scholarly journals DDRE-25. INVESTIGATING MITOCHONDRIAL SLC25A TRANSPORTERS INVOLVED IN SUPPORTING BRAIN TUMOUR METABOLISM AND SURVIVAL UNDER HYPOXIC CONDITIONS

2020 ◽  
Vol 3 (Supplement_1) ◽  
pp. i11-i12
Author(s):  
Katherine Eales ◽  
Alina Finch ◽  
Victoria Wykes ◽  
Colin Watts ◽  
Daniel Tennant
Keyword(s):  
Brain Tumour ◽  
Glioma Cell ◽  
Cell Metabolism ◽  
Treatment Resistance ◽  
Tumour Microenvironment ◽  
Adult Brain ◽  
Metabolic Adaptation ◽  
Adaptation To Hypoxia ◽  
Tumour Metabolism ◽  
Hypoxic Conditions

Abstract Advancements in prevention, detection and treatment over the last 40 years have significantly transformed cancer healthcare however there are a few cancers, such as brain tumours, which are consistently lagging behind. The most common adult brain tumour is glioma; a highly aggressive cancer that invades deep into the surrounding brain consequently making treatment challenging. The severe hypoxic nature of glioma adds further complications to therapeutic efficacy as hypoxia limits efficient drug delivery as well as increasing treatment resistance. Therapies that therefore target both the hypoxic tumour microenvironment and metabolic pathways that sustain growth have significant potential to improve patient prognosis. It is well known that cancer cells demonstrate an abnormal metabolism, resulting in an altered requirement for amino acids to aid uncontrolled proliferation. Furthermore, tumour metabolism can also be influenced by this hostile hypoxic microenvironment, leading to a more malignant phenotype. We are therefore interested in a family of mitochondrial transporters, SLC25A, which translocate numerous solutes across the mitochondrial membrane and are crucial for many metabolic reactions. TCGA analysis has shown that many of these amino acid carriers are upregulated in glioma. Remarkably however, around 23 of the 53 mammalian SLC25A members lack defined substrate selectivity and so we are interested in identifying which transporters are particularly important in the metabolic adaptation to hypoxia. Using CRISPR and siRNA technologies we have identified transporters that are functionally required to maintain cell proliferation of glioma cell lines and patient tumour cells. Furthermore, using stable isotope-enriched nutrients, we have identified novel means by which glioma cell metabolism can be perturbed by inhibition of these transporters. Characterising which SLC25A transporters are important for hypoxic tumour metabolism could therefore expose a way to exploit these hypoxic areas subsequently making them more vulnerable to treatment and thus impacting patient survival.

scholarly journals Targeting Metabolism in Cancer Cells and the Tumour Microenvironment for Cancer Therapy

Molecules ◽  
2020 ◽  
Vol 25 (20) ◽  
pp. 4831
Author(s):  
Jiaqi Li ◽  
Jie Qing Eu ◽  
Li Ren Kong ◽  
Lingzhi Wang ◽  
Yaw Chyn Lim ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Immune Cells ◽  
Therapeutic Strategy ◽  
Treatment Resistance ◽  
Tumour Microenvironment ◽  
Therapeutic Strategies ◽  
Metabolic Reprogramming ◽  
Cancer Associated Fibroblasts ◽  
Tumour Metabolism

Targeting altered tumour metabolism is an emerging therapeutic strategy for cancer treatment. The metabolic reprogramming that accompanies the development of malignancy creates targetable differences between cancer cells and normal cells, which may be exploited for therapy. There is also emerging evidence regarding the role of stromal components, creating an intricate metabolic network consisting of cancer cells, cancer-associated fibroblasts, endothelial cells, immune cells, and cancer stem cells. This metabolic rewiring and crosstalk with the tumour microenvironment play a key role in cell proliferation, metastasis, and the development of treatment resistance. In this review, we will discuss therapeutic opportunities, which arise from dysregulated metabolism and metabolic crosstalk, highlighting strategies that may aid in the precision targeting of altered tumour metabolism with a focus on combinatorial therapeutic strategies.

scholarly journals Targeting obesity-related dysfunction in hormonally driven cancers

2021 ◽  
Author(s):  
Maria M. Rubinstein ◽  
Kristy A. Brown ◽  
Neil M. Iyengar
Keyword(s):  
Cell Signalling ◽  
Treatment Resistance ◽  
Tumour Microenvironment ◽  
Subsequent Increase ◽  
Treatment And Prevention ◽  
Cancer Pathogenesis ◽  
Diet And Exercise ◽  
Systemic Factors ◽  
Tumour Vascularity ◽  
Obesity And Cancer

