bims-medica 2023-09-24 papers

bims-medica

Biomed News

on Metabolism and diet in cancer

Issue of 2023–09–24
eleven papers selected by
Brett Chrest, East Carolina University

Dietary fat and lipid metabolism in the tumor microenvironment.
High-Fat Ketogenic Diets and Ketone Monoester Supplements Differentially Affect Substrate Metabolism during Aerobic Exercise.
Tumor lipid metabolism: a mechanistic link between diet and cancer progression.
Ketogenic diet and metastasis: A critical review of the literature and possible mechanisms.
Identification and validation of a fatty acid metabolism gene signature for the promotion of metastasis in liver cancer.
Alternate-day fat diet and exenatide modulate the brain leptin JAK2/STAT3/SOCS3 pathway in a fat diet-induced obesity and insulin resistance mouse model.
Suppression of tumor cell lactate-generating signaling pathways eradicates murine PTEN/p53-deficient aggressive-variant prostate cancer via macrophage phagocytosis.
Role of tissue markers associated with tumor microenvironment in the progression and immune suppression of oral squamous cell carcinoma.
Brain Glutathione Increase and Seizure Burden Decrease in Patients with Intractable Epilepsy on Ketogenic Diet.
Cancer-associated fibroblasts reuse cancer-derived lactate to maintain a fibrotic and immunosuppressive microenvironment in pancreatic cancer.
Stem cell factor modulates HIF-1α levels and diminishes 5-FU sensitivity in 5-FU resistant pancreatic cells by altering the anabolic glucose metabolism.

Biochim Biophys Acta Rev Cancer. 2023 Sep 16. pii: S0304-419X(23)00133-6. [Epub ahead of print] 188984

Dietary fat and lipid metabolism in the tumor microenvironment.

Swagata Goswami, Qiming Zhang, Cigdem Elif Celik, Ethan M Reich, Ömer H Yilmaz.

  Metabolic reprogramming has been considered a core hallmark of cancer, in which excessive accumulation of lipids promote cancer initiation, progression and metastasis. Lipid metabolism is often considered as the digestion and absorption process of dietary fat, and the ways in which cancer cells utilize lipids are often influenced by the complex interactions within the tumor microenvironment. Among multiple cancer risk factors, obesity has a positive association with multiple cancer types, while diets like calorie restriction and fasting improve health and delay cancer. Impact of these diets on tumorigenesis or cancer prevention are generally studied on cancer cells, despite heterogeneity of the tumor microenvironment. Cancer cells regularly interact with these heterogeneous microenvironmental components, including immune and stromal cells, to promote cancer progression and metastasis, and there is an intricate metabolic crosstalk between these compartments. Here, we focus on discussing fat metabolism and response to dietary fat in the tumor microenvironment, focusing on both immune and stromal components and shedding light on therapeutic strategies surrounding lipid metabolic and signaling pathways.

Keywords:  Fatty acid; High fat diet; Immunosuppression; Lipid metabolism; Obesity; Therapeutic intervention; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.bbcan.2023.188984
Am J Physiol Cell Physiol. 2023 Sep 18.

High-Fat Ketogenic Diets and Ketone Monoester Supplements Differentially Affect Substrate Metabolism during Aerobic Exercise.

Lee M Margolis, Stefan M Pasiakos, Emily E Howard.

  Chronically adhering to high-fat ketogenic diets or consuming ketone monoester supplements elicits ketosis. Resulting changes in substrate metabolism appear to be drastically different between ketogenic diets and ketone supplements. Consuming a ketogenic diet increases fatty acid oxidation with concomitant decreases in endogenous carbohydrate oxidation. Increased fat oxidation eventually results in an accumulation of circulating ketone bodies, which are metabolites of fatty acids that serve as an alternative source of fuel. Conversely, consuming ketone monoester supplements rapidly increases circulating ketone body concentrations that typically exceed those achieved by adhering to ketogenic diets. Rapid increases in ketone body concentrations with ketone monoester supplementation elicits a negative feedback inhibition that reduces fatty acid mobilization during aerobic exercise. Supplement-derived ketosis appears to have minimal impact on sparing of muscle glycogen or minimizing of carbohydrate oxidation during aerobic exercise. This review will discuss the substrate metabolic and associated aerobic performance responses to ketogenic diets and ketone supplements.

Keywords:  Aerobic performance; endurance exercise; glycogen; high-fat, low-carbohydrate diet; β-hydroxybutyrate

DOI:  https://doi.org/10.1152/ajpcell.00359.2023
Curr Opin Biotechnol. 2023 Sep 13. pii: S0958-1669(23)00103-9. [Epub ahead of print]84 102993

Tumor lipid metabolism: a mechanistic link between diet and cancer progression.

