bims-medica 2023-10-01 papers

bims-medica

Biomed News

on Metabolism and diet in cancer

Issue of 2023–10–01
thirty-two papers selected by
Brett Chrest, East Carolina University

Editorial for "The Role of Ketogenic Diet in Human Health and Diseases": The Multifaceted Impact of Ketogenic Diets on Health and Disease.
Role of the tumor microenvironment in the lymphatic metastasis of cervical cancer (Review).
Metabolic adaptation of NK cell activity and behavior in tumors: challenges and therapeutic opportunities.
Toward a Unifying Hypothesis for Redesigned Lipid Catabolism as a Clinical Target in Advanced, Treatment-Resistant Carcinomas.
Impact of Opioids on Cellular Metabolism: Implications for Metabolic Pathways Involved in Cancer.
Coculturing Liver Cancer Cells and Monocytes in Spheroids Conditions Monocytes to Adopt Tumor-associated Macrophage Phenotypes that Favor Tumor Growth via Cholesterol Metabolism.
Pyruvate Kinase Activity Regulates Cystine Starvation Induced Ferroptosis through Malic Enzyme 1 in Pancreatic Cancer Cells.
Role of cancer-associated fibroblasts in colorectal cancer and their potential as therapeutic targets.
The Impact of Ketone Body Metabolism on Mitochondrial Function and Cardiovascular Diseases.
Targeting fatty acid uptake and metabolism in cancer cells: A promising strategy for cancer treatment.
The Role of Acyl-CoA β-Oxidation in Brain Metabolism and Neurodegenerative Diseases.
UDP-glucose dehydrogenase (UGDH) in clinical oncology and cancer biology.
Promotion Effect of Coexposure to a High-Fat Diet and Nano-Diethylnitrosamine on the Progression of Fatty Liver Malignant Transformation into Liver Cancer.
Computational Analysis of Plasma Lipidomics from Mice Fed Standard Chow and Ketogenic Diet.
Isoliquiritigenin inhibits gastric cancer growth through suppressing GLUT4 mediated glucose uptake and inducing PDHK1/PGC-1α mediated energy metabolic collapse.
Metabolic and epigenetic reprogramming in the pathogenesis of glioblastoma: Toward the establishment of "metabolism-based pathology".
Multi-Faceted Role of Cancer-Associated Adipocytes in Colorectal Cancer.
Integration of Transcriptomics and Lipidomics Profiling to Reveal the Therapeutic Mechanism Underlying Ramulus mori (Sangzhi) Alkaloids for the Treatment of Liver Lipid Metabolic Disturbance in High-Fat-Diet/Streptozotocin-Induced Diabetic Mice.
Targeting chemoresistance and mitochondria-dependent metabolic reprogramming in acute myeloid leukemia.
The Effect of Semi-Synthetic and High-Fat High-Carbohydrate Diets Containing Cholesterol on Lipid and Cholesterol Metabolism in Male Wistar Rats.
Sphingolipid Metabolism in Tumor Cells.
SIRT3 Regulates the ROS-FPR1/HIF-1α Axis under Hypoxic Conditions to Influence Lung Cancer Progression.
Cellular and Molecular Mechanisms of the Tumor Stroma in Colorectal Cancer: Insights into Disease Progression and Therapeutic Targets.
Exploring the Therapeutic Potential of Ethyl 3-Hydroxybutyrate in Alleviating Skeletal Muscle Wasting in Cancer Cachexia.
Microenvironmental stiffness induces metabolic reprogramming in glioblastoma.
TIME-RESTRICTED FEEDING COMBINED WITH RESISTANCE EXERCISE TRAINING PREVENTS OBESITY AND IMPROVES LIPID METABOLISM IN THE LIVER OF MICE FED A HIGH-FAT DIET.
Cystine/glutamate antiporter xCT deficiency reduces metastasis without impairing immune system function in breast cancer mouse models.
Adipose Tissue Protects against Hepatic Steatosis in Male Rats Fed a High-Fat Diet plus Liquid Fructose: Sex-Related Differences.
Low dosage combination treatment with metformin and simvastatin inhibits obesity-promoted pancreatic cancer development in male KrasG12D mice.
Preimplantation embryo exposure to ketone bodies exerts sex-specific effects on mouse fetal and placental transcriptomes.
Can Exercise Enhance the Efficacy of Checkpoint Inhibition by Modulating Anti-Tumor Immunity?
Integration of Patient-Derived Organoids and Organ-on-Chip Systems: Investigating Colorectal Cancer Invasion within the Mechanical and GABAergic Tumor Microenvironment.

Nutrients. 2023 Sep 17. pii: 4027. [Epub ahead of print]15(18):

Editorial for "The Role of Ketogenic Diet in Human Health and Diseases": The Multifaceted Impact of Ketogenic Diets on Health and Disease.

Mikiko Watanabe, Silvia Savastano, Carla Lubrano, Giovanni Spera.

The ketogenic diet (KD), characterized by a very low carbohydrate intake and variable protein, fat and calorie intake, has long been in the spotlight for its potential therapeutic applications [...].

DOI: https://doi.org/10.3390/nu15184027
Exp Ther Med. 2023 Oct;26(4): 486

Role of the tumor microenvironment in the lymphatic metastasis of cervical cancer (Review).

Lufang Wang, Shuyan Yi, Yun Teng, Wenhan Li, Jing Cai.

  Lymphatic metastasis is the primary type of cervical cancer metastasis and is associated with an extremely poor prognosis in patients. The tumor microenvironment primarily includes cancer-associated fibroblasts, tumor-associated macrophages, myeloid-derived suppressor cells, immune and inflammatory cells, and blood and lymphatic vascular networks, which can promote the establishment of lymphatic metastatic sites within immunosuppressive microenvironments or promote lymphatic metastasis by stimulating lymphangiogenesis and epithelial-mesenchymal transformation. As the most important feature of the tumor microenvironment, hypoxia plays an essential role in lymph node metastasis. In this review, the known mechanisms of hypoxia, and the involvement of stromal components and immune inflammatory cells in the tumor microenvironment of lymphatic metastasis of cervical cancer are discussed. Additionally, a summary of the clinical trials targeting the tumor microenvironment for the treatment of cervical cancer is provided, emphasizing the potential and challenges of immunotherapy.

Keywords:  cancer-associated fibroblast; cervical cancer; lymphatic metastasis; tumor microenvironment; tumor-associated macrophage

DOI:  https://doi.org/10.3892/etm.2023.12185
Trends Pharmacol Sci. 2023 Sep 26. pii: S0165-6147(23)00179-7. [Epub ahead of print]

Metabolic adaptation of NK cell activity and behavior in tumors: challenges and therapeutic opportunities.

Shambhavi Borde, Sandro Matosevic.

  The adaptation of natural killer (NK) cells to conditions in the microenvironment of tumors is deeply affected by their metabolic activity, itself a result of nutrient availability and the metabolism of the cancer cells themselves. Elevated rates of glycolysis and lipid metabolism in cancers not only lead to the accumulation of immunosuppressive byproducts but also contribute to an environment of elevated concentrations of extracellular metabolites. This results in altered NK cell bioenergetics through changes in transcriptional and translational profiles, ultimately affecting their pharmacology and impairing NK cell responses. However, understanding the metabolic processes that drive alterations in immunological signaling on NK cells remains both difficult and vastly underexplored. We discuss the varied and complex drivers of NK cell metabolism in homeostasis and the tumor microenvironment (TME), challenges associated with their targetability, and unexplored therapeutic opportunities.