AbstractObesity is a risk factor for at least 13 different types of cancer, many of which are hormonally driven, and is associated with increased cancer incidence and morbidity. Adult obesity rates are steadily increasing and a subsequent increase in cancer burden is anticipated. Obesity-related dysfunction can contribute to cancer pathogenesis and treatment resistance through various mechanisms, including those mediated by insulin, leptin, adipokine, and aromatase signalling pathways, particularly in women. Furthermore, adiposity-related changes can influence tumour vascularity and inflammation in the tumour microenvironment, which can support tumour development and growth. Trials investigating non-pharmacological approaches to target the mechanisms driving obesity-mediated cancer pathogenesis are emerging and are necessary to better appreciate the interplay between malignancy, adiposity, diet and exercise. Diet, exercise and bariatric surgery are potential strategies to reverse the cancer-promoting effects of obesity; trials of these interventions should be conducted in a scientifically rigorous manner with dose escalation and appropriate selection of tumour phenotypes and have cancer-related clinical and mechanistic endpoints. We are only beginning to understand the mechanisms by which obesity effects cell signalling and systemic factors that contribute to oncogenesis. As the rates of obesity and cancer increase, we must promote the development of non-pharmacological lifestyle trials for the treatment and prevention of malignancy.

scholarly journals The metabolic adaptation mechanism of metastatic organotropism

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Chao Wang ◽  
Daya Luo
Keyword(s):  
Cancer Cells ◽  
Cancer Cell ◽  
Cancer Progression ◽  
Cancer Metabolism ◽  
Cancer Metastasis ◽  
Tumour Microenvironment ◽  
Metabolic Adaptation ◽  
Adaptation Mechanism ◽  
Metastatic Sites ◽  
The Impact

AbstractMetastasis is a complex multistep cascade of cancer cell extravasation and invasion, in which metabolism plays an important role. Recently, a metabolic adaptation mechanism of cancer metastasis has been proposed as an emerging model of the interaction between cancer cells and the host microenvironment, revealing a deep and extensive relationship between cancer metabolism and cancer metastasis. However, research on how the host microenvironment affects cancer metabolism is mostly limited to the impact of the local tumour microenvironment at the primary site. There are few studies on how differences between the primary and secondary microenvironments promote metabolic changes during cancer progression or how secondary microenvironments affect cancer cell metastasis preference. Hence, we discuss how cancer cells adapt to and colonize in the metabolic microenvironments of different metastatic sites to establish a metastatic organotropism phenotype. The mechanism is expected to accelerate the research of cancer metabolism in the secondary microenvironment, and provides theoretical support for the generation of innovative therapeutic targets for clinical metastatic diseases.

scholarly journals Temporal Quantitative Proteomics Analysis of Neuroblastoma Cells Treated with Bovine Milk-Derived Extracellular Vesicles Highlights the Anti-Proliferative Properties of Milk-Derived Extracellular Vesicles

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 750
Author(s):  
Pamali Fonseka ◽  
Taeyoung Kang ◽  
Sing Chee ◽  
Sai V. Chitti ◽  
Rahul Sanwlani ◽  
...  
Keyword(s):  
High Risk ◽  
Extracellular Vesicles ◽  
Quantitative Proteomics ◽  
Cell Metabolism ◽  
Bovine Milk ◽  
Neuroblastoma Cells ◽  
Treatment Strategies ◽  
Treatment Resistance ◽  
Label Free ◽  
The Impact

Neuroblastoma (NBL) is a pediatric cancer that accounts for 15% of childhood cancer mortality. Amplification of the oncogene N-Myc occurs in 20% of NBL patients and is considered high risk as it correlates with aggressiveness, treatment resistance and poor prognosis. Even though the treatment strategies have improved in the recent years, the survival rate of high-risk NBL patients remain poor. Hence, it is crucial to explore new therapeutic avenues to sensitise NBL. Recently, bovine milk-derived extracellular vesicles (MEVs) have been proposed to contain anti-cancer properties. However, the impact of MEVs on NBL cells is not understood. In this study, we characterised MEVs using Western blotting, NTA and TEM. Importantly, treatment of NBL cells with MEVs decreased the proliferation and increased the sensitivity of NBL cells to doxorubicin. Temporal label-free quantitative proteomics of NBL cells highlighted the depletion of proteins involved in cell metabolism, cell growth and Wnt signalling upon treatment with MEVs. Furthermore, proteins implicated in cellular senescence and apoptosis were enriched in NBL cells treated with MEVs. For the first time, this study highlights the temporal proteomic profile that occurs in cancer cells upon MEVs treatment.