Yu-Jin Jeong, Thomas J Rogers, Carolyn E Anderson, Evan C Lien.

The potential for 'anti-cancer' diets to markedly alter cancer risk and prognosis has captured the imagination of patients, physicians, and researchers alike, but many of these dietary recommendations come from correlative studies that attribute certain diets to altered cancer risk. While provocative, little is known about the molecular mechanisms behind how these dietary interventions impact cancer progression. Within this context, however, changes in tumor lipid metabolism are emerging as a key contributor. In this review, we examine the current understanding of lipid metabolism in the tumor microenvironment (TME), suggesting how diet-induced changes in lipid composition may regulate tumor progression and therapeutic efficacy. By dissecting various cellular pathways involved in lipid metabolism, we highlight how diet modulates the balance between saturated and unsaturated fatty acid (FA) species in tumors to impact cancer cell and stromal cell function. Finally, we describe how current cancer therapies may synergize with diet to improve therapeutic efficacy.

DOI: https://doi.org/10.1016/j.copbio.2023.102993
Clin Nutr ESPEN. 2023 Oct;pii: S2405-4577(23)00182-1. [Epub ahead of print]57 207-212

Ketogenic diet and metastasis: A critical review of the literature and possible mechanisms.

Lucas Soares Bezerra, Marcelo Antônio Oliveira Santos-Veloso.

  The ketogenic diet (KD) is a low-carb diet that has been indicated as a possible coadjuvant in cancer therapy, mainly due to its capacity to reduce glycolysis production, inflammation, and oxidative stress. However, KD's role in metastasis remains poorly explored. This study aims to provide a critical review of the literature about KD's efficacy in metastasis therapy and the possible molecular mechanisms behind it. Initially, general concepts on KD and metastasis are discussed. Then, it delves deeper into the main cancer mechanisms explored by KD experimental studies, discussing the central results obtained in metastasis research and their main limiting conditions. Following, there is a critical analysis of clinical trials, including those in the grey literature. In the end, there is a summary of the actual studies' limitations and barriers to future research. To date, it is possible to conclude that there is not enough evidence supporting the efficacy of KD in the treatment of metastasis.

Keywords:  Carbohydrates; Ketogenic diet; Metastasis; Neoplasms

DOI:  https://doi.org/10.1016/j.clnesp.2023.06.038
Oncol Lett. 2023 Oct;26(4): 457

Identification and validation of a fatty acid metabolism gene signature for the promotion of metastasis in liver cancer.

Zhenshan Zhang, Jun Sun, Chao Jin, Likun Zhang, Leilei Wu, Gendong Tian.

  Metastasis is a fatal status for liver cancer, and the identification of an effective prediction model and promising therapeutic target is essential. Given the known relationship between fatty acid (FA) metabolism and the liver, the present study aimed to investigate dysregulation of genes associated with FA metabolism in liver cancer. Bioinformatics analyses were performed on data from patients with hepatocellular carcinoma (HCC) obtained from The Cancer Genome Atlas database using R software packages. Online public tools such as the Human Protein Atlas, Tumor Immune Single-Cell Hub and the University of Alabama at Birmingham Cancer Data Analysis portal were also utilized. Some essential results were further verified using in vitro experiments using HepG2 liver cancer cells. A signature consisting of three genes associated with the progression and prognosis of HCC and FA metabolism was identified. When samples were scored based on the expression of these genes and divided according to the median value, the higher score group showed a worse outcome and repressive immune microenvironment than the lower score group. Downstream pathways such as hypoxia, IL6/JAK/STAT3 and epithelial-mesenchymal transition were found to be significantly activated in the higher score group. As the core factor in the signature, mitochondrial ribosomal protein L35 (MRPL35) was found to be upregulated in HCC and to have certain impacts on the dysregulation of effective immunity. Further investigations and in vitro experiments indicated that MRPL35 facilitates the migration and invasion abilities of liver cancer, and the resistance of HCC to treatment. These findings have important implications regarding the characteristics and mechanisms of metastasis in liver cancer, and provide a promising signature based on FA metabolism-related genes that may be used to predict outcomes and explored as a novel therapeutic target in liver cancer.

Keywords:  MRPL35; fatty acid metabolism; hepatocellular carcinoma; liver cancer; metastasis

DOI:  https://doi.org/10.3892/ol.2023.14044
Arch Med Sci. 2023 ;19(5): 1508-1519

Alternate-day fat diet and exenatide modulate the brain leptin JAK2/STAT3/SOCS3 pathway in a fat diet-induced obesity and insulin resistance mouse model.