Keywords:  NK cells; cancer immunotherapy; cancer metabolism; immunometabolism; tumor bioenergetics

DOI:  https://doi.org/10.1016/j.tips.2023.08.009
Int J Mol Sci. 2023 Sep 21. pii: 14365. [Epub ahead of print]24(18):

Toward a Unifying Hypothesis for Redesigned Lipid Catabolism as a Clinical Target in Advanced, Treatment-Resistant Carcinomas.

Paul M Bingham, Zuzana Zachar.

  We review extensive progress from the cancer metabolism community in understanding the specific properties of lipid metabolism as it is redesigned in advanced carcinomas. This redesigned lipid metabolism allows affected carcinomas to make enhanced catabolic use of lipids in ways that are regulated by oxygen availability and is implicated as a primary source of resistance to diverse treatment approaches. This oxygen control permits lipid catabolism to be an effective energy/reducing potential source under the relatively hypoxic conditions of the carcinoma microenvironment and to do so without intolerable redox side effects. The resulting robust access to energy and reduced potential apparently allow carcinoma cells to better survive and recover from therapeutic trauma. We surveyed the essential features of this advanced carcinoma-specific lipid catabolism in the context of treatment resistance and explored a provisional unifying hypothesis. This hypothesis is robustly supported by substantial preclinical and clinical evidence. This approach identifies plausible routes to the clinical targeting of many or most sources of carcinoma treatment resistance, including the application of existing FDA-approved agents.

Keywords:  CPI-613; cancer; crizotinib; fatty acid; lipid; metabolism; resistance; thioridazine

DOI:  https://doi.org/10.3390/ijms241814365
Pharmaceutics. 2023 Aug 29. pii: 2225. [Epub ahead of print]15(9):

Impact of Opioids on Cellular Metabolism: Implications for Metabolic Pathways Involved in Cancer.

Doorsa Tarazi, Jason T Maynes.

  Opioid utilization for pain management is prevalent among cancer patients. There is significant evidence describing the many effects of opioids on cancer development. Despite the pivotal role of metabolic reprogramming in facilitating cancer growth and metastasis, the specific impact of opioids on crucial oncogenic metabolic pathways remains inadequately investigated. This review provides an understanding of the current research on opioid-mediated changes to cellular metabolic pathways crucial for oncogenesis, including glycolysis, the tricarboxylic acid cycle, glutaminolysis, and oxidative phosphorylation (OXPHOS). The existing literature suggests that opioids affect energy production pathways via increasing intracellular glucose levels, increasing the production of lactic acid, and reducing ATP levels through impediment of OXPHOS. Opioids modulate pathways involved in redox balance which may allow cancer cells to overcome ROS-mediated apoptotic signaling. The majority of studies have been conducted in healthy tissue with a predominant focus on neuronal cells. To comprehensively understand the impact of opioids on metabolic pathways critical to cancer progression, research must extend beyond healthy tissue and encompass patient-derived cancer tissue, allowing for a better understanding in the context of the metabolic reprogramming already undergone by cancer cells. The current literature is limited by a lack of direct experimentation exploring opioid-induced changes to cancer metabolism as they relate to tumor growth and patient outcome.

Keywords:  TCA; cancer; glycolysis; metabolic pathway; metabolomics; morphine; opioid; tumor

DOI:  https://doi.org/10.3390/pharmaceutics15092225
J Leukoc Biol. 2023 Sep 23. pii: qiad114. [Epub ahead of print]

Coculturing Liver Cancer Cells and Monocytes in Spheroids Conditions Monocytes to Adopt Tumor-associated Macrophage Phenotypes that Favor Tumor Growth via Cholesterol Metabolism.

Pornlapat Keawvilai, Patipark Kueanjinda, Jeerameth Klomsing, Tanapat Palaga.

  Tumor-infiltrating immune cells and their crosstalk with cancer cells in the tumor microenvironment (TME) play a crucial role in shaping tumor progression and response to therapy. We utilized three-dimension (3D) liver cancer spheroids incorporating human primary monocytes to investigate the crosstalk between tumor-associated macrophages (TAMs) and Hepatocellular carcinoma (HCC) cells, HepG2 and PLC/PRF5. Using multiplexed gene expression panels, the critical pathways involved in shaping primary human monocytes to adopt TAMs phenotypes were identified. Specific inhibitor for identified pathway was used to explore its involvement in polarization of TAMs. In the cocultured spheroids comprised of the human HCC cell lines, the infiltrating monocytes resembled protumor M2-like macrophage phenotypes. Gene expression panels of the infiltrating monocytes demonstrated that the upregulated genes were enriched in the cholesterol metabolism pathway. Cholesterol metabolism-related genes were upregulated together with the nuclear receptors, PPARG and LXR. When lysosomal acid lipase (LAL), the key enzyme necessary for the hydrolysis of lipoprotein, was inhibited, infiltrating monocytes in 3D spheroid coculture showed significantly decreased M2 marker and lipid uptake receptor expression as well as increased cellular lipid content, which indicated that cholesterol metabolism was important for conditioning the TAMs. Moreover, LAL inhibition reduced the spheroid growth and invasiveness of HCC cell lines. siRNA-mediated LAL silencing in monocytes yielded similar results upon spheroid coculture. These data indicated that liver cancer cells and infiltrating monocytes participate in crosstalk via cholesterol metabolism to condition monocytes toward TAMs, which favors tumor growth and survival, thereby promoting liver cancer progression.

Keywords:  cholesterol metabolism; liver cancer; monocytes; tumor-associated macrophages

DOI:  https://doi.org/10.1093/jleuko/qiad114
bioRxiv. 2023 Sep 17. pii: 2023.09.15.557984. [Epub ahead of print]

Pyruvate Kinase Activity Regulates Cystine Starvation Induced Ferroptosis through Malic Enzyme 1 in Pancreatic Cancer Cells.

Elliot Ensink, Tessa Jordan, Hyllana C D Medeiros, Galloway Thurston, Anmol Pardal, Lei Yu, Sophia Y Lunt.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with high mortality and limited efficacious therapeutic options. PDAC cells undergo metabolic alterations to survive within a nutrient-depleted tumor microenvironment. One critical metabolic shift in PDAC cells occurs through altered isoform expression of the glycolytic enzyme, pyruvate kinase (PK). Pancreatic cancer cells preferentially upregulate pyruvate kinase muscle isoform 2 isoform (PKM2). PKM2 expression reprograms many metabolic pathways, but little is known about its impact on cystine metabolism. Cystine metabolism is critical for supporting survival through its role in defense against ferroptosis, a non-apoptotic iron-dependent form of cell death characterized by unchecked lipid peroxidation. To improve our understanding of the role of PKM2 in cystine metabolism and ferroptosis in PDAC, we generated PKM2 knockout (KO) human PDAC cells. Fascinatingly, PKM2KO cells demonstrate a remarkable resistance to cystine starvation mediated ferroptosis. This resistance to ferroptosis is caused by decreased PK activity, rather than an isoform-specific effect. We further utilized stable isotope tracing to evaluate the impact of glucose and glutamine reprogramming in PKM2KO cells. PKM2KO cells depend on glutamine metabolism to support antioxidant defenses against lipid peroxidation, primarily by increased glutamine flux through the malate aspartate shuttle and utilization of ME1 to produce NADPH. Ferroptosis can be synergistically induced by the combination of PKM2 activation and inhibition of the cystine/glutamate antiporter in vitro . Proof-of-concept in vivo experiments demonstrate the efficacy of this mechanism as a novel treatment strategy for PDAC.
Highlights: PKM2KO in pancreatic ductal adenocarcinoma (PDAC) cells produces enhanced defense against cystine starvation induced ferroptosis.Pharmacologic activation of pyruvate kinase (PK) activity promotes ferroptosis under cystine starvation, while inhibition promotes ferroptosis survival in PDAC cells.Decrease in PK activity reprograms glutamine metabolism to increase use of malic enzyme 1 and promote survival under cystine starvation in PDAC cells. Cystine starvation and activation of pyruvate kinase synergistically decreases progression of pancreatic cancer in vivo .

