bims-medica Biomed News
on Metabolism and diet in cancer
Issue of 2023–09–17
eleven papers selected by
Brett Chrest, East Carolina University
  1. Irreversible electroporation combined with chemotherapy and PD-1/PD-L1 blockade enhanced antitumor immunity for locally advanced pancreatic cancer.
  2. The Role of Stroma in Cancer Metabolism.
  3. Effects of Ketogenic Diet on Reproductive Hormones in Women With Polycystic Ovary Syndrome.
  4. Multimodal Imaging of Pancreatic Cancer Microenvironment in Response to an Antiglycolytic Drug.
  5. Metabolomic and Lipidomic Characterization of Meningioma Grades Using LC-HRMS and Machine Learning.
  6. Homogeneous luminescent quantitation of cellular guanosine and adenosine triphosphates (GTP and ATP) using QT-LucGTP&ATP assay.
  7. Exploring the impact of ketogenic diet on multiple sclerosis: obesity, anxiety, depression, and the glutamate system.
  8. Oncogenic KRASG12D reprograms lipid metabolism by upregulating SLC25A1 to drive pancreatic tumorigenesis.
  9. Oxyhaemoglobin saturation NIR-IIb imaging for assessing cancer metabolism and predicting the response to immunotherapy.
  10. Effect of Moxibustion Combined With Cisplatin on Tumor Microenvironment Hypoxia and Vascular Normalization in Lewis Lung Cancer Mice.
  11. Total parenteral nutrition for patients with gastrointestinal cancers: a clinical practice review.
  1. Front Immunol. 2023 ;14 1193040
    Irreversible electroporation combined with chemotherapy and PD-1/PD-L1 blockade enhanced antitumor immunity for locally advanced pancreatic cancer.
    Yangyang Ma, Yanli Xing, Hongmei Li, Ting Yuan, Bing Liang, Rongrong Li, Jianyu Li, Zhonghai Li, Shuying Li, Lizhi Niu.
       Background: Irreversible electroporation (IRE) is a novel local tumor ablation approach with the potential to stimulate an antitumor immune response. However, it is not effective in preventing distant metastasis in isolation. This study aimed to compare the potential of augmenting the antitumor immune response in patients with locally advanced pancreatic cancer (LAPC) who underwent IRE combined with chemotherapy and PD-1/PD-L1 blockade with those who underwent IRE combined with chemotherapy.
    Methods: A retrospective review was conducted on LAPC patients treated either with IRE in combination with chemotherapy and PD-1/PD-L1 blockade (group A) or with IRE with chemotherapy alone (group B) from July 2015 to June 2021. The primary outcomes were overall survival (OS) and progression-free survival (PFS), with immune responses and adverse events serving as secondary endpoints. Risk factors for OS and PFS were identified using univariate and multivariate analyses.
    Results: A total of 103 patients were included in the final analysis, comprising 25 in group A and 78 in group B. The median duration of follow-up was 18.2 months (3.0-38.6 months). Group A patients demonstrated improved survival compared to group B (median OS: 23.6 vs. 19.4 months, p = 0.001; median PFS: 18.2 vs. 14.7 months, p = 0.022). The data suggest a robust immune response in group A, while adverse events related to the treatment were similar in both groups. The multivariate analysis identified the combination of IRE, chemotherapy, and PD-1/PD-L1 blockade as an independent prognostic factor for OS and PFS.
    Conclusion: The addition of PD-1/PD-L1 blockade to the regimen of IRE combined with chemotherapy enhanced antitumor immunity and extended survival in LAPC patients.
    Keywords:  PD-1/PD-L1 blockade; anticancer immunity; chemotherapy; irreversible electroporation; locally advanced pancreatic cancer
    DOI:  https://doi.org/10.3389/fimmu.2023.1193040
  2. Cold Spring Harb Perspect Med. 2023 Sep 11. pii: a041540. [Epub ahead of print]
    The Role of Stroma in Cancer Metabolism.
    Alec C Kimmelman, Mara H Sherman.
      The altered metabolism of tumor cells is a well-known hallmark of cancer and is driven by multiple factors such as mutations in oncogenes and tumor suppressor genes, the origin of the tissue where the tumor arises, and the microenvironment of the tumor. These metabolic changes support the growth of cancer cells by providing energy and the necessary building blocks to sustain proliferation. Targeting these metabolic alterations therapeutically is a potential strategy to treat cancer, but it is challenging due to the metabolic plasticity of tumors. Cancer cells have developed ways to scavenge nutrients through autophagy and macropinocytosis and can also form metabolic networks with stromal cells in the tumor microenvironment. Understanding the role of the tumor microenvironment in tumor metabolism is crucial for effective therapeutic targeting. This review will discuss tumor metabolism and the contribution of the stroma in supporting tumor growth through metabolic interactions.