Mona K Tawfik, Dahlia I Badran, Mohammed M Keshawy, Samy Makary, Mohamed Abdo.

   Introduction: Obesity is one of the most burdensome health problems and is closely linked to leptin resistance. The study examined whether an alternate-day high-fat diet (ADF) and/or GLP-1 agonist (exenatide) modulate brain leptin resistance caused by a high-fat diet (HFD).
Material and methods: Sixty adult male mice were divided into 6 groups: (i) normal palatable diet (NPD), (ii) exenatide control (NPD received exenatide) (iii) HFD, (iv) ADF treated, (v) exenatide treated, (vi) ADF and exenatide treated. All animal groups were fed a HFD for 8 weeks, before they received treatment (ADF and/or exenatide) for 8 additional weeks. Body weight was assessed at the start and at the end of the experiment. Lipid profile, brain leptin and its receptor expression with the leptin-sensitive pathway, JAK2/STAT3/SOCS3/PTP1B, fasting blood glucose (FBG), serum insulin, liver metabolic handling via its regulators IRS1/PI3K/GLUT4 for hyperinsulinemia/obesity-induced PDK3/NAFLD2 modification, and liver enzymes were determined at the end of the experiment.
Results: ADF and exenatide reduced body weight and FBG in HFD-obese mice (p < 0.05). The combined ADF and exenatide regimen enhanced the brain anorexic leptin/JAK2/STAT3 and attenuated the SOCS3/PTP1B pathway (p < 0.05). The ADF/exenatide anorexigenic brain effect also modulated liver glucose via IRS1/PI3K/GLUT4 expression (p < 0.05), attenuating NAFLD2 and PDK3 expression (p < 0.05). Liver enzymes and the histopathological profile confirmed the improvement.
Conclusions: In HFD caloric consumption, a combination of ADF and GLP-1 agonist enhances the brain leptin anorexigenic effect with the improvement of the metabolic sequelae of hyperinsulinemia, hyperlipidemia and liver steatosis.

Keywords:  alternate-day high-fat diet; exenatide; high-fat diet; hyperinsulinemia; leptin

DOI:  https://doi.org/10.5114/aoms/158534
Clin Cancer Res. 2023 Sep 18.

Suppression of tumor cell lactate-generating signaling pathways eradicates murine PTEN/p53-deficient aggressive-variant prostate cancer via macrophage phagocytosis.

Kiranj Chaudagar, Hanna M Hieromnimon, Anne Kelley, Brian Labadie, Jordan Shafran, Srikrishnan Rameshbabu, Catherine Drovetsky, Kaela Bynoe, Ani Solanki, Erica Markiewicz, Xiaobing Fan, Massimo Loda, Akash Patnaik.

PURPOSE: PTEN loss-of-function/PI3K pathway hyperactivation is associated with poor therapeutic outcomes and immune checkpoint inhibitor resistance across multiple malignancies. Our prior studies in Pb-Cre;PTENfl/flTrp53fl/fl genetically engineered mice (GEM) with aggressive-variant prostate cancer (AVPC) demonstrated tumor growth control in 60% mice following androgen deprivation therapy (ADT)/PI3K inhibitor (PI3Ki)/PD-1 antibody combination, via abrogating lactate cross-talk between cancer cells and tumor-associated macrophages (TAM), and suppression of histone lactylation (H3K18lac)/phagocytic activation within TAM. Here, we targeted immunometabolic mechanism(s) of PI3Ki resistance, with the goal of durable tumor control in AVPC.
EXPERIMENTAL DESIGN: Pb-Cre;PTENfl/flTrp53fl/fl GEM were treated with PI3Ki (copanlisib), MEK inhibitor (trametinib) or Porcupine inhibitor (LGK`974) singly or their combinations. MRI was used to monitor tumor kinetics and immune/proteomic profiling/ex vivo co-culture mechanistic studies were performed on GEM tumors or corresponding tumor-derived cell lines.
RESULTS: Given our proteomic profiling showing persistent MEK signaling within tumors of PI3Ki-resistant GEM, we tested whether addition of trametinib to copanlisib enhances tumor control in GEM, and observed 80% overall response rate via additive suppression of lactate within TME and H3K18lac within TAM, relative to copanlisib (37.5%) monotherapy. The 20% resistant mice demonstrated feedback Wnt/b-catenin activation, resulting in restoration of lactate secretion by tumor cells and H3K18lac within TAM. Co-targeting Wnt/b-catenin signaling with LGK'974 in combination with PI3Ki/MEKi, demonstrated durable tumor control in 100% mice via H3K18lac suppression and complete TAM activation.
CONCLUSIONS: Abrogation of lactate-mediated cross-talk between cancer cells and TAM results in durable ADT-independent tumor control in PTEN/p53-deficient AVPC, and warrants further investigation in clinical trials.