DOI: https://doi.org/10.1101/2023.09.15.557984
Biochem Biophys Res Commun. 2023 Sep 23. pii: S0006-291X(23)01101-4. [Epub ahead of print]681 127-135

Role of cancer-associated fibroblasts in colorectal cancer and their potential as therapeutic targets.

Liping Yan, Jian Zheng, Qingyu Wang, Hua Hao.

  Cancer-associated fibroblasts (CAFs) are mesenchymal cells in the tumor microenvironment (TME). CAFs are the most abundant cellular components in the TME of solid tumors. They affect the progression and course of chemotherapy and radiotherapy in various types of tumors including colorectal cancer (CRC). CAFs can promote tumor proliferation, invasion, and metastasis; protect tumor cells from immune surveillance; and resist tumor cell apoptosis caused by chemotherapy, resulting in drug resistance to chemotherapy. In recent years, researchers have become increasingly interested CAF functions and have conducted extensive research. However, compared to other types of malignancies, our understanding of the interaction between CRC cells and CAFs remains limited. Therefore, we searched the relevant literature published in the past 10 years, and reviewed the origin, biological characteristics, heterogeneity, role in the TME, and potential therapeutic targets of CAFs, to aid future research on CAFs and tumors.

Keywords:  Cancer-associated fibroblasts; Colorectal cancer; Signaling pathways; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.bbrc.2023.09.065
J Atheroscler Thromb. 2023 Sep 28.

The Impact of Ketone Body Metabolism on Mitochondrial Function and Cardiovascular Diseases.

Yuichiro Arima.

  Ketone bodies, consisting of beta-hydroxybutyrate, acetoacetate, and acetone, are metabolic byproducts known as energy substrates during fasting. Recent advancements have shed light on the multifaceted effects of ketone body metabolism, which led to increased interest in therapeutic interventions aimed at elevating ketone body levels. However, excessive elevation of ketone body concentration can lead to ketoacidosis, which may have fatal consequences. Therefore, in this review, we aimed to focus on the latest insights on ketone body metabolism, particularly emphasizing its association with mitochondria as the primary site of interaction. Given the distinct separation between ketone body synthesis and breakdown pathways, we provide an overview of each metabolic pathway. Additionally, we discuss the relevance of ketone bodies to conditions such as nonalcoholic fatty liver disease or nonalcoholic steatohepatitis and cardiovascular diseases. Moreover, we explore the utilization of ketone body metabolism, including dietary interventions, in the context of aging, where mitochondrial dysfunction plays a crucial role. Through this review, we aim to present a comprehensive understanding of ketone body metabolism and its intricate relationship with mitochondrial function, spanning the potential implications in various health conditions and the aging process.

Keywords:  Aging; Cardiovascular diseases; Ketone body metabolism; Mitochondria

DOI:  https://doi.org/10.5551/jat.RV22011
Biomed Pharmacother. 2023 Sep 27. pii: S0753-3322(23)01389-6. [Epub ahead of print]167 115591

Targeting fatty acid uptake and metabolism in cancer cells: A promising strategy for cancer treatment.

Rahul Mallick, Prasenjit Bhowmik, Asim K Duttaroy.

  Despite scientific development, cancer is still a fatal disease. The development of cancer is thought to be significantly influenced by fatty acids. Several mechanisms that control fatty acid absorption and metabolism are reported to be altered in cancer cells to support their survival. Cancer cells can use de novo synthesis or uptake of extracellular fatty acid if one method is restricted. This factor makes it more difficult to target one pathway while failing to treat the disease properly. Side effects may also arise if several inhibitors simultaneously target many targets. If a viable inhibitor could work on several routes, the number of negative effects might be reduced. Comparative investigations against cell viability have found several potent natural and manmade substances. In this review, we discuss the complex roles that fatty acids play in the development of tumors and the progression of cancer, newly discovered and potentially effective natural and synthetic compounds that block the uptake and metabolism of fatty acids, the adverse side effects that can occur when multiple inhibitors are used to treat cancer, and emerging therapeutic approaches.

Keywords:  Fatty Acid; Lipid droplets; Tricarboxylic acid cycle, inhibitor, compound, de novo synthesis

DOI:  https://doi.org/10.1016/j.biopha.2023.115591
Int J Mol Sci. 2023 Sep 12. pii: 13977. [Epub ahead of print]24(18):

The Role of Acyl-CoA β-Oxidation in Brain Metabolism and Neurodegenerative Diseases.

Sylwia Szrok-Jurga, Jacek Turyn, Areta Hebanowska, Julian Swierczynski, Aleksandra Czumaj, Tomasz Sledzinski, Ewa Stelmanska.

  This review highlights the complex role of fatty acid β-oxidation in brain metabolism. It demonstrates the fundamental importance of fatty acid degradation as a fuel in energy balance and as an essential component in lipid homeostasis, brain aging, and neurodegenerative disorders.

Keywords:  aging; beta-oxidation; brain; fatty acid metabolism; neurodegenerative diseases

DOI:  https://doi.org/10.3390/ijms241813977
Oncotarget. 2023 Sep 28. 14 843-857

UDP-glucose dehydrogenase (UGDH) in clinical oncology and cancer biology.

Meghan J Price, Annee D Nguyen, Jovita K Byemerwa, Jasmine Flowers, César D Baëta, C Rory Goodwin.

  UDP-glucose-6-dehydrogenase (UGDH) is a cytosolic, hexameric enzyme that converts UDP-glucose to UDP-glucuronic acid (UDP-GlcUA), a key reaction in hormone and xenobiotic metabolism and in the production of extracellular matrix precursors. In this review, we classify UGDH as a molecular indicator of tumor progression in multiple cancer types, describe its involvement in key canonical cancer signaling pathways, and identify methods to inhibit UGDH, its substrates, and its downstream products. As such, we position UGDH as an enzyme to be exploited as a potential prognostication marker in oncology and a therapeutic target in cancer biology.

Keywords:  UDP-6 glucose dehydrogenase; UGDH; cancer; cancer biology; oncology

DOI:  https://doi.org/10.18632/oncotarget.28514
Int J Mol Sci. 2023 Sep 15. pii: 14162. [Epub ahead of print]24(18):

Promotion Effect of Coexposure to a High-Fat Diet and Nano-Diethylnitrosamine on the Progression of Fatty Liver Malignant Transformation into Liver Cancer.

Xin Yin, Yu-Sang Li, Sha-Zhou Ye, Ting Zhang, Yi-Wen Zhang, Yang Xi, He-Bin Tang.

