promotes drug resistance, cell proliferation, migration and invasion in non‑small cell lung cancer (NSCLC). Endothelial cell‑specific molecule‑1 (ESM1) is a molecule shown to be overexpressed in several types of tumors. The purpose of this study was to investigate the correlation between CIH and ESM1 and their potential roles in the progression of NSCLC. Tumorspheres, cell viability and colony formation assays were used to evaluate cell proliferation. The expression levels of cancer stem cell (CSC) markers CD44, CD133, OCT4 and SOX2 were measured with western blotting and/or RT‑qPCR. Transwell assays were applied to assess cell migration and invasion. Changes in the expression levels of epithelial‑mesenchymal transition (EMT)‑associated proteins were also detected by western blotting. The results indicated that CIH enhanced lung cancer stem cell (LCSC) NSCLC progression by promoting stemness, drug resistance, cell proliferation, migration and invasion via the ESM1/HIF‑1α pathway. Unexpectedly, inhibition of ESM1 reversed the CIH‑involved negative effects on LCSCs and in a mouse model. ESM1 therefore appears to be crucial mediator of CIH‑mediated lung cancer progression.

DOI: https://doi.org/10.3892/or.2020.7913
Cancers (Basel). 2021 Feb 24. pii: 941. [Epub ahead of print]13(5):

Blocking Aerobic Glycolysis by Targeting Pyruvate Dehydrogenase Kinase in Combination with EGFR TKI and Ionizing Radiation Increases Therapeutic Effect in Non-Small Cell Lung Cancer Cells.

Sissel E Dyrstad, Maria L Lotsberg, Tuan Zea Tan, Ina K N Pettersen, Silje Hjellbrekke, Deusdedit Tusubira, Agnete S T Engelsen, Thomas Daubon, Arnaud Mourier, Jean Paul Thiery, Olav Dahl, James B Lorens, Karl Johan Tronstad, Gro V Røsland.

  Increased glycolytic activity is a hallmark of cancer initiation and progression and is often observed in non-small cell lung cancer (NSCLC). Pyruvate dehydrogenase (PDH) complex acts as a gatekeeper between glycolysis and oxidative phosphorylation, and activation of PDH is known to inhibit glycolytic activity. As part of a standard therapeutic regimen, patients with NSCLC harboring oncogenic mutations in the epidermal growth factor receptor (EGFR) are treated with EGFR tyrosine kinase inhibitors (EGFR TKIs). Independent of good initial response, development of resistance to this therapy is inevitable. In the presented work, we propose that inhibition of glycolysis will add to the therapeutic effects and possibly prevent development of resistance against both EGFR TKIs and ionizing radiation in NSCLC. Analysis of transcriptome data from two independent NSCLC patient cohorts identified increased expression of pyruvate dehydrogenase kinase 1 (PDHK1) as well as upregulated expression of genes involved in glucose metabolism in tumors compared to normal tissue. We established in vitro models of development of resistance to EGFR TKIs to study metabolism and determine if targeting PDHK would prevent development of resistance to EGFR TKIs in NSCLC cells. The PDHK1 inhibitor dichloroacetate (DCA) in combination with EGFR TKIs and/or ionizing radiation was shown to increase the therapeutic effect in our NSCLC cell models. This mechanism was associated with redirected metabolism towards pyruvate oxidation and reduced lactate production, both in EGFR TKI sensitive and resistant NSCLC cells. Using DCA, the intracellular pool of pyruvate available for lactic fermentation becomes limited. Consequently, pyruvate is redirected to the mitochondria, and reinforces mitochondrial activity. Addition of DCA to cell culture deacidifies the extracellular microenvironment as less lactate is produced and excreted. In our study, we find that this redirection of metabolism adds to the therapeutic effect of EGFR TKI and ionizing radiation in NSCLC.

