bims-meluca Biomed News
on Metabolism of non-small cell lung carcinoma
Issue of 2022‒06‒26
nine papers selected by
Cristina Muñoz Pinedo
L’Institut d’Investigació Biomèdica de Bellvitge
  1. Changes in Metabolism as a Diagnostic Tool for Lung Cancer: Systematic Review.
  2. Longitudinal plasma proteomic profiling of patients with non-small cell lung cancer undergoing immune checkpoint blockade.
  3. Systemic Ketone Replacement Does Not Improve Survival or Cancer Cachexia in Mice With Lung Cancer.
  4. Vascular endothelial growth factor receptor 2 expression and immunotherapy efficacy in non-small cell lung cancer.
  5. Glucose restriction induces ROS-AMPK-mediated CTR1 expression and increases cisplatin efficiency in NSCLC.
  6. Peripheral Blood Mononuclear Cells Predict Therapeutic Efficacy of Immunotherapy in NSCLC.
  7. The Molecular Role of IL-35 in Non-Small Cell Lung Cancer.
  8. The Molecular Basis and Therapeutic Potential of Leukemia Inhibitory Factor in Cancer Cachexia.
  9. Clinical Impact of Sarcopenia 1 Year After Surgery for Patients with Early-Stage Non-small Cell Lung Cancer.
  1. Metabolites. 2022 Jun 14. pii: 545. [Epub ahead of print]12(6):
    Changes in Metabolism as a Diagnostic Tool for Lung Cancer: Systematic Review.
    Hanne Mariën, Elien Derveaux, Karolien Vanhove, Peter Adriaensens, Michiel Thomeer, Liesbet Mesotten.
      Lung cancer is the leading cause of cancer-related mortality worldwide, with five-year survival rates varying from 3-62%. Screening aims at early detection, but half of the patients are diagnosed in advanced stages, limiting therapeutic possibilities. Positron emission tomography-computed tomography (PET-CT) is an essential technique in lung cancer detection and staging, with a sensitivity reaching 96%. However, since elevated 18F-fluorodeoxyglucose (18F-FDG) uptake is not cancer-specific, PET-CT often fails to discriminate between malignant and non-malignant PET-positive hypermetabolic lesions, with a specificity of only 23%. Furthermore, discrimination between lung cancer types is still impossible without invasive procedures. High mortality and morbidity, low survival rates, and difficulties in early detection, staging, and typing of lung cancer motivate the search for biomarkers to improve the diagnostic process and life expectancy. Metabolomics has emerged as a valuable technique for these pitfalls. Over 150 metabolites have been associated with lung cancer, and several are consistent in their findings of alterations in specific metabolite concentrations. However, there is still more variability than consistency due to the lack of standardized patient cohorts and measurement protocols. This review summarizes the identified metabolic biomarkers for early diagnosis, staging, and typing and reinforces the need for biomarkers to predict disease progression and survival and to support treatment follow-up.
    Keywords:  lung cancer; metabolite profile; metabolomics
    DOI:  https://doi.org/10.3390/metabo12060545
  2. J Immunother Cancer. 2022 Jun;pii: e004582. [Epub ahead of print]10(6):
    Longitudinal plasma proteomic profiling of patients with non-small cell lung cancer undergoing immune checkpoint blockade.
    Michal Harel, Coren Lahav, Eyal Jacob, Nili Dahan, Itamar Sela, Yehonatan Elon, Shani Raveh Shoval, Galit Yahalom, Iris Kamer, Alona Zer, Ofer Sharon, David P Carbone, Adam P Dicker, Jair Bar, Yuval Shaked.
      BACKGROUND: Immune checkpoint inhibitors (ICIs) have revolutionized the cancer therapy landscape due to long-term benefits in patients with advanced metastatic disease. However, robust predictive biomarkers for response are still lacking and treatment resistance is not fully understood.METHODS: We profiled approximately 800 pre-treatment and on-treatment plasma proteins from 143 ICI-treated patients with non-small cell lung cancer (NSCLC) using ELISA-based arrays. Different clinical parameters were collected from the patients including specific mutations, smoking habits, and body mass index, among others. Machine learning algorithms were used to identify a predictive signature for response. Bioinformatics tools were used for the identification of patient subtypes and analysis of differentially expressed proteins and pathways in each response group.
    RESULTS: We identified a predictive signature for response to treatment comprizing two proteins (CXCL8 and CXCL10) and two clinical parameters (age and sex). Bioinformatic analysis of the proteomic profiles identified three distinct patient clusters that correlated with multiple parameters such as response, sex and TNM (tumors, nodes, and metastasis) staging. Patients who did not benefit from ICI therapy exhibited significantly higher plasma levels of several proteins on-treatment, and enrichment in neutrophil-related proteins.