  Overconsumption of high-fat foods increases the risk of fatty liver disease (FLD) and liver cancer with long pathogenic cycles. It is also known that the intake of the chemical poison nitrosamine and its nanopreparations can promote the development of liver injuries, such as FLD, and hepatic fibrosis, and significantly shorten the formation time of the liver cancer cycle. The present work confirmed that the coexposure of a high-fat diet (HFD) and nano-diethylnitrosamine (nano-DEN) altered the tumor microenvironment and studied the effect of this coexposure on the progression of fatty liver malignant transformation into liver cancer. Gene transcriptomics and immunostaining were used to evaluate the tumor promotion effect of the coexposure in mice. After coexposure treatment, tumor nodules were obviously increased, and inflammation levels were elevated. The liver transcriptomics analysis showed that the expression levels of inflammatory, fatty, and fibrosis-related factors in the coexposed group were increased in comparison with the nano-DEN- and high-fat-alone groups. The Kyoto Encyclopedia of Genes and Genomes (KEGG) results showed that coexposure aggravated the high expression of genes related to the carcinomatous pathway and accelerated the formation of the tumor microenvironment. The immunohistochemical staining results showed that the coexposure significantly increased the abnormal changes in proteins related to inflammation, proliferation, aging, and hypoxia in mouse liver tissues. The coexposure of high fat and nano-DEN aggravated the process of steatosis and carcinogenesis. In conclusion, the habitual consumption of pickled foods containing nitrosamines in a daily HFD significantly increases the risk of liver pathology lesions progressing from FLD to liver cancer.

Keywords:  fatty liver; high-fat diet; liver cancer; nano-diethylnitrosamine; transcriptomics

DOI:  https://doi.org/10.3390/ijms241814162
Bio Protoc. 2023 Sep 20. 13(18): e4819

Computational Analysis of Plasma Lipidomics from Mice Fed Standard Chow and Ketogenic Diet.

Amy L Seufert, James W Hickman, Jaewoo Choi, Brooke A Napier.

  Dietary saturated fatty acids (SFAs) are upregulated in the blood circulation following digestion. A variety of circulating lipid species have been implicated in metabolic and inflammatory diseases; however, due to the extreme variability in serum or plasma lipid concentrations found in human studies, established reference ranges are still lacking, in addition to lipid specificity and diagnostic biomarkers. Mass spectrometry is widely used for identification of lipid species in the plasma, and there are many differences in sample extraction methods within the literature. We used ultra-high performance liquid chromatography (UPLC) coupled to a high-resolution hybrid triple quadrupole-time-of-flight (QToF) mass spectrometry (MS) to compare relative peak abundance of specific lipid species within the following lipid classes: free fatty acids (FFAs), triglycerides (TAGs), phosphatidylcholines (PCs), and sphingolipids (SGs), in the plasma of mice fed a standard chow (SC; low in SFAs) or ketogenic diet (KD; high in SFAs) for two weeks. In this protocol, we used Principal Component Analysis (PCA) and R to visualize how individual mice clustered together according to their diet, and we found that KD-fed mice displayed unique blood profiles for many lipid species identified within each lipid class compared to SC-fed mice. We conclude that two weeks of KD feeding is sufficient to significantly alter circulating lipids, with PCs being the most altered lipid class, followed by SGs, TAGs, and FFAs, including palmitic acid (PA) and PA-saturated lipids. This protocol is needed to advance knowledge on the impact that SFA-enriched diets have on concentrations of specific lipids in the blood that are known to be associated with metabolic and inflammatory diseases. Key features • Analysis of relative plasma lipid concentrations from mice on different diets using R. • Lipidomics data collected via ultra-high performance liquid chromatography (UPLC) coupled to a high-resolution hybrid triple quadrupole-time-of-flight (QToF) mass spectrometry (MS). • Allows for a comprehensive comparison of diet-dependent plasma lipid profiles, including a variety of specific lipid species within several different lipid classes. • Accumulation of certain free fatty acids, phosphatidylcholines, triglycerides, and sphingolipids are associated with metabolic and inflammatory diseases, and plasma concentrations may be clinically useful.

Keywords:  Circulating lipids; Free fatty acids; Ketogenic diet; Lipidomics; Mass spectrometry; Phosphatidylcholines; Sphingolipids; Triglycerides

DOI:  https://doi.org/10.21769/BioProtoc.4819
Phytomedicine. 2023 Sep 02. pii: S0944-7113(23)00406-3. [Epub ahead of print]121 155045

Isoliquiritigenin inhibits gastric cancer growth through suppressing GLUT4 mediated glucose uptake and inducing PDHK1/PGC-1α mediated energy metabolic collapse.

Mingzhu Yu, Qiaoling Pan, Wenbiao Li, Tingting Du, Fei Huang, Hui Wu, Yixin He, Xiaojun Wu, Hailian Shi.

   BACKGROUND: Isoliquiritigenin (ISL), a natural flavonoid, has anti-tumor activity. But, the understanding of the impact and molecular mechanism of ISL on the growth of gastric cancer (GC) remains limited.
PURPOSE: The study was to explore the tumor suppressive effect of ISL on GC growth both in vitro and in vivo, meanwhile, clarify its molecular mechanisms.
METHODS: Cell viability was detected by cell counting kit-8 (CCK-8) assay. Apoptotic cells in vitro were monitored by Hoechst 33,342 solution. Protein expression was assessed by Western blot. Reactive oxygen species (ROS) level was evaluated by utilizing 2',7'- dichlorofluorescin diacetate (DCFH-DA). Lactic acid level was detected with L-lactate assay kit. Glucose uptake was monitored with fluorescently tagged glucose 2-[N-(7-nitrobenz-2-oxa-1,3-diaxol-4-yl)amino]-2-deoxyglucose (2-NBDG). Glycolytic proton efflux rate (GlycoPER) was evaluated by glycolytic rate assay kit. Oxygen consumption rate (OCR) was conducted by mito stress test kit. A nude mouse model of gastric cancer cell xenograft was established by subcutaneous injection with MGC803 cells. Pathological changes were evaluated by using H&E staining. Cell apoptosis in vivo was evaluated by terminal deoxy-nucleotide transferase mediated dUTP nick end labeling (TUNEL) assay.
RESULTS: ISL remarkably suppressed GC growth and increased cell apoptosis. It regulated apoptosis-related and metabolism-related protein expression both in vitro and in vivo. ISL blocked glucose uptake and suppressed production and secretion of lactic acid, which was accompanied with suppressed mitochondrial oxidative phosphorylation (OXPHOS) and glycolysis but increased ROS accumulation. Overexpression of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α), cellular-myelocytomatosis viral oncogene (c-Myc), hypoxia inducible factor-1α (HIF-1α), glucose transporter 4 (GLUT4) or pyruvate dehydrogenase kinase 1 (PDHK1), could abolish ISL-induced inhibition of cell viability in GC cells.
CONCLUSION: These findings implicated that ISL inhibits GC growth by decreasing GLUT4 mediated glucose uptake and inducing PDHK1/PGC-1α-mediated energy metabolic collapse through depressing protein expression of c-Myc and HIF-1α in GC, suggesting its potential application for GC treatment.

Keywords:  Glycolysis; HIF-1α; Lactic acid; Mitochondrial oxidative phosphorylation; Tumor; c-Myc

DOI:  https://doi.org/10.1016/j.phymed.2023.155045
Pathol Int. 2023 Sep 27.

Metabolic and epigenetic reprogramming in the pathogenesis of glioblastoma: Toward the establishment of "metabolism-based pathology".

Kenta Masui, Paul S Mischel.

  Molecular genetic approaches are now mandatory for cancer diagnostics, especially for brain tumors. Genotype-based diagnosis has predominated over the phenotype-based approach, with its prognostic and predictive powers. However, comprehensive genetic testing would be difficult to perform in the clinical setting, and translational research is required to histologically decipher the peculiar biology of cancer. Of interest, recent studies have demonstrated discrete links between oncogenotypes and the resultant metabolic phenotypes, revealing cancer metabolism as a promising histologic surrogate to reveal specific characteristics of each cancer type and indicate the best way to manage cancer patients. Here, we provide an overview of our research progress to work on cancer metabolism, with a particular focus on the genomically well-characterized malignant tumor glioblastoma. With the use of clinically relevant animal models and human tissue, we found that metabolic reprogramming plays a major role in the aggressive cancer biology by conferring therapeutic resistance to cancer cells and rewiring their epigenomic landscapes. We further discuss our future endeavor to establish "metabolism-based pathology" on how the basic knowledge of cancer metabolism could be leveraged to improve the management of patients by linking cancer cell genotype, epigenotype, and phenotype through metabolic reprogramming.