scholarly journals Comparison of Serum HIF-1α Levels in Swimming Athletes Before and After Hypoxic Non-Hypoxic Exercise

2020 ◽  
Vol 21 (1) ◽  
pp. 36-39
Author(s):  
Syahrastani Syahrastani ◽  
Argantos Argantos ◽  
Siska Alicia Farma
Keyword(s):  
Aerobic Exercise ◽  
The Body ◽  
Anaerobic Exercise ◽  
Adaptation To Hypoxia ◽  
Cross Sectional ◽  
Hypoxic Conditions ◽  
Before And After ◽  
Cross Sectional Design ◽  
Age Range ◽  
Hypoxic Exercise

The situation of lack of oxygen supply to cells and tissues is often not realized by many people (hypoxia). Hypoxia can occur in various situations in life. The main effect of hypoxia is the effect on the brain, so the body will do everything it can to restore the state of homeostasis. HIF-1α protein is a marker of hypoxic conditions. HIF-1α regulates the synthesis of many genes to maintain and restore body homeostasis from hypoxia to normoxia. This study was a descriptive study with cross-sectional design. The sample of this study were six swimming athletes with a 12-19 year age range who met the inclusion and exclusion criteria. The HIF-1α protein is measured by the ELISA method. Data were analyzed statistically. The results showed higher levels of HIF-1α after anaerobic exercise than the levels of HIF-1α before and after aerobic exercise. This is greatly influenced by the intensity of the exercise carried out. This proves that cellular adaptation to hypoxia is more stable in aerobic exercise, where the body's metabolism during aerobic exercise is more stable  

scholarly journals The Factor Inhibiting HIF Asparaginyl Hydroxylase Regulates Oxidative Metabolism and Accelerates Metabolic Adaptation to Hypoxia

2018 ◽  
Vol 27 (4) ◽  
pp. 898-913.e7 ◽  
Author(s):  
Jingwei Sim ◽  
Andrew S. Cowburn ◽  
Asis Palazon ◽  
Basetti Madhu ◽  
Petros A. Tyrakis ◽  
...  
Keyword(s):  
Oxidative Metabolism ◽  
Metabolic Adaptation ◽  
Adaptation To Hypoxia ◽  
Asparaginyl Hydroxylase

Reduced Susceptibility of Roots of Safflower to Phytophthora cryptogea After Prior Adaptation of Roots to Hypoxic Conditions

1994 ◽  
Vol 42 (1) ◽  
pp. 29 ◽  
Author(s):  
BJ Atwell ◽  
AD Heritage
Keyword(s):  
Carthamus Tinctorius ◽  
Solution Culture ◽  
Adaptation To Hypoxia ◽  
Aerenchyma Formation ◽  
Phytophthora Cryptogea ◽  
Hypoxic Conditions ◽  
Profound Influence ◽  
Root Aerenchyma ◽  
Phytoalexin Synthesis ◽  
Prior Adaptation

Safflower (Carthamus tinctorius L. cv. Gila) was grown in solution culture; the roots were inoculated with zoospores of Phytophthora cryptogea 28 d after sowing. The period for which roots were subjected to hypoxia prior to inoculation (5%(v/v) O2 in the gas stream) had a profound influence on the degree of hyphal damage to roots 8 d after inoculation. Roots exposed to hypoxia for 7 d prior to inoculation were not more than 20% necrotic 8 d after inoculation and the shoots were fully hydrated, presumably through sustained water transport by the root. Plants which were exposed to hypoxia for just 1 d after inoculation, on the other hand, developed almost total necrosis of the root system and the shoots wilted severely subsequent to infection. We propose that while short periods of hypoxia pre-dispose safflower roots to hyphal infection, a longer period of adaptation to hypoxia reverses this susceptibility. The mechanism for this protective effect, while not known, could reside in root aerenchyma formation, phytoalexin synthesis, or other metabolic and ultrastructual changes characteristic of roots exposed to low O2 conditions.

scholarly journals TMIC-15. HYPERACTIVATING THE HIPPO PATHWAY EFFECTOR TAZ DIFFERENTIALLY DISTORTS THE TUMOR MICROENVIRONMENT, PROMOTES TUMOR-ASSOCIATED NEUTROPHIL INFILTRATION, AND PHENOCOPIES MESENCHYMAL-GLIOBLASTOMA