    CONCLUSIONS: Our study reveals potential biomarkers in blood plasma for predicting response to ICI therapy in patients with NSCLC and sheds light on mechanisms underlying therapy resistance.
    Keywords:  lung neoplasms; translational medical research; tumor biomarkers
    DOI:  https://doi.org/10.1136/jitc-2022-004582
  3. Front Oncol. 2022 ;12 903157
    Systemic Ketone Replacement Does Not Improve Survival or Cancer Cachexia in Mice With Lung Cancer.
    Henning Tim Langer, Shakti Ramsamooj, Roger J Liang, Rahul Grover, Seo-Kyoung Hwang, Marcus DaSilva Goncalves.
      Cachexia is a debilitating comorbidity affecting many lung cancer patients. We have previously found that cachectic mice with lung cancer have reduced serum ketone body levels due to low PPARα activity in the liver. Restoring hepatic PPARα activity with fenofibrate increased circulating ketones and delayed muscle and white adipose tissue wasting. We hypothesized that the loss of circulating ketones plays a pathophysiologic role in cachexia and performed two dietary intervention studies to test this hypothesis. In the first study, male and female mice were randomized to consume either a very low carbohydrate, ketogenic diet (KD) or normal chow (NC) after undergoing tumor induction. The KD successfully restored serum ketone levels and decreased blood glucose in cachectic mice but did not improve body weight maintenance or survival. In fact, there was a trend for the KD to worsen survival in male but not in female mice. In the second study, we compounded a ketone ester supplement into the NC diet (KE) and randomized tumor-bearing mice to KE or NC after tumor induction. We confirmed that KE was able to acutely and chronically increase ketone body abundance in the serum compared to NC. However, the restoration of ketones in the circulation was not able to improve body weight maintenance or survival in male or female mice with lung cancer. Finally, we investigated PPARα activity in the liver of mice fed KE and NC and found that animals fed a ketone ester supplement showed a significant increase in mRNA expression of several PPARα targets. These data negate our initial hypothesis and suggest that restoring ketone body availability in the circulation of mice with lung cancer does not alter cachexia development or improve survival, despite increasing hepatic PPARα activity.
    Keywords:  PPAR alpha; beta hydroxybutyrate; cachexia; ketogenic diet (KD); ketone ester supplementation; lung cancer
    DOI:  https://doi.org/10.3389/fonc.2022.903157
  4. Cancer Sci. 2022 Jun 20.
    Vascular endothelial growth factor receptor 2 expression and immunotherapy efficacy in non-small cell lung cancer.
    Kenji Nakahama, Hiroyasu Kaneda, Masahiko Osawa, Mitsuru Fukui, Motohiro Izumi, Naoki Yoshimoto, Akira Sugimoto, Hiroaki Nagamine, Koichi Ogawa, Yoshiya Matsumoto, Kenji Sawa, Yoko Tani, Shigeki Mitsuoka, Tetsuya Watanabe, Kazuhisa Asai, Tomoya Kawaguchi.
      It is unclear whether tumor vascular endothelial growth factor receptor 2 expression affects the therapeutic efficacy of immune-checkpoint inhibitors and anti-angiogenic agents. This retrospective, multi-center study included patients with advanced non-small cell lung cancer who were treated with immune-checkpoint inhibitors. We constructed tissue microarrays and performed immunohistochemistry with an anti-vascular endothelial growth factor receptor 2 antibody. We analyzed immune and tumor cell staining separately in order to determine their correlation with the objective response rate, progression-free survival and overall survival in patients receiving immune-checkpoint inhibitors. Of 364 patients, 37 (10%) expressed vascular endothelial growth factor receptor 2 in immune cells and 165 (45%) in tumor cells. The objective response rate, progression-free survival and overall survival were significantly worse in patients treated with immune-checkpoint inhibitor monotherapy who expressed vascular endothelial growth factor receptor 2 in immune cells than those who did not (10% vs. 30%, p = 0.028; median = 2.2 vs. 3.6 months, p = 0.012; median = 7.9 vs. 17.0 months, p = 0.049, respectively), while there was no significant difference based on tumor cell expression (24% vs. 30%, p = 0.33; median = 3.1 vs 3.5 months, p = 0.55; median = 13.6 vs. 16.8 months, p = 0.31). There was no significant difference in overall survival between patients treated with and without anti-angiogenic agents in any treatment period based on vascular endothelial growth factor receptor 2 expression. Immune-checkpoint inhibitor efficacy was limited in patients expressing vascular endothelial growth factor receptor 2 in immune cells.