Keywords:  cancer metabolism; epigenome; glioblastoma; metabolism-based pathology; molecular genetics

DOI:  https://doi.org/10.1111/pin.13379
Biomedicines. 2023 Aug 28. pii: 2401. [Epub ahead of print]11(9):

Multi-Faceted Role of Cancer-Associated Adipocytes in Colorectal Cancer.

Adriana Grigoraș, Cornelia Amalinei.

  Colorectal cancer (CRC) is one of the most commonly diagnosed types of cancer, especially in obese patients, and the second cause of cancer-related death worldwide. Based on these data, extensive research has been performed over the last decades to decipher the pivotal role of the tumor microenvironment (TME) and its cellular and molecular components in CRC development and progression. In this regard, substantial progress has been made in the identification of cancer-associated adipocytes' (CAAs) characteristics, considering their active role in the CCR tumor niche, by releasing a panel of metabolites, growth factors, and inflammatory adipokines, which assist the cancer cells' development. Disposed in the tumor invasion front, CAAs exhibit a fibroblastic-like phenotype and establish a bidirectional molecular dialogue with colorectal tumor cells, which leads to functional changes in both cell types and contributes to tumor progression. CAAs also modulate the antitumor immune cells' response and promote metabolic reprogramming and chemotherapeutic resistance in colon cancer cells. This review aims to report recent cumulative data regarding the molecular mechanisms of CAAs' differentiation and their activity spectrum in the TME of CRC. A better understanding of CAAs and the molecular interplay between CAAs and tumor cells will provide insights into tumor biology and may open the perspective of new therapeutic opportunities in CRC patients.

Keywords:  cancer-associated adipocytes; colorectal cancer; therapy; tumor microenvironment

DOI:  https://doi.org/10.3390/biomedicines11092401
Nutrients. 2023 Sep 08. pii: 3914. [Epub ahead of print]15(18):

Integration of Transcriptomics and Lipidomics Profiling to Reveal the Therapeutic Mechanism Underlying Ramulus mori (Sangzhi) Alkaloids for the Treatment of Liver Lipid Metabolic Disturbance in High-Fat-Diet/Streptozotocin-Induced Diabetic Mice.

Fan Wang, Sai-Jun Xu, Fan Ye, Bin Zhang, Xiao-Bo Sun.

  Non-alcoholic fatty liver disease (NAFLD) is the most common liver disorder, with a global prevalence of 25%. Currently, there remains no approved therapy. Ramulus mori (Sangzhi) alkaloids (SZ-As), a novel natural medicine, have achieved comprehensive benefits in the treatment of type 2 diabetes; however, few studies have focused on its role in ameliorating hepatic lipid metabolic disturbance. Herein, the therapeutic effect and mechanism of SZ-As on a high-fat diet (HFD) combined with streptozotocin (STZ)-induced NAFLD mice were investigated via incorporating transcriptomics and lipidomics. SZ-As reduced body weight and hepatic lipid levels, restored pathological alternation and converted the blood biochemistry perturbations. SZ-A treatment also remarkedly inhibited lipogenesis and enhanced lipolysis, fatty acid oxidation and thermogenesis. Transcriptomics analysis confirmed that SZ-As mainly altered fatty acid oxidative metabolism and the TNF signaling pathway. SZ-As were further demonstrated to downregulate inflammatory factors and effectively ameliorate hepatic inflammation. Lipidomics analysis also suggested that SZ-As affected differential lipids including triglyceride (TG) and phosphatidylcholine (PC) expression, and the main metabolic pathways included glycerophospholipid, sphingomyelins and choline metabolism. Collectively, combined with transcriptomics and metabolomics data, it is suggested that SZ-As exert their therapeutic effect on NAFLD possibly through regulating lipid metabolism pathways (glycerophospholipid metabolism and choline metabolism) and increasing levels of PC and lysophosphatidylcholine (LPC) metabolites. This study provides the basis for more widespread clinical applications of SZ-As.

Keywords:  SZ-As; hepatic metabolome; inflammation response; lipid metabolism; lipidomics analysis; nonalcoholic fatty liver disease; transcriptomics analysis

DOI:  https://doi.org/10.3390/nu15183914
Front Oncol. 2023 ;13 1244280

Targeting chemoresistance and mitochondria-dependent metabolic reprogramming in acute myeloid leukemia.

Lili Feng, Philip Y Zhang, Wenda Gao, Jinming Yu, Simon C Robson.

  Chemoresistance often complicates the management of cancer, as noted in the instance of acute myeloid leukemia (AML). Mitochondrial function is considered important for the viability of AML blasts and appears to also modulate chemoresistance. As mitochondrial metabolism is aberrant in AML, any distinct pathways could be directly targeted to impact both cell viability and chemoresistance. Therefore, identifying and targeting those precise rogue elements of mitochondrial metabolism could be a valid therapeutic strategy in leukemia. Here, we review the evidence for abnormalities in mitochondria metabolic processes in AML cells, that likely impact chemoresistance. We further address several therapeutic approaches targeting isocitrate dehydrogenase 2 (IDH2), CD39, nicotinamide phosphoribosyl transferase (NAMPT), electron transport chain (ETC) complex in AML and also consider the roles of mesenchymal stromal cells. We propose the term "mitotherapy" to collectively refer to such regimens that attempt to override mitochondria-mediated metabolic reprogramming, as used by cancer cells. Mounting evidence suggests that mitotherapy could provide a complementary strategy to overcome chemoresistance in liquid cancers, as well as in solid tumors.

Keywords:  acute myeloid leukemia; chemoresistance; metabolic reprogramming; mitochondrial metabolism; mitotherapy

DOI:  https://doi.org/10.3389/fonc.2023.1244280
Bull Exp Biol Med. 2023 Sep 28.

The Effect of Semi-Synthetic and High-Fat High-Carbohydrate Diets Containing Cholesterol on Lipid and Cholesterol Metabolism in Male Wistar Rats.

N A Biryulina, Yu S Sidorova, N A Petrov, G V Guseva, V K Mazo.

  The choice of an optimal biological model of exogenous hypercholesterolemia is necessary for correct assessment of the cholesterol-lowering properties of bioactive substances and specialized food products and for validity of the experimental results. We studied the effects of cholesterol consumption in the composition of the standard semi-synthetic diet and high-fat high-carbohydrate diet for more than 3 months on lipid and cholesterol metabolism in male Wistar rats. Our findings suggest that cholesterol consumption in both diets led to a significant impairment of lipid and cholesterol metabolism, as well as an increase in insulin resistance in rats.

Keywords:  biomarkers; biomodelling; cholesterol; lipid metabolism disorders; obesity

DOI:  https://doi.org/10.1007/s10517-023-05884-1
Biochemistry (Mosc). 2023 Jul;88(7): 847-866

Sphingolipid Metabolism in Tumor Cells.

Vadim S Pokrovsky, Veronika I Ivanova-Radkevich, Olga M Kuznetsova.