DOI: https://doi.org/10.1158/1078-0432.CCR-23-1441
Med Oncol. 2023 Sep 20. 40(10): 303

Role of tissue markers associated with tumor microenvironment in the progression and immune suppression of oral squamous cell carcinoma.

Suganya Ramalingam, Sivaramakrishnan Shantha, Susruthan Muralitharan, Uma Sudhakar, Harikrishnan Thamizhchelvan, Venkatachalam Deepa Parvathi.

  Head and neck cancers (HNC) continues to dominate major cancers contributing to mortality worldwide. Squamous cell carcinoma is the major type of HNC. Oral Squamous Cell Carcinoma grouped under HNC is a malignant tumor occurring in the oral cavity. The primary risk factors of OSCC are tobacco, alcohol consumption, etc. This review focuses on modulations, mechanisms, growth and differentiation of oral squamous cell carcinoma. Cancer cell surrounds itself with a group of elements forming a favorable environment known as tumor microenvironment (TME). It consists of numerous cells which includes immune cells, blood cells and acellular components that are responsible for the progression, immunosuppression, metastasis and angiogenesis of cancer. This review highlights the most important tissue biomarkers (mTOR, CAF, FOXp3, CD163, CD33, CD34) that are associated with TME cells. mTOR remains as the primary regulator responsible in cancer and its importance towards immune-suppression is highlighted. Tumor-associated macrophages associated with cancer development and its relationship with immunomodulatory mechanism and Tregs, which are potential blockers of immune response and its mechanism and aberrations are discussed. Cancer-associated fibroblasts that are a part of TME and their role in evading the immune response and myeloid derived suppressor cells that have slight control over the immune response and their mechanism in the tumor progression is further explained. These markers have been emphasised as therapeutic targets and are currently in different stages of clinical trials.

Keywords:  CD163; CD33; CD34; Cancer-associated fibroblasts (CAF); FOXp3; Oral squamous cell carcinoma (OSCC); Tumor microenvironment; mTOR

DOI:  https://doi.org/10.1007/s12032-023-02169-5
J Epilepsy Res. 2023 Jun 30. 13(1): 1-6

Brain Glutathione Increase and Seizure Burden Decrease in Patients with Intractable Epilepsy on Ketogenic Diet.

Saman Hazany, Brittany DeClouette, Jessica Lowe, Darryl H Hwang, Paul E Kim, Stefan Bluml, Arthur Partikian.

   Background and Purpose: Ketogenic diet (KD) improves seizure control in patients with drug-resistant epilepsy. As increased mitochondrial levels of glutathione (GSH) might contribute to a change in seizure susceptibility, we quantified changes of absolute GSH levels in the brain by in vivo 1H magnetic resonance spectroscopy (1H MRS) and correlate that with degree of seizure control in patients on KD.
Methods: Five cognitively normal adult patients with drug-resistant epilepsy were initially included and 2 completed the study. Each patient was evaluated by a neurologist and registered dietitian at baseline, 1, 3, and 6 months for seizure status and diet adherence after initiation of a modified atkins diet. Multiple metabolites including GSH were quantified using LCModel (version 6.3-1P; Stephen Provencher, Oakville, ON, CA) on a short echo time single-voxel 1H MRS in parieto/occipital grey matter and parietal white matter on a 3 Tesla General Electric magnet prior to starting the ketogenic diet and at 6 months.
Results: Both patients (42-years-old male and 35-years-old female) demonstrated marked increases in absolute GSH level in both gray matter (0.12 to 1.40 and 0.10 to 0.70 international unit [IU]) and white matter (0.65 to 1.50 and 0.80 to 2.00 IU), as well as 50% improvements in seizure duration and frequency. Other metabolites including ketone bodies did not demonstrate consistent changes.
Conclusions: Markedly increased levels of GSH (7-fold and 14-fold) were observed in longitudinal prospective study of two adult patients with intractable epilepsy with 50% seizure improvement after initiation of ketogenic diets. This pilot study supports the possible anticonvulsant role of GSH in the brain.