    Keywords:  immune checkpoint inhibitor; lung cancer; programmed death-ligand 1; tissue microarray; vascular endothelial growth factor receptor
    DOI:  https://doi.org/10.1111/cas.15464
  5. Cancer Lett. 2022 Jun 15. pii: S0304-3835(22)00277-4. [Epub ahead of print]543 215793
    Glucose restriction induces ROS-AMPK-mediated CTR1 expression and increases cisplatin efficiency in NSCLC.
    Pengpeng Zhang, Bohan Li, Qianfeng Chen, Hui Wang, Qing Feng.
      Cisplatin is one of the principal platinum-based chemotherapeutic agents for many types of cancer, including non-small-cell lung cancer (NSCLC). Copper transporter 1 (CTR1) plays a significant role in increasing cellular cisplatin uptake and sensitivity. The current study found that glucose restriction upregulated AMPK (AMP-activated protein kinase) through reactive oxygen species (ROS) to induce CTR1 expression in NSCLC cells. Direct upregulation of ROS levels also activated AMPK expression. The changes in CTR1 expression were consistent with glucose concentrations and AMPK expression. Feeding a low-carbohydrate ketogenic diet (a glucose restriction diet) to a severe combined immune deficiency (SCID) mouse xenograft model significantly enhanced the efficacy of cisplatin. The tumor size was significantly smaller in the group treated with cisplatin plus the low-carbohydrate ketogenic diet than in the group treated with cisplatin alone. Survival was longer in mice treated with the low-carbohydrate ketogenic diet than in the controls. Mice fed the low-carbohydrate ketogenic diet showed increased expression of CTR1 and AMPK in tumor tissues. These results suggest a novel mechanism whereby glucose restriction induces ROS-AMPK-mediated CTR1 expression in NSCLC, indicating glucose restriction as an effective adjuvant NSCLC therapy.
    Keywords:  AMPK; CTR1; Glucose restriction; NSCLC; ROS
    DOI:  https://doi.org/10.1016/j.canlet.2022.215793
  6. Cancers (Basel). 2022 Jun 12. pii: 2898. [Epub ahead of print]14(12):
    Peripheral Blood Mononuclear Cells Predict Therapeutic Efficacy of Immunotherapy in NSCLC.
    Jacobo Rogado, Fernando Pozo, Kevin Troule, José Miguel Sánchez-Torres, Nuria Romero-Laorden, Rebeca Mondejar, Olga Donnay, Anabel Ballesteros, Vilma Pacheco-Barcia, Javier Aspa, Fátima Al-Shahrour, Arantzazu Alfranca, Ramon Colomer.
      In lung cancer immunotherapy, biomarkers to guide clinical decisions are limited. We now explore whether the detailed immunophenotyping of circulating peripheral blood mononuclear cells (PBMCs) can predict the efficacy of anti-PD-1 immunotherapy in patients with advanced non-small-cell lung cancer (NSCLC). We determined 107 PBMCs subpopulations in a prospective cohort of NSCLC patients before starting single-agent anti-PD-1 immunotherapy (study group), analyzed by flow cytometry. As a control group, we studied patients with advanced malignancies before initiating non-immunotherapy treatment. The frequency of PBMCs was correlated with treatment outcome. Patients were categorized as having either high or low expression for each biomarker, defined as those above the 55th or below the 45th percentile of the overall marker expression within the cohort. In the study group, three subpopulations were associated with significant differences in outcome: high pretreatment levels of circulating CD4+CCR9+, CD4+CCR10+, or CD8+CXCR4+ T cells correlated with poorer overall survival (15.7 vs. 35.9 months, HR 0.16, p = 0.003; 22.0 vs. NR months, HR 0.10, p = 0.003, and 22.0 vs. NR months, HR 0.29, p = 0.02). These differences were specific to immunotherapy-treated patients. High baseline levels of circulating T cell subpopulations related to tissue lymphocyte recruitment are associated with poorer outcomes of immunotherapy-treated advanced NSCLC patients.
    Keywords:  anti-PD-1 antibodies; biomarkers; immunotherapy; non-small cell lung cancer; peripheral blood mononuclear cells
    DOI:  https://doi.org/10.3390/cancers14122898
  7. Front Oncol. 2022 ;12 874823
    The Molecular Role of IL-35 in Non-Small Cell Lung Cancer.
    Yuqiu Hao, Hongna Dong, Wei Li, Xuejiao Lv, Bingqing Shi, Peng Gao.
      Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and a common cause of cancer-related death. Better understanding of the molecular mechanisms, pathogenesis, and treatment of NSCLC can help improve patient outcomes. Significant progress has been made in the treatment of NSCLC, and immunotherapy can prolong patient survival. However, the overall cure and survival rates are low, especially in patients with advanced metastases. Interleukin-35 (IL-35), an immunosuppressive factor, is associated with the onset and prognosis of various cancers. Studies have shown that IL-35 expression is elevated in NSCLC, and it is closely related to the progression and prognosis of NSCLC. However, there are few studies on the mechanism of IL-35 in NSCLC. This study discusses the role of IL-35 and its downstream signaling pathways in the pathogenesis of NSCLC and provides new insights into its therapeutic potential.
    Keywords:  IL-35; NSCLC; PD-1/PD-L1; Th17; Treg
    DOI:  https://doi.org/10.3389/fonc.2022.874823
  8. Cancers (Basel). 2022 Jun 15. pii: 2955. [Epub ahead of print]14(12):
    The Molecular Basis and Therapeutic Potential of Leukemia Inhibitory Factor in Cancer Cachexia.
    Ruijiang Zeng, Chang Tong, Xiangyang Xiong.
      Cachexia is a chronic metabolic syndrome that is characterized by sustained weight and muscle mass loss and anorexia. Cachexia can be secondary to a variety of diseases and affects the prognosis of patients significantly. The increase in inflammatory cytokines in plasma is deeply related to the occurrence of cachexia. As a member of the IL-6 cytokine family, leukemia inhibitory factor (LIF) exerts multiple biological functions. LIF is over-expressed in the cancer cells and stromal cells of various tumors, promoting the malignant development of tumors via the autocrine and paracrine systems. Intriguingly, increasing studies have confirmed that LIF contributes to the progression of cachexia, especially in patients with metastatic tumors. This review combines all of the evidence to summarize the mechanism of LIF-induced cachexia from the following four aspects: (i) LIF and cancer-associated cachexia, (ii) LIF and alterations of adipose tissue in cachexia, (iii) LIF and anorexia nervosa in cachexia, and (iv) LIF and muscle atrophy in cachexia. Considering the complex mechanisms in cachexia, we also focus on the interactions between LIF and other key cytokines in cachexia and existing therapeutics targeting LIF.
    Keywords:  anorexia nervosa; cachexia; cancer; fat loss; leukemia inhibitory factor (LIF); muscle atrophy
    DOI:  https://doi.org/10.3390/cancers14122955
  9. Ann Surg Oncol. 2022 Jun 21.
    Clinical Impact of Sarcopenia 1 Year After Surgery for Patients with Early-Stage Non-small Cell Lung Cancer.
    Yuria Ushitani, Yoshihisa Shimada, Yuki Yamada, Yujin Kudo, Takafumi Yamada, Taro Tanaka, Tatsuo Ohira, Norihiko Ikeda.
      BACKGROUND: Sarcopenia is associated with prognostic outcomes for patients with various solid tumors, whereas the clinical significance of sarcopenia 1 year after surgery (post-sarcopenia) for non-small cell lung cancer (NSCLC) has not been investigated. This study aimed to clarify the clinical impact of post-sarcopenia and factors associated with post-sarcopenia in NSCLC patients without preoperative sarcopenia.METHODS: This study enrolled 443 patients with clinical stage 1 or 2 NSCLC (234 patients without preoperative sarcopenia [NS group] and 209 patients with preoperative sarcopenia [S group]) who underwent computed tomography (CT) at two time points (before surgery and a year afterward) or more. The study assessed CT images at the L3 level to calculate the psoas muscle area index (PAI). The PAI cutoff value for sarcopenia was defined as 6.36 cm2/m2 for the men and 3.92 cm2/m2 for the women.
    RESULTS: In the NS group, the diagnosis for 40.1% of the women and 52.6% of the men was post-sarcopenia (NS-S group). The overall survival (OS) for the S and NS-S cohorts was worse than for the non-sarcopenic patients before and after surgery (p < 0.001 and p = 0.017, respectively). In the multivariable analysis, sarcopenia, either before or after surgery (hazard ratio, 3.272; p = 0.002), in the NS group was independently associated with OS, whereas the factors associated with post-sarcopenia were male sex (p = 0.002), aging (p < 0.001), and low body mass index (p < 0.001).
    CONCLUSIONS: Sarcopenia, either before or after surgery, is prognostic in early-stage NSCLC. Male sex, aging, and low body mass index (BMI) are associated with post-sarcopenia.
    DOI:  https://doi.org/10.1245/s10434-022-11999-y
This page is being maintained by Thomas Krichel. It was last updated on 2022‒06‒29 at 10:47:27.