  Sphingolipids are a diverse family of complex lipids typically composed of a sphingoid base bound to a fatty acid via amide bond. The metabolism of sphingolipids has long remained out of focus of biochemical studies. Recently, it has been attracting an increasing interest of researchers because of different and often multidirectional effects demonstrated by sphingolipids with a similar chemical structure. Sphingosine, ceramides (N-acylsphingosines), and their phosphorylated derivatives (sphingosine-1-phosphate and ceramide-1-phosphates) act as signaling molecules. Ceramides induce apoptosis and regulate stability of cell membranes and cell response to stress. Ceramides and sphingoid bases slow down anabolic and accelerate catabolic reactions, thus suppressing cell proliferation. On the contrary, their phosphorylated derivatives (ceramide-1-phosphate and sphingosine-1-phosphate) stimulate cell proliferation. Involvement of sphingolipids in the regulation of apoptosis and cell proliferation makes them critically important in tumor progression. Sphingolipid metabolism enzymes and sphingolipid receptors can be potential targets for antitumor therapy. This review describes the main pathways of sphingolipid metabolism in human cells, with special emphasis on the properties of this metabolism in tumor cells.

Keywords:  cancer; ceramide; dihydroceramide; proliferation; sphingolipids; sphingomyelin; sphingosine-1-phosphate; tumor

DOI:  https://doi.org/10.1134/S0006297923070015
Cell Biochem Biophys. 2023 Sep 25.

SIRT3 Regulates the ROS-FPR1/HIF-1α Axis under Hypoxic Conditions to Influence Lung Cancer Progression.

Bo Huang, Jie Ding, HongRong Guo, HongJuan Wang, JianQun Xu, Quan Zheng, LiJun Zhou.

  Hypoxia-inducible factor (HIF-1α) is a therapeutic target in lung cancer, and the deacetylase sirtuin 3 (SIRT3) is closely associated with tumorigenesis. Formyl peptide receptor 1 (FPR1) is involved in a wide range of physiopathological processes in various tumor cells. We explored whether SIRT3 affects the development of lung cancer by regulating the reactive oxygen species (ROS)-FPR1/HIF-1α axis under hypoxic conditions. The effects of SIRT3 overexpression on the levels of FPR1, HIF-1α, ROS, inflammatory factors, and cell proliferation and migration in A549 cells under hypoxic conditions were assessed in combination with the FPR1 inhibitor. BALB/c nude mice were subcutaneously injected with cancer cells transfected/untransfected with SIRT3 overexpressing lentiviral vectors. Immunohistochemistry and enzyme-linked immunosorbent assay were performed to detect SIRT3 expression and the expression levels of IL-1β, TNF-α, and IL-6, respectively, in tumor tissues. Cell proliferation, invasion, migration, and IL-1β, TNF-α, IL-6, and ROS levels were significantly higher in the Hypoxia group than in the Control group. Moreover, the mRNA and protein expression levels of SIRT3 were significantly down-regulated, whereas they were significantly up-regulated for FPR1 and HIF-1α. In contrast, SIRT3 overexpression in a hypoxic environment inhibited cell proliferation, invasion, and migration, decreased IL-1β, TNF-α, IL-6, and ROS levels, up-regulated the mRNA and protein expression levels of SIRT3, and down-regulated the mRNA and protein expression levels of FPR1 and HIF-1α. In addition, we found the same results in tumorigenic experiments in nude mice. SIRT3 in hypoxic environments may affect tumor cell proliferation, invasion, migration, and inflammation levels via the ROS-FPR1/HIF-1α axis, thereby inhibiting tumor cell development.

Keywords:  Inflammatory response; Lung cancer; Proliferation; ROS-FPR1/HIF-1α axis; SIRT3

DOI:  https://doi.org/10.1007/s12013-023-01180-x
Biomedicines. 2023 Aug 23. pii: 2361. [Epub ahead of print]11(9):

Cellular and Molecular Mechanisms of the Tumor Stroma in Colorectal Cancer: Insights into Disease Progression and Therapeutic Targets.

Nikolay Shakhpazyan, Liudmila Mikhaleva, Arkady Bedzhanyan, Zarina Gioeva, Nikolay Sadykhov, Alexander Mikhalev, Dmitri Atiakshin, Igor Buchwalow, Markus Tiemann, Alexander Orekhov.

  Colorectal cancer (CRC) is a major health burden worldwide and is the third most common type of cancer. The early detection and diagnosis of CRC is critical to improve patient outcomes. This review explores the intricate interplay between the tumor microenvironment, stromal interactions, and the progression and metastasis of colorectal cancer. The review begins by assessing the gut microbiome's influence on CRC development, emphasizing its association with gut-associated lymphoid tissue (GALT). The role of the Wnt signaling pathway in CRC tumor stroma is scrutinized, elucidating its impact on disease progression. Tumor budding, its effect on tumor stroma, and the implications for patient prognosis are investigated. The review also identifies conserved oncogenic signatures (COS) within CRC stroma and explores their potential as therapeutic targets. Lastly, the seed and soil hypothesis is employed to contextualize metastasis, accentuating the significance of both tumor cells and the surrounding stroma in metastatic propensity. This review highlights the intricate interdependence between CRC cells and their microenvironment, providing valuable insights into prospective therapeutic approaches targeting tumor-stroma interactions.

Keywords:  Wnt signaling pathway; colorectal cancer; conserved oncogenic signatures; gut microbiome; gut-associated lymphoid tissue; metastasis; tumor budding; tumor stroma

DOI:  https://doi.org/10.3390/biomedicines11092361
Biomolecules. 2023 Aug 30. pii: 1330. [Epub ahead of print]13(9):

Exploring the Therapeutic Potential of Ethyl 3-Hydroxybutyrate in Alleviating Skeletal Muscle Wasting in Cancer Cachexia.

Yu Zhou, Ruohan Lu, Fusheng Lin, Shu Chen, Qi-Qing He, Guoyang Wu, Caihua Huang, Donghai Lin.

  Cachexia (CAC) is a debilitating metabolic syndrome. Although dietary interventions are attractive, long-term adherence to specific diets is difficult to maintain and can lead to systemic side effects. Ethyl 3-hydroxybutyrate (EHB) is a commonly used food additive found in wine and Tribolium castaneum. In this study, we investigated the effects of EHB administration in cachectic mice. After a single intraperitoneal injection of EHB into mice, 3-hydroxybutyrate (3-HB) levels were significantly increased in the serum and gastrocnemius of mice. The administration of EHB alleviated cachexia-related symptoms, ameliorated skeletal muscle atrophy, and improved survival in cachectic mice. In addition, the supplementation of cachectic mice with 3-HB by EHB administration significantly reduced tumor weights, indicating the anti-tumor effects of 3-HB. Remarkably, the addition of 3-HB to the culture medium significantly attenuated the C2C12 myotube atrophy induced by the culture supernatant of CT26 cell lines, highlighting its potential to counteract the destructive effects of tumor-derived elements on muscle tissue. NMR-based metabolomics analysis provided insights into the underlying mechanisms and revealed that the anti-cachexia effects of 3-HB treatment can be attributed to three key mechanisms: the promotion of the TCA cycle and the attenuation of proteolysis, the promotion of protein synthesis and the improvement of metabolic homeostasis, and a reduction in inflammation and an enhancement of the antioxidant capacity. This study provided compelling evidence for the protective effects of 3-HB treatment on the cachectic gastrocnemius and highlighted the efficacy of EHB administration as a ketone supplementation approach to achieve nutritional ketosis without the need for dietary restriction.

Keywords:  3-hydroxybutyrate; Ethyl 3-hydroxybutyrate; cancer cachexia; ketogenic diet; metabonomics

DOI:  https://doi.org/10.3390/biom13091330
Cell Rep. 2023 Sep 26. pii: S2211-1247(23)01187-7. [Epub ahead of print]42(10): 113175

Microenvironmental stiffness induces metabolic reprogramming in glioblastoma.