Keywords:  1H MRS; Epilepsy; GSH; Glutathione; Ketogenic diet; MR spectroscopy

DOI:  https://doi.org/10.14581/jer.23001
JCI Insight. 2023 Sep 21. pii: e163022. [Epub ahead of print]

Cancer-associated fibroblasts reuse cancer-derived lactate to maintain a fibrotic and immunosuppressive microenvironment in pancreatic cancer.

Fumimasa Kitamura, Takashi Semba, Noriko Yasuda-Yoshihara, Kosuke Yamada, Akiho Nishimura, Juntaro Yamasaki, Osamu Nagano, Tadahito Yasuda, Atsuko Yonemura, Yilin Tong, Huaitao Wang, Takahiko Akiyama, Kazuki Matsumura, Norio Uemura, Rumi Itoyama, Luke Bu, Lingfeng Fu, Xichen Hu, Feng Wei, Kosuke Mima, Katsunori Imai, Hiromitsu Hayashi, Yo-Ichi Yamashita, Yuji Miyamoto, Hideo Baba, Takatsugu Ishimoto.

  Glycolysis is highly enhanced in Pancreatic ductal adenocarcinoma (PDAC) cells; thus, glucose restrictions are imposed on nontumor cells in the PDAC tumor microenvironment (TME). However, little is known about how such glucose competition alters metabolism and confers phenotypic changes in stromal cells in the TME. Here, we report that cancer-associated fibroblasts (CAFs) with restricted glucose availability utilize lactate from glycolysis-enhanced cancer cells as a fuel and exert immunosuppressive activity in the PDAC TME. The expression of lactate dehydrogenase A (LDHA), which regulates lactate production, was a poor prognostic factor for PDAC patients, and LDHA depletion suppressed tumor growth in a CAF-rich murine PDAC model. Coculture of CAFs with PDAC cells revealed that most of the glucose was taken up by the tumor cells and that CAFs consumed lactate via monocarboxylate transporter 1 to enhance proliferation through the TCA cycle. Moreover, lactate-stimulated CAFs upregulated IL6 expression and suppressed cytotoxic immune cell activity synergistically with lactate. Finally, the LDHA inhibitor FX11 reduced tumor growth and improved antitumor immunity in CAF-rich PDAC tumors. Our study provides new insights into crosstalk among tumor cells, CAFs, and immune cells mediated by lactate and offers therapeutic strategies for targeting LDHA enzymatic activity in PDAC cells.

Keywords:  Cancer; Metabolism; Oncology

DOI:  https://doi.org/10.1172/jci.insight.163022
J Biochem Mol Toxicol. 2023 Sep 17. e23487

Stem cell factor modulates HIF-1α levels and diminishes 5-FU sensitivity in 5-FU resistant pancreatic cells by altering the anabolic glucose metabolism.

Fu Xiang, Fuwen Luo.

  Resistance to chemotherapy in cancer leads to poor therapeutic outcomes and also leads to challenges in treatment. The present work evaluated the mechanism involved in the resistance of 5-flurouracil (5-FU) in pancreatic cancer. At least 14 different pancreatic cancer (PC) cell lines were used for the study. For in vivo study female nude mice were selected. Patient-derived tumor xenograft samples were obtained from patients. The study involved, study for glucose uptake, fluorescence-activated cell sorting for glucose transporter, 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide for cell survival, Picto-micrography for clonogenic assay, glutamine uptake assay, extracellular acidification and oxygen consumption rate, carbon dioxide release assay and lactate assay were also done. In addition to this, quantitative real-time polymerase chain reaction analysis for expression of genes, chromatin immunoprecipitation assay, western blot for protein expression, and immunohistochemical analysis in tumor sections, the tumors were studied by imaging for hypoxia and localization of TKT and CTPS-2. Also, patient-derived xenograft tumors were engrafted in nude mice, followed by a glucose uptake assay. We reported that elevated glycolytic flux causes dependence on glucose in cancer cells and, at the same time, increases pyrimidine biosynthesis. It was also found that stem cell factor-mediated stabilization of hypoxia-inducible factor-1a (HIF-1α) modulates the resistance in PC. Targeting HIF-1α in combination with 5-FU, strongly reduced the tumor burden. The study concludes that stem cell factor modulates HIF-1α and decreases the sensitivity in 5-FU resistant pancreatic cancer cells by targeting glucose metabolism. Deceased expression levels of CTPS-2 and TKT, which are regulators of pyrimidine biosynthesis could better the chance of survival in patients of pancreatic cancer receiving treatment of 5-FU.

Keywords:  CTPS1; HIF-1α; TKT; pancreatic cancer

DOI:  https://doi.org/10.1002/jbt.23487