    DOI:  https://doi.org/10.1101/cshperspect.a041540
  3. J Endocr Soc. 2023 Aug 28. 7(10): bvad112
    Effects of Ketogenic Diet on Reproductive Hormones in Women With Polycystic Ovary Syndrome.
    Karniza Khalid, Saraswathy Apparow, Irma Liyana Mushaddik, Amalina Anuar, Syed A A Rizvi, Anasufiza Habib.
       Context: Ketogenic diet has recently made a comeback as a part of lifestyle and dietary modifications in patients with polycystic ovary syndrome (PCOS). Despite studies suggesting its beneficial effects in reversing hormonal imbalance in women with PCOS, evidence has been patchy and derived from small populations under varying conditions.
    Objective: To pool evidence from clinical trials to study the effects of ketogenic diet on reproductive hormones (LH/FSH ratio, free testosterone, serum progesterone) and observe evidence of weight change.
    Methods: PubMed, ScienceDirect, Scopus, and Web of Science core collection were searched for clinical trials evaluating the effects of ketogenic diet in established PCOS women consistent with the Rotterdam classification. Single- or double-arm studies that included an outcome of interest were included. Two investigators worked independently to screen potential articles and a designated investigator extracted data on study characteristics and evaluated the outcomes. Data were pooled using a random-effects model. The quality of selected studies was assessed using the Cochrane Risk of Bias Tool.
    Results: Following ≥45 days of intervention with ketogenic diet among women with PCOS, significant improvement was observed in reproductive hormone levels, with reduced LH/FSH ratio (d -0.851; 95% CI -1.015, -0.686; P < .001), reduced serum free testosterone (d -0.223; 95% CI -0.328, -0.119; P  < .001), and an increased in serum sex hormone binding globulin (SHBG) (d 9.086; 95% CI 3.379, 14.792; P = .002). Significant weight loss was unanimously observed in all included studies (d -11.56; 95% CI -14.97, -8.15; P < .001).
    Conclusion: Short-term ketogenic diet potentially improved hormonal imbalances commonly associated with PCOS.
    Keywords:  clinical trial; ketogenic diet; lifestyle; meta-analysis; polycystic ovary syndrome
    DOI:  https://doi.org/10.1210/jendso/bvad112
  4. Adv Healthc Mater. 2023 Sep 14. e2301815
    Multimodal Imaging of Pancreatic Cancer Microenvironment in Response to an Antiglycolytic Drug.
    Elnaz Sheikh, Kirti Agrawal, Sanjit Roy, David Burk, Fabrizio Donnarumma, Young H Ko, Praveen Kumar Guttula, Nrusingh C Biswal, Hem D Shukla, Manas Ranjan Gartia.
      Lipid metabolism and glycolysis play crucial roles in the progression and metastasis of cancer, and the use of 3-bromopyruvate (3-BP) as an antiglycolytic agent has shown promise in killing pancreatic cancer cells. However, developing an effective strategy to avoid chemoresistance requires the ability to probe the interaction of cancer drugs with complex tumor-associated microenvironments (TAMs). Unfortunately, no robust and multiplexed molecular imaging technology is currently available to analyze TAMs. In this study, we demonstrate the simultaneous profiling of three protein biomarkers using SERS nanotags and antibody-functionalized nanoparticles in a syngeneic mouse model of pancreatic cancer. This allows for comprehensive information about biomarkers and TAM alterations before and after treatment. Our multimodal imaging techniques include surface-enhanced Raman spectroscopy (SERS), immunohistochemistry, polarized light microscopy, second harmonic generation (SHG) microscopy, fluorescence lifetime imaging microscopy (FLIM), and untargeted liquid chromatography and mass spectrometry (LC-MS) analysis. The study reveals the efficacy of 3-BP in treating pancreatic cancer and identifies drug treatment-induced lipid species remodeling and associated pathways through bioinformatics analysis. This article is protected by copyright. All rights reserved.