Alireza Sohrabi, Austin E Y T Lefebvre, Mollie J Harrison, Michael C Condro, Talia M Sanazzaro, Gevick Safarians, Itay Solomon, Soniya Bastola, Shadi Kordbacheh, Nadia Toh, Harley I Kornblum, Michelle A Digman, Stephanie K Seidlits.

  The mechanical properties of solid tumors influence tumor cell phenotype and the ability to invade surrounding tissues. Using bioengineered scaffolds to provide a matrix microenvironment for patient-derived glioblastoma (GBM) spheroids, this study demonstrates that a soft, brain-like matrix induces GBM cells to shift to a glycolysis-weighted metabolic state, which supports invasive behavior. We first show that orthotopic murine GBM tumors are stiffer than peritumoral brain tissues, but tumor stiffness is heterogeneous where tumor edges are softer than the tumor core. We then developed 3D scaffolds with μ-compressive moduli resembling either stiffer tumor core or softer peritumoral brain tissue. We demonstrate that the softer matrix microenvironment induces a shift in GBM cell metabolism toward glycolysis, which manifests in lower proliferation rate and increased migration activities. Finally, we show that these mechanical cues are transduced from the matrix via CD44 and integrin receptors to induce metabolic and phenotypic changes in cancer cells.

Keywords:  CP: Cancer; CP: Metabolism; extracellular matrix; tissue mechanics

DOI:  https://doi.org/10.1016/j.celrep.2023.113175
Am J Physiol Endocrinol Metab. 2023 Sep 27.

TIME-RESTRICTED FEEDING COMBINED WITH RESISTANCE EXERCISE TRAINING PREVENTS OBESITY AND IMPROVES LIPID METABOLISM IN THE LIVER OF MICE FED A HIGH-FAT DIET.

Robson Damasceno de Lima, Renan Fudoli Lins Vieira, Vitor Rosetto Muñoz, Amandine Chaix, Ana Paula Azevedo Macedo, Gabriel Calheiros Antunes, Maíra Felonato, Renata Rosetta Braga, Susana Castelo Branco Ramos Nakandakari, Rafael Calais Gaspar, Adelino Sanchez Ramos da Silva, Dennys Esper Cintra, Leandro Pereira de Moura, Rania A Mekary, Eduardo Rochete Ropelle, José Rodrigo Pauli.

  Non-alcoholic fatty liver disease (NAFLD), a condition characterized by the accumulation of fat in the liver, is estimated to be the most common liver disease worldwide. Obesity is a major risk factor and contributor, and, accordingly, weight loss can improve NAFLD. Previous studies in preclinical models of diet-induced obesity and fatty liver disease have shown the independent benefits of resistance exercise training (RT) and time-restricted feeding (TRF) in preventing weight gain and hepatic build-up of fat. Here, we tested the combined effect of TRF and RT on obesity and NAFLD in mice fed a high-fat diet. Our results showed that both TRF - 8h food access in the active phase - and RT - consisting of three weekly sessions of ladder climbing - attenuated body weight gain, improved glycemic homeostasis, and decreased the accumulation of lipids in the liver. TRF combined with RT improved respiratory exchange rate, energy expenditure, and mitochondrial respiration in the liver. Furthermore, gene expression analysis in the liver revealed lower mRNA expression of lipogenesis and inflammation genes along with increased mRNA of fatty acid oxidation genes in the TRF+RT group. Importantly, combined TRF+RT proved more efficient in preventing obesity and metabolic disorders. In conclusion, TRF and RT exert complementary or additive actions compared to isolated interventions, with significant effects on metabolic disorders and NAFLD in mice.

Keywords:  Liver; Non-Alcoholic Fatty Liver Disease; Obesity; Resistance Exercise Training; Time-Restricted Feeding

DOI:  https://doi.org/10.1152/ajpendo.00129.2023
J Exp Clin Cancer Res. 2023 Sep 29. 42(1): 254

Cystine/glutamate antiporter xCT deficiency reduces metastasis without impairing immune system function in breast cancer mouse models.

Roberto Ruiu, Chiara Cossu, Antonella Iacoviello, Laura Conti, Elisabetta Bolli, Luca Ponzone, Jolanda Magri, Alekya Rumandla, Enzo Calautti, Federica Cavallo.

   BACKGROUND: The upregulation of antioxidant mechanisms is a common occurrence in cancer cells, as they strive to maintain balanced redox state and prevent oxidative damage. This includes the upregulation of the cystine/glutamate antiporter xCT, which plays a crucial role in protecting cancer cells from oxidative stress. Consequently, targeting xCT has become an attractive strategy for cancer treatment. However, xCT is also expressed by several types of immune cells where it has a role in proliferation and effector functions. In light of these observations, a comprehensive understanding of the specific role of xCT in the initiation and progression of cancer, as well as its potential impact on the immune system within the tumor microenvironment and the anti-tumor response, require further investigation.
METHODS: We generated xCTnull BALB/c mice to investigate the role of xCT in the immune system and xCTnull/Erbb2-transgenic BALB-neuT mice to study the role of xCT in a mammary cancer-prone model. We also used mammary cancer cells derived from BALB-neuT/xCTnull mice and xCTKO 4T1 cells to test the contribution of xCT to malignant properties in vitro and in vivo.
RESULTS: xCT depletion in BALB-neuT/xCTnull mice does not alter autochthonous tumor initiation, but tumor cells isolated from these mice display proliferation and redox balance defects in vitro. Although xCT disruption sensitizes 4T1 cells to oxidative stress, it does not prevent transplantable tumor growth, but reduces cell migration in vitro and lung metastasis in vivo. This is accompanied by an altered immune cell recruitment in the pre-metastatic niche. Finally, systemic depletion of xCT in host mice does not affect transplantable tumor growth and metastasis nor impair the proper mounting of both humoral and cellular immune responses in vivo.
CONCLUSIONS: xCT is dispensable for proper immune system function, thus supporting the safety of xCT targeting in oncology. Nevertheless, xCT is involved in several processes required for the metastatic seeding of mammary cancer cells, thus broadening the scope of xCT-targeting approaches.

Keywords:  Breast cancer; Immune system; Metastasis; Metastatic niche; SLC7A11; xCT

DOI:  https://doi.org/10.1186/s13046-023-02830-x
Nutrients. 2023 Sep 08. pii: 3909. [Epub ahead of print]15(18):

Adipose Tissue Protects against Hepatic Steatosis in Male Rats Fed a High-Fat Diet plus Liquid Fructose: Sex-Related Differences.

Roger Bentanachs, Laia Blanco, Maria Montesinos, Aleix Sala-Vila, Iolanda Lázaro, Jose Rodríguez-Morató, Rosa María Sánchez, Juan Carlos Laguna, Núria Roglans, Marta Alegret.

  Non-alcoholic fatty liver disease is a sexual dimorphic disease, with adipose tissue playing an essential role. Our previous work showed that female rats fed a high-fat high-fructose diet devoid of cholesterol (HFHFr) developed simple hepatic steatosis dissociated from obesity. This study assessed the impact of the HFHFr diet on the male rat metabolism compared with data obtained for female rats. A total of 16 Sprague Dawley (SD) male rats were fed either a control (standard rodent chow and water) or HFHFr (high-fat diet devoid of cholesterol, plus 10% fructose in drinking water) diet for 3 months. Unlike female rats, and despite similar increases in energy consumption, HFHFr males showed increased adiposity and hyperleptinemia. The expression of hormone-sensitive lipase in the subcutaneous white adipose tissue was enhanced, leading to high free fatty acid and glycerol serum levels. HFHFr males presented hypertriglyceridemia, but not hepatic steatosis, partially due to enhanced liver PPARα-related fatty acid β-oxidation and the VLDL-promoting effect of leptin. In conclusion, the SD rats showed a sex-related dimorphic response to the HFHFr diet. Contrary to previous results for HFHFr female rats, the male rats were able to expand the adipose tissue, increase fatty acid catabolism, or export it as VLDL, avoiding liver lipid deposition.