Keywords:  DCA; EGFR TKI; NSCLC; PDH; PDHK; Warburg effect; glycolysis; ionizing radiation; mitochondria

DOI:  https://doi.org/10.3390/cancers13050941
Eur J Cardiothorac Surg. 2021 Feb 28. pii: ezab046. [Epub ahead of print]

Preoperative prognostic nutritional index level is associated with tumour-infiltrating lymphocyte status in patients with surgically resected lung squamous cell carcinoma.

Hirokazu Kitahara, Fumihiro Shoji, Takaki Akamine, Fumihiko Kinoshita, Naoki Haratake, Tomoyoshi Takenaka, Tetsuzo Tagawa, Takashi Sonoda, Mototsugu Shimokawa, Yoshihiko Maehara, Masaki Mori.

   OBJECTIVES: The prognostic nutritional index (PNI) is an indicator of systemic immune-nutritional condition and is a well-known prognostic biomarker in lung cancer patients. Tumour-infiltrating lymphocytes (TILs) is a specific histological feature of cancers, influencing an individual's immunological tumour responses. However, whether PNI can reflect lung cancer patients' prognosis through local immunity such as TIL is unclear.
METHODS: We selected 64 lung squamous cell carcinoma patients who underwent curative operations. We investigated the significance of preoperative PNI level and evaluated the relationship between PNI and immune cells surrounding the lung cancer tissue using immunohistochemical analysis of a cluster of differentiation (CD)3, CD4, CD8 and CD68.
RESULTS: A low-PNI level was significantly associated with a worse postoperative prognosis (P = 0.042). The PNI (hazard ratio 2.768, 95% confidence interval 1.320-5.957; P = 0.007) was an independent prognostic factor. The low-PNI group had a significantly shorter recurrence-free survival and overall survival (P = 0.013 and P = 0.002, log-rank test) compared with the high-PNI group. A significant positive correlation between PNI components including preoperative peripheral blood lymphocyte count and serum albumin concentration, and TILs, was observed. Absolute numbers of TILs in the preoperative high-PNI group were significantly increased compared with those in the preoperative low-PNI group (CD3+ cells; P = 0.002, CD4+ cells; P = 0.049 and CD8+ cells; P = 0.024).
CONCLUSIONS: The preoperative PNI level was strongly associated with the postoperative outcome in lung cancer patients. Considering the positive relationship between preoperative PNI level and TIL status, preoperative immune-nutritional condition may influence lung cancer patients' postoperative prognosis through local immunity as well as systemic immune response.

Keywords:  Lung squamous cell carcinoma; Preoperative prognostic nutritional index; Prognostic factor; Tumour-infiltrating lymphocytes

DOI:  https://doi.org/10.1093/ejcts/ezab046
Cancer Immunol Immunother. 2021 Mar 03.

Identified lung adenocarcinoma metabolic phenotypes and their association with tumor immune microenvironment.

Xian-Ning Wu, Dan Su, Yi-De Mei, Mei-Qing Xu, Hao Zhang, Ze-Yu Wang, Li-Ling Li, Li Peng, Jun-Yi Jiang, Jia-Yi Yang, Dong-Jie Li, Hui Cao, Zhi-Wei Xia, Wen-Jing Zeng, Quan Cheng, Nan Zhang.

   BACKGROUND: Lung adenocarcinoma (LUAD), a subtype of non-small cell lung cancer (NSCLC), causes high mortality around the world. Previous studies have suggested that the metabolic pattern of tumor is associated with tumor response to immunotherapy and patient's survival outcome. Yet, this relationship in LUAD is still unknown.
METHODS: Therefore, in this study, we identified the immune landscape in different tumor subtypes classified by metabolism-related genes expression with a large-scale dataset (tumor samples, n = 2181; normal samples, n = 419). We comprehensively correlated metabolism-related phenotypes with diverse clinicopathologic characteristics, genomic features, and immunotherapeutic efficacy in LUAD patients.
RESULTS: And we confirmed tumors with activated lipid metabolism tend to have higher immunocytes infiltration and better response to checkpoint immunotherapy. This work highlights the connection between the metabolic pattern of tumor and tumor immune infiltration in LUAD. A scoring system based on metabolism-related gene expression is not only able to predict prognosis of patient with LUAD but also applied to pan-cancer. LUAD response to checkpoint immunotherapy can also be predicted by this scoring system.
CONCLUSIONS: This work revealed the significant connection between metabolic pattern of tumor and tumor immune infiltration, regulating LUAD patients' response to immunotherapy.