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi250-vi250
Author(s):  
Patricia Yee ◽  
Yiju Wei ◽  
Zhijun Liu ◽  
Hui Guo ◽  
Umeshkumar Manjibhai Vekariya ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Progression ◽  
Myeloid Cells ◽  
Treatment Resistance ◽  
Neutrophil Infiltration ◽  
Adult Brain ◽  
Tumor Evolution ◽  
Binding Motif ◽  
Mesenchymal Transition ◽  
The Impact

Abstract Glioblastoma (GBM), the deadliest and most common adult brain malignancy, is molecularly and clinically heterogeneous. The most common subtype (both primary and recurrent), mesenchymal (MES)-GBM, has the worst prognosis and highest treatment resistance. MES-GBM exhibits hyperactive transcriptional coactivator with PDZ-binding motif (TAZ), a Hippo tumor suppressive pathway effector whose expression in GBMs predicts short survival. Yet, how Hippo-TAZ dysregulation might drive GBM MES transition remains elusive, precluding subtype-specific treatments. Tumor evolution requires signaling dysregulation and co-opting the tumor microenvironment (TME). Understanding GBM heterogeneity was recently complicated by the notion that subtypes vary in TME immune composition. The MES-GBM TME is differentially-distorted in silico, with more tumor-associated macrophages/microglia (TAMs) and neutrophils (TANs). Yet, how TAZ hyperactivity, MES transition, and GBM TME distortion interrelate and impact tumor progression remains unknown. We suspected that TME distortion facilitates immune evasion, MES transition, and tumor progression, worsening treatment responses. To test this, we devised an orthotopic xenograft mouse model phenotypically and histopathologically recapitulating human MES-GBM by expressing constitutively-active TAZ (TAZ4SA) in human GBM cells lacking MES signatures (GBM4SA). GBM4SA mice lived significantly shorter compared to mice with GBM expressing vector (GBMvector) or mutant TAZ unable to bind its effector, TEAD (GBM4SA-S51A). Moreover, more myeloid cells infiltrate the GBM4SA TME than the GBMvector or GBM4SA-S51A TMEs. While most myeloid cells infiltrating the GBMvector and GBM4SA-S51A TMEs were TAMs, most infiltrating the GBM4SA TME were TANs, suggesting TAZ hyperactivation differentially distorts the TME. Next, to delineate the roles of TANs in GBM4SA tumor progression, mice were depleted of neutrophils by administering Ly6G antibody. Serial blood smears and flow cytometry revealed effective depletion was achieved. We are currently investigating the impact of systemic neutrophil depletion on GBM mesenchymal transition and tumor progression in hopes of informing future GBM clinical management and novel TME-targeted immunotherapies.

scholarly journals Energy Metabolism in Cancer: The Roles of STAT3 and STAT5 in the Regulation of Metabolism-Related Genes

Cancers ◽  
2020 ◽  
Vol 12 (1) ◽  
pp. 124 ◽  
Author(s):  
Arturo Valle-Mendiola ◽  
Isabel Soto-Cruz
Keyword(s):  
Energy Metabolism ◽  
Transcriptional Activation ◽  
Oxidative Metabolism ◽  
Cell Metabolism ◽  
Tumour Microenvironment ◽  
Mitochondrial Activity ◽  
Growth And Survival ◽  
Stat Proteins ◽  
Metabolism Regulation ◽  
Central Characteristic

A central characteristic of many types of cancer is altered energy metabolism processes such as enhanced glucose uptake and glycolysis and decreased oxidative metabolism. The regulation of energy metabolism is an elaborate process involving regulatory proteins such as HIF (pro-metastatic protein), which reduces oxidative metabolism, and some other proteins such as tumour suppressors that promote oxidative phosphorylation. In recent years, it has been demonstrated that signal transducer and activator of transcription (STAT) proteins play a pivotal role in metabolism regulation. STAT3 and STAT5 are essential regulators of cytokine- or growth factor-induced cell survival and proliferation, as well as the crosstalk between STAT signalling and oxidative metabolism. Several reports suggest that the constitutive activation of STAT proteins promotes glycolysis through the transcriptional activation of hypoxia-inducible factors and therefore, the alteration of mitochondrial activity. It seems that STAT proteins function as an integrative centre for different growth and survival signals for energy and respiratory metabolism. This review summarises the functions of STAT3 and STAT5 in the regulation of some metabolism-related genes and the importance of oxygen in the tumour microenvironment to regulate cell metabolism, particularly in the metabolic pathways that are involved in energy production in cancer cells.

Sign in / Sign up

Export Citation Format

Share Document