    Keywords:  3-bromopyruvate; Raman spectroscopy; Warburg effect; cancer microenvironment; glycolysis; lipid metabolism; pancreatic cancer
    DOI:  https://doi.org/10.1002/adhm.202301815
  5. J Am Soc Mass Spectrom. 2023 Sep 14.
    Metabolomic and Lipidomic Characterization of Meningioma Grades Using LC-HRMS and Machine Learning.
    Hoda Safari Yazd, Sina Feizbakhsh Bazargani, Garrett Fitzpatrick, Richard A Yost, Jesse Kresak, Timothy J Garrett.
      Meningiomas are among the most common brain tumors that arise from the leptomeningeal cover of the brain and spinal cord and account for around 37% of all central nervous system tumors. According to the World Health Organization, meningiomas are classified into three histological subtypes: benign, atypical, and anaplastic. Sometimes, meningiomas with a histological diagnosis of benign tumors show clinical characteristics and behavior of aggressive tumors. In this study, we examined the metabolomic and lipidomic profiles of meningioma tumors, focusing on comparing low-grade and high-grade tumors and identifying potential markers that can discriminate between benign and malignant tumors. High-resolution mass spectrometry coupled to liquid chromatography was used for untargeted metabolomics and lipidomics analyses of 85 tumor biopsy samples with different meningioma grades. We then applied feature selection and machine learning techniques to find the features with the highest information to aid in the diagnosis of meningioma grades. Three biomarkers were identified to differentiate low- and high-grade meningioma brain tumors. The use of mass-spectrometry-based metabolomics and lipidomics combined with machine learning analyses to prospect and characterize biomarkers associated with meningioma grades may pave the way for elucidating potential therapeutic and prognostic targets.
    Keywords:  Brain Tumor; Lipidomics; Machine Learning; Mass Spectrometry; Meningioma; Metabolomics
    DOI:  https://doi.org/10.1021/jasms.3c00158
  6. Anal Bioanal Chem. 2023 Sep 16.
    Homogeneous luminescent quantitation of cellular guanosine and adenosine triphosphates (GTP and ATP) using QT-LucGTP&ATP assay.
    Kari Kopra, Randa Mahran, Titta Yli-Hollo, Sho Tabata, Emmiliisa Vuorinen, Yuki Fujii, Iida Vuorinen, Aki Ogawa-Iio, Akiyoshi Hirayama, Tomoyoshi Soga, Atsuo T Sasaki, Harri Härmä.
      Guanosine triphosphate (GTP) and adenosine triphosphate (ATP) are essential nucleic acid building blocks and serve as energy molecules for a wide range of cellular reactions. Cellular GTP concentration fluctuates independently of ATP and is significantly elevated in numerous cancers, contributing to malignancy. Quantitative measurement of ATP and GTP has become increasingly important to elucidate how concentration changes regulate cell function. Liquid chromatography-coupled mass spectrometry (LC-MS) and capillary electrophoresis-coupled MS (CE-MS) are powerful methods widely used for the identification and quantification of biological metabolites. However, these methods have limitations related to specialized instrumentation and expertise, low throughput, and high costs. Here, we introduce a novel quantitative method for GTP concentration monitoring (GTP-quenching resonance energy transfer (QRET)) in homogenous cellular extracts. CE-MS analysis along with pharmacological control of cellular GTP levels shows that GTP-QRET possesses high dynamic range and accuracy. Furthermore, we combined GTP-QRET with luciferase-based ATP detection, leading to a new technology, termed QT-LucGTP&ATP, enabling high-throughput compatible dual monitoring of cellular GTP and ATP in a homogenous fashion. Collectively, GTP-QRET and QT-LucGTP&ATP offer a unique, high-throughput opportunity to explore cellular energy metabolism, serving as a powerful platform for the development of novel therapeutics and extending its usability across a range of disciplines.
    Keywords:  Adenosine triphosphate (ATP); Capillary electrophoresis (CE); Guanosine triphosphate (GTP); Immunoassay; Mass spectrometry (MS); Time-resolved luminescence (TRL)
    DOI:  https://doi.org/10.1007/s00216-023-04944-9
  7. Front Nutr. 2023 ;10 1227431
    Exploring the impact of ketogenic diet on multiple sclerosis: obesity, anxiety, depression, and the glutamate system.
    Jose Enrique de la Rubia Ortí, María Cuerda-Ballester, Claudia Emmanuela Sanchis-Sanchis, Jose María Lajara Romance, Esther Navarro-Illana, María Pilar García Pardo.