Keywords:  Immune infiltration; Immunotherapy; Lung adenocarcinoma; Metabolism; PD-1

DOI:  https://doi.org/10.1007/s00262-021-02896-6
J Environ Pathol Toxicol Oncol. 2021 ;40(1): 65-74

Hypoxia Induces Overexpression of CCL28 to Recruit Treg Cells to Enhance Angiogenesis in Lung Adenocarcinoma.

Bingchun Liu, Chunyan Wei.

Lung cancer is the world-leading causative factor of disease-related death. CD4+CD25+ regulatory T cells (CD4+CD25+ Treg), which are involved in immune escape of tumor cells, are highly related to tumor development and metastasis. Hypoxia induces the overexpression of chemokine (C-C motif) ligand 28 (CCL28), thus enhancing the angiogenesis and metastasis of lung adenocarcinoma. Our study revealed that most clinical lung adenocarcinoma samples showed positive expressions of HIF-lα, VEGF, FoxP3, and CCL28. More CD4+CD25+ Treg cells were detected in the cancerous samples. In addition, hypoxia increased the expression of HIF-1α and upregulated CCL28 to recruit CD4+CD25+ Treg cells; knockdown of HIF-1α could reverse this process. Treg cells also promoted invasion, migration, and angiogenesis in two human lung adenocarcinoma cell lines A549 and H1975. Our study suggested a novel potential molecular mechanism involved in the progression of lung adenocarcinoma could be a potential therapeutic target for the treatment of lung cancer.

DOI: https://doi.org/10.1615/JEnvironPatholToxicolOncol.2020035859
J Transl Med. 2021 Feb 28. 19(1): 92

High lymphocyte population-related predictive factors for a long-term response in non-small cell lung cancer patients treated with pemetrexed: a retrospective observational study.

Issei Sumiyoshi, Takahiro Okabe, Shinsaku Togo, Haruhi Takagi, Hiroaki Motomura, Yusuke Ochi, Naoko Shimada, Mizuki Haraguchi, Rina Shibayama, Yuichi Fujimoto, Junko Watanabe, Moe Iwai, Kotaro Kadoya, Shin-Ichiro Iwakami, Kazuhisa Takahashi.

   BACKGROUND: Regimens combining pemetrexed (PEM) and immune checkpoint inhibitors (ICIs) targeting programmed cell death-1 (PD-1) or programmed death-ligand 1 (PD-L1) are widely used for the treatment of advanced non-squamous non-small-cell lung cancer (NSq-NSCLC). Recently, PEM was shown to induce immunogenic cell death (ICD) and to enhance immune-regulatory genes. Some patients demonstrate an extremely long-term response to PEM. It is possible that the continued response in these patients is dependent on not only the pharmacological induction of cytotoxic cell death but also antitumor immunity. However, factors that can predict outcomes associated with long-term PEM administration using blood test results have not yet been elucidated. We investigated the clinical characteristics and predictive factors in patients with advanced NSq-NSCLC who underwent long-term PEM maintenance therapy.
METHODS: In total, 504 patients with advanced NSq-NSCLC who received PEM combination therapy/monotherapy (n = 414) or paclitaxel (PTX) combination therapy (n = 90) between January 2010 and November 2019 were recruited; 381 patients were retained for the final analysis. Patients treated with PEM (n = 301) were divided into subgroups according to the total cycles of PEM (≥ 17 [n = 25] for the long-term administration group and ≤ 16 [n = 276] for the intermediate/short-term group) and compared with another population (n = 80) treated with PTX combination regimen. We investigated clinical features and predictive biomarkers, focusing on immune-regulatory factors, absolute lymphocyte count (ALC), neutrophil-to-lymphocyte ratio (NLR), and PD-1 and PD-L1 expression, to predict long-term response to PEM.
RESULTS: The long-term PEM administration group exhibited a higher ALC and a lower NLR than the shorter-term group did. Both these markers displayed greater association with progression-free survival and overall survival in the PEM combination therapy group than in the PTX combination therapy group. Increased PD-1 lymphocytes were associated with the long-term PEM response group, as PD-L1 expression in tumors was associated with a high incidence of immune-related adverse effects following ICI administration.
CONCLUSIONS: ALC, NLR, and PD-1 expression are PEM-mediated predictive biomarkers that are indirectly related to tumor immunity and can provide useful predictive information on the long-term response to PEM in patients with NSq-NSCLC.