Keywords:  adipose tissue; fructose; high-fat diet; leptin; non-esterified fatty acids

DOI:  https://doi.org/10.3390/nu15183909
Sci Rep. 2023 09 26. 13(1): 16144

Low dosage combination treatment with metformin and simvastatin inhibits obesity-promoted pancreatic cancer development in male KrasG12D mice.

Yaroslav Teper, Linda Ye, Richard T Waldron, Aurelia Lugea, Xiaoying Sun, James Sinnett-Smith, Oscar J Hines, Stephen J Pandol, Enrique Rozengurt, Guido Eibl.

Pancreatic ductal adenocarcinoma (PDAC), a highly lethal disease with limited therapeutic options, may benefit from repurposing of FDA-approved drugs in preventive or interceptive strategies in high-risk populations. Previous animal studies demonstrated that the use of metformin and statins as single agents at relatively high doses restrained PDAC development. Here, four-week-old mice expressing KrasG12D in all pancreatic lineages (KC mice) and fed an obesogenic high fat, high calorie diet that promotes early PDAC development were randomized onto low dosage metformin, simvastatin, or both drugs in combination administered orally. Dual treatment attenuated weight gain, fibro-inflammation, and development of advanced PDAC precursor lesions (pancreatic intraepithelial neoplasia [PanIN]-3) in male KC mice, without significant effect in females or when administered individually. Dual-treated KC mice had reduced proliferation of PanIN cells and decreased transcriptional activity of the Hippo effectors, YAP and TAZ, which are important regulators of PDAC development. Metformin and simvastatin also synergistically inhibited colony formation of pancreatic cancer cells in vitro. Together, our data demonstrated that a combination of low doses of metformin and simvastatin inhibits PDAC development and imply that both drugs are promising agents for being tested in clinical trials for preventing pancreatic cancer progression.

DOI: https://doi.org/10.1038/s41598-023-43498-9
Reprod Biomed Online. 2023 Jul 28. pii: S1472-6483(23)00420-0. [Epub ahead of print]47(5): 103320

Preimplantation embryo exposure to ketone bodies exerts sex-specific effects on mouse fetal and placental transcriptomes.

Emma G Whatley, Thi T Truong, Alexandra J Harvey, David K Gardner.

   RESEARCH QUESTION: Does in vitro exposure of preimplantation mouse embryos to the ketone bodies β-hydroxybutyrate (βOHB) and acetoacetate (AcAc) impact post-transfer fetal and placental gene expression?
DESIGN: Blastocysts cultured in vitro with or without 2 mmol/l βOHB alone ('βOHB') or combined with 0.8 mmol/l AcAc ('Keto') underwent embryo transfer. Transcriptional profiles of sexed placenta, liver and brain at gestational day 14.5 were examined via RNA sequencing and DAVID functional analysis.
RESULTS: A sexually dimorphic response to in vitro ketone exposure was observed. Both βOHB and Keto exposure down-regulated genes related to oxidative phosphorylation specifically in female liver. βOHB down-regulated female placental steroid biosynthetic processes, while Keto treatment up-regulated genes relevant to blood vessel formation and cell migration in male placenta. Brain transcriptomes were minimally affected. X-linked genes and chromatin modifiers were identified as differentially expressed in both liver and placenta, alluding to a sex-specific regulatory mechanism.
CONCLUSIONS: Transient preimplantation ketone exposure perturbs sex-specific fetal liver and placental gene expression, demonstrating a developmental programming effect that warrants future investigation of the postnatal metabolic health of male and female offspring.

Keywords:  Acetoacetate; Developmental origins of health and disease; Ketogenic diet; Nutrients; Periconception; β-hydroxybutyrate

DOI:  https://doi.org/10.1016/j.rbmo.2023.103320
Cancers (Basel). 2023 Sep 21. pii: 4668. [Epub ahead of print]15(18):

Can Exercise Enhance the Efficacy of Checkpoint Inhibition by Modulating Anti-Tumor Immunity?

Christina Brummer, Tobias Pukrop, Joachim Wiskemann, Christina Bruss, Ines Ugele, Kathrin Renner.

  Immune checkpoint inhibition (ICI) has revolutionized cancer therapy. However, response to ICI is often limited to selected subsets of patients or not durable. Tumors that are non-responsive to checkpoint inhibition are characterized by low anti-tumoral immune cell infiltration and a highly immunosuppressive tumor microenvironment. Exercise is known to promote immune cell circulation and improve immunosurveillance. Results of recent studies indicate that physical activity can induce mobilization and redistribution of immune cells towards the tumor microenvironment (TME) and therefore enhance anti-tumor immunity. This suggests a favorable impact of exercise on the efficacy of ICI. Our review delivers insight into possible molecular mechanisms of the crosstalk between muscle, tumor, and immune cells. It summarizes current data on exercise-induced effects on anti-tumor immunity and ICI in mice and men. We consider preclinical and clinical study design challenges and discuss the role of cancer type, exercise frequency, intensity, time, and type (FITT) and immune sensitivity as critical factors for exercise-induced impact on cancer immunosurveillance.

Keywords:  NK cells; PD-1; PD-L1; T cells; anti-tumor immunity; cancer; exercise; immune checkpoint inhibition (ICI); immunotherapy; physical activity (PA); tumor microenvironment (TME)

DOI:  https://doi.org/10.3390/cancers15184668
bioRxiv. 2023 Sep 17. pii: 2023.09.14.557797. [Epub ahead of print]

Integration of Patient-Derived Organoids and Organ-on-Chip Systems: Investigating Colorectal Cancer Invasion within the Mechanical and GABAergic Tumor Microenvironment.

Carly Strelez, Rachel Perez, John S Chlystek, Christopher Cherry, Ah Young Yoon, Bethany Haliday, Curran Shah, Kimya Ghaffarian, Ren X Sun, Hannah Jiang, Roy Lau, Aaron Schatz, Heinz-Josef Lenz, Jonathan E Katz, Shannon M Mumenthaler.

Three-dimensional (3D) in vitro models are essential in cancer research, but they often neglect physical forces. In our study, we combined patient-derived tumor organoids with a microfluidic organ-on-chip system to investigate colorectal cancer (CRC) invasion in the tumor microenvironment (TME). This allowed us to create patient-specific tumor models and assess the impact of physical forces on cancer biology. Our findings showed that the organoid-on-chip models more closely resembled patient tumors at the transcriptional level, surpassing organoids alone. Using 'omics' methods and live-cell imaging, we observed heightened responsiveness of KRAS mutant tumors to TME mechanical forces. These tumors also utilized the γ-aminobutyric acid (GABA) neurotransmitter as an energy source, increasing their invasiveness. This bioengineered model holds promise for advancing our understanding of cancer progression and improving CRC treatments.
Highlights: Microfluidic organ-on-chip system integrated with patient-derived CRC organoidsPhysical forces influence invasion, particularly in KRAS mutant tumor cellsGABAergic signaling contributes to increased invasion within a dynamic TMEThis model explores patient heterogeneity, TME interactions, and cancer progression.
GRAPHICAL ABSTRACT:

DOI: https://doi.org/10.1101/2023.09.14.557797