       Background: Multiple sclerosis (MS) is a neurodegenerative disorder. Individuals with MS frequently present symptoms such as functional disability, obesity, and anxiety and depression. Axonal demyelination can be observed and implies alterations in mitochondrial activity and increased inflammation associated with disruptions in glutamate neurotransmitter activity. In this context, the ketogenic diet (KD), which promotes the production of ketone bodies in the blood [mainly β-hydroxybutyrate (βHB)], is a non-pharmacological therapeutic alternative that has shown promising results in peripheral obesity reduction and central inflammation reduction. However, the association of this type of diet with emotional symptoms through the modulation of glutamate activity in MS individuals remains unknown.
    Aim: To provide an update on the topic and discuss the potential impact of KD on anxiety and depression through the modulation of glutamate activity in subjects with MS.
    Discussion: The main findings suggest that the KD, as a source of ketone bodies in the blood, improves glutamate activity by reducing obesity, which is associated with insulin resistance and dyslipidemia, promoting central inflammation (particularly through an increase in interleukins IL-1β, IL-6, and IL-17). This improvement would imply a decrease in extrasynaptic glutamate activity, which has been linked to functional disability and the presence of emotional disorders such as anxiety and depression.
    Keywords:  anxiety; depression; glutamate; ketogenic diets; multiple sclerosis; obesity
    DOI:  https://doi.org/10.3389/fnut.2023.1227431
  8. Cancer Res. 2023 Sep 11.
    Oncogenic KRASG12D reprograms lipid metabolism by upregulating SLC25A1 to drive pancreatic tumorigenesis.
    Ruowen Zhang, Xiaogang Peng, James Xianxing Du, Rebecca Boohaker, Igor L Estevao, Brian I Grajeda, Marc B Cox, Igor C Almeida, Weiqin Lu.
      Pancreatic cancer is a highly lethal disease with obesity as one of the risk factors. Oncogenic KRAS mutations are prevalent in pancreatic cancer and can rewire lipid metabolism by altering fatty acid (FA) uptake, FA oxidation (FAO), and lipogenesis. Identification of the underlying mechanisms could lead to improved therapeutic strategies for treating KRAS mutant pancreatic cancer. Here, we observed that KRASG12D upregulated the expression of SLC25A1, a citrate transporter that is a key metabolic switch to mediate FAO, fatty acid synthesis (FAS), glycolysis, and gluconeogenesis. In genetically engineered mouse models and human pancreatic cancer cells, KRASG12D induced SLC25A1 upregulation via GLI1, which directly stimulated SLC25A1 transcription by binding its promoter. The enhanced expression of SLC25A1 increased levels of cytosolic citrate, FAs, and key enzymes in lipid metabolism. In addition, a high-fat diet (HFD) further stimulated the KRASG12D-GLI1-SLC25A1 axis and the associated increase in citrate and FAs. Pharmacological inhibition of SLC25A1 and upstream GLI1 significantly suppressed pancreatic tumorigenesis in KrasG12D/+ mice on a HFD. These results reveal a KRASG12D-GLI1-SLC25A1 regulatory axis with SLC25A1 as an important node that regulates lipid metabolism during pancreatic tumorigenesis, thus indicating an intervention strategy for oncogenic KRAS-driven pancreatic cancer.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-22-2679
  9. Nat Nanotechnol. 2023 Sep 11.
    Oxyhaemoglobin saturation NIR-IIb imaging for assessing cancer metabolism and predicting the response to immunotherapy.
    Zhiguo Fang, Chenlei Wang, Jingrun Yang, Zhizheng Song, Chunyu Xie, Yu Ji, Zhongliang Wang, Xiaohui Du, Qiang Zheng, Chunying Chen, Zhiyuan Hu, Yeteng Zhong.
      In vivo quantitative assessment of oxyhaemoglobin saturation (sO2) status in tumour-associated vessels could provide insights into cancer metabolism and behaviour. Here we develop a non-invasive in vivo sO2 imaging technique to visualize the sO2 levels of healthy and tumour tissue based on photoluminescence bioimaging in the near-infrared IIb (NIR-IIb; 1,500-1,700 nm) window. Real-time dynamic sO2 imaging with a high frame rate (33 Hz) reveals the cerebral arteries and veins through intact mouse scalp/skull, and this imaging is consistent with the haemodynamic analysis results. Utilizing our non-invasive sO2 imaging, the tumour-associated-vessel sO2 levels of various cancer models are evaluated. A positive correlation between the tumour-associated-vessel sO2 levels and the basal oxygen consumption rate of corresponding cancer cells at the early stages of tumorigenesis suggests that cancer cells modulate the tumour metabolic microenvironment. We also find that a positive therapeutic response to the checkpoint blockade cancer immunotherapy could lead to a dramatic decrease of the tumour-associated-vessel sO2 levels. Two-plex dynamic NIR-IIb imaging can be used to simultaneously observe tumour-vessel sO2 and PD-L1, allowing a more accurate prediction of immunotherapy response.