Keywords:  Absolute lymphocyte count; Immunogenic cell death; Neutrophil-to-lymphocyte ratio; Non-small-cell lung cancer; Pemetrexed; Programmed cell death-1; Programmed death-ligand 1

DOI:  https://doi.org/10.1186/s12967-021-02761-1
Diabetes Metab Syndr Obes. 2021 ;14 773-781

Pre-Existing Diabetes Limits Survival Rate After Immune Checkpoint Inhibitor Treatment for Advanced Lung Cancer: A Retrospective Study in Japan.

Kaori Hisanaga, Hiroshi Uchino, Naoko Kakisu, Masahiko Miyagi, Fukumi Yoshikawa, Genki Sato, Kazutoshi Isobe, Kazuma Kishi, Sakae Homma, Takahisa Hirose.

   Background: Although immune checkpoint inhibitors (ICIs) are promising in the treatment of advanced cancer, their use is associated with immune-related adverse events (irAEs) that affect endocrine organ systems. Although development of irAEs was associated with improved cancer-specific survival, the risk of irAEs is unclear. We investigated the association of pre-ICI comorbidities-including diabetes-with irAEs, overall survival (OS), and progression-free survival (PFS) in advanced lung cancer.
Methods: Patients with lung cancer who were treated with ICIs during the period from September 1, 2015 through July 31, 2018 were retrospectively enrolled. All data were collected from the NEPTUNE database of university patients. Hazard ratios were estimated by using Cox regression weighted for propensity scores. Odds ratios were calculated by logistic regression and adjusted for unbalanced variables. The Kaplan-Meier method was used to compare OS, and the generalized Wilcoxon test was used to compare median survival.
Results: Among the 88 patients identified, 22 (25.0%) had diabetes (DM) before ICI treatment and 57 (75.0%) did not (non-DM); irAEs developed in 12.2% of patients with DM and in 9.1% of patients in non-DM (p=0.87). Diabetes status was not associated with irAE risk in relation to baseline characteristics (age, sex, TNM staging, thyroid and renal function) or in propensity score-matched analysis (age, TNM staging). During a mean follow-up of 30 months, OS and cancer-specific PFS were significantly higher in patients who developed irAEs (Kaplan-Meier estimates, p=0·04 and 0·03, respectively). In propensity score-matched analysis, diabetes was significantly associated with lower OS (multivariate hazard ratio, 0·36; 95% CI, 0·13-0·98) unrelated to irAEs. Irrespective of irAEs, PFS was also lower among patients with DM than among non-DM patients (Kaplan-Meier estimate, p=0·04).
Conclusion: Pre-existing diabetes was associated with higher mortality in advanced lung cancer, regardless of irAE development during treatment with ICI.

Keywords:  diabetes; immune checkpoint inhibitor; overall survival; progression-free survival

DOI:  https://doi.org/10.2147/DMSO.S289446