    DOI:  https://doi.org/10.1038/s41565-023-01501-4
  10. Integr Cancer Ther. 2023 Jan-Dec;22:22 15347354231198195
    Effect of Moxibustion Combined With Cisplatin on Tumor Microenvironment Hypoxia and Vascular Normalization in Lewis Lung Cancer Mice.
    Ni Mao, Xiaobo Wu, Chaofeng Wang, Huijuan Mao, Jianzi Wei.
       PURPOSE: This study was developed to evaluate the effects of moxibustion on tumor microenvironmental hypoxia in a murine model of Lewis lung carcinoma (LLC).
    METHODS: Twenty-four tumor-bearing mice were randomized into tumor group (T), tumor + cisplatin group (TC), tumor + moxibustion group (TM), and tumor + cisplatin + moxibustion group (TMC) (n = 6/group). Six age-matched C57BL/6 mice were employed as control group (Ctrl). A tumor model was established by implanting LLC cells into the right flank of each mouse. Animals in the TM group received moxibustion treatment at the ST36 (bilateral) and GV4 acupoints on the day of visible tumor formation. Moxibustion treatment was performed every other day for a total of 7 sessions. Animals in the TC group were intraperitoneally injected with cisplatin (3 mg/kg) on day 3 after visible tumor formation, and this treatment was performed every 3 days for 4 times. Animals in the TMC group underwent combined moxibustion and chemotherapy treatment, following the same conditions as outlined above. Following treatment, the concentrations of hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF), CD31, and Ki67 were measured using ELISA, Western blot, and immunohistochemical staining.
    RESULTS: Compared to the tumor group, treatment in the TM, TC, and TCM groups resulted in varying reductions in tumor growth (P < .001 or P < .05), while tumor microenvironmental hypoxia was alleviated as evidenced by the downregulation of HIF-1α, VEGFA, and CD31(P < .001-P < .05).
    CONCLUSION: Our results suggest that a combined approach of moxibustion and cisplatin can alleviate intratumoral hypoxia, promote vascular normalization, and slow the growth of LLC tumors in mice.
    Keywords:  animal research; cisplatin; lung cancer; moxibustion; tumor microenvironment
    DOI:  https://doi.org/10.1177/15347354231198195
  11. Ann Palliat Med. 2023 Aug 21. pii: apm-22-1380. [Epub ahead of print]
    Total parenteral nutrition for patients with gastrointestinal cancers: a clinical practice review.
    Emily Zametkin, Dana Guyer, Yael Tarshish, Kinan Bash, Khaldoun Almhanna.
      The use of total parenteral nutrition (TPN) in patients with gastrointestinal cancers is a wellestablished practice, yet there is substantial variability in its use across institutions. Decision-making around the initiation of TPN is complex. An interdisciplinary team can help identify patient factors and clinical situations that influence whether a patient is likely to benefit from parenteral nutrition. We present the case of a woman with a gastrointestinal cancer who benefited from the initiation of TPN as a bridge therapy to further cancer treatment. This case highlights the importance of establishing a plan for nutrition with specific goals in mind, such as optimizing patients for more cancer-directed therapy. Although patients with gastrointestinal cancers may be candidates for TPN, many patient-specific factors, such as functional status and opportunities for future treatments, must be considered prior to the initiation of parenteral nutrition. An interdisciplinary approach should be used to make recommendations based on patient goals, with a focus on patient and cancer characteristics that are associated with positive outcomes after initiation of TPN. These characteristics include functional status, nutritional status, degree of symptom control, and ability to safely administer nutrition. It is important to continually assess whether parenteral nutrition is beneficial in respect to a patient's preferences and prognosis.
    Keywords:  Artificial nutrition; cancer cachexia; gastrointestinal malignancy; palliative care
    DOI:  https://doi.org/10.21037/apm-22-1380
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