bims-almceb Biomed News
on Acute Leukemia Metabolism and Cell Biology
Issue of 2023–01–01
fourteen papers selected by
Camila Kehl Dias, Federal University of Rio Grande do Sul
  1. Effects of metabolic cancer therapy on tumor microenvironment.
  2. Ultrasensitive Small-Molecule Fluorescent Thermometer Reveals Hot Mitochondria in Surgically Resected Human Tumors.
  3. How does density of the inner mitochondrial membrane influence mitochondrial performance?
  4. The prospect of tumor microenvironment-modulating therapeutical strategies.
  5. Editorial: Microbiota and metabolites in cancer immunotherapy.
  6. Relapsed Childhood Acute Myeloid Leukemia: Experience from a Single Tertiary Center in Thailand.
  7. Bypassing anti-PD-(L)1 therapy: Mechanisms and management strategies.
  8. Targeting T-cell metabolism to boost immune checkpoint inhibitor therapy.
  9. Proteogenomic analysis of acute myeloid leukemia associates relapsed disease with reprogrammed energy metabolism both in adults and children.
  10. Decoding the coupled decision-making of the epithelial-mesenchymal transition and metabolic reprogramming in cancer.
  11. Long-term retrospective study of retinoic acid combined with arsenic and chemotherapy for acute promyelocytic leukemia.
  12. Mitochondria and peroxisomes: partners in autophagy.
  13. Importance of lactate dehydrogenase (LDH) and monocarboxylate transporters (MCTs) in cancer cells.
  14. Role of CD36 in cancer progression, stemness, and targeting.
  1. Front Oncol. 2022 ;12 1046630
    Effects of metabolic cancer therapy on tumor microenvironment.
    Petra Hyroššová, Mirko Milošević, Josef Škoda, Jiří Vachtenheim, Jakub Rohlena, Kateřina Rohlenová.
      Targeting tumor metabolism for cancer therapy is an old strategy. In fact, historically the first effective cancer therapeutics were directed at nucleotide metabolism. The spectrum of metabolic drugs considered in cancer increases rapidly - clinical trials are in progress for agents directed at glycolysis, oxidative phosphorylation, glutaminolysis and several others. These pathways are essential for cancer cell proliferation and redox homeostasis, but are also required, to various degrees, in other cell types present in the tumor microenvironment, including immune cells, endothelial cells and fibroblasts. How metabolism-targeted treatments impact these tumor-associated cell types is not fully understood, even though their response may co-determine the overall effectivity of therapy. Indeed, the metabolic dependencies of stromal cells have been overlooked for a long time. Therefore, it is important that metabolic therapy is considered in the context of tumor microenvironment, as understanding the metabolic vulnerabilities of both cancer and stromal cells can guide new treatment concepts and help better understand treatment resistance. In this review we discuss recent findings covering the impact of metabolic interventions on cellular components of the tumor microenvironment and their implications for metabolic cancer therapy.
    Keywords:  cancer; endothelial cells; fatty acid metabolism; glycolysis; metabolism; nucleotide metabolism; oxidative phoshorylation; tumor micro environment (TME)
    DOI:  https://doi.org/10.3389/fonc.2022.1046630
  2. ACS Sens. 2022 Dec 27.
    Ultrasensitive Small-Molecule Fluorescent Thermometer Reveals Hot Mitochondria in Surgically Resected Human Tumors.
    Qing Zhu, Yue Sun, Manlin Fu, Mianli Bian, Xiaomei Zhu, Kai Wang, Haoxing Geng, Wei Zeng, Wei Shen, Yi Hu.
      The Warburg effect suggests that upregulated glycolysis arising from high glucose uptake in cancer cells might be accompanied with suppressed mitochondrial respiration. However, recent studies have shown that the mitochondrial temperature in cancer cells could be relatively higher than that in normal cells, suggesting hyperactive mitochondrial respiration in cancer cells. However, hot mitochondria have not been reported in patients with cancer. Here, near-infrared small-molecule fluorescent probes TRNs are rationally designed with two ethyl amino groups as the temperature-sensitive moiety. Afterward, a mitochondrial targeting group is installed via ether bonds on TRN-8 to build MTN. To the best of our knowledge, MTN is the near-infrared probe with the highest sensitivity for mitochondrial temperature. Moreover, it also displays high photostability, wide linearity, and high specificity. Using MTN, we can monitor the ups and downs of mitochondrial temperature in cancer cells upon the perturbations of mitochondrial respiration. Furthermore, we demonstrate that the mitochondrial temperature in surgically resected human tumors is relatively higher than that in paracancerous tissues. Our results indicate that relatively hot mitochondria may exist in tumors from patients. We envisage that our study provides critical evidence for revisiting the Warburg effect and cancer metabolism.
    Keywords:  NIR; diethyl amino group; mitochondria; temperature-sensitive probe; tumor
    DOI:  https://doi.org/10.1021/acssensors.2c01563
  3. Am J Physiol Regul Integr Comp Physiol. 2022 Dec 26.
    How does density of the inner mitochondrial membrane influence mitochondrial performance?
    Kyle B Heine, Hailey A Parry, Wendy R Hood.
      Our current understanding of variation in mitochondrial performance is incomplete. The production of ATP via oxidative phosphorylation is dependent, in part, upon the structure of the inner mitochondrial membrane. Morphology of the inner membrane is crucial for the formation of the proton gradient across the inner membrane and, therefore, ATP synthesis. The inner mitochondrial membrane is dynamic, changing shape and surface area. These changes alter density (amount per volume) of the inner mitochondrial membrane within the confined space of the mitochondrion. Because the number of electron transport system proteins within the inner mitochondrial membrane changes with inner mitochondrial membrane area, a change in the amount of inner membrane alters the capacity for ATP production within the organelle. This review outlines the evidence that the association between ATP synthases, inner mitochondrial membrane density, and mitochondrial density (number of mitochondria per cell), impact ATP production by mitochondria. Further, we consider possible constraints on the capacity of mitochondria to produce ATP by increasing inner mitochondrial membrane density.
    Keywords:  ATP synthase; cristae; inter-membrane space; matrix; oxidative phosphorylation
    DOI:  https://doi.org/10.1152/ajpregu.00254.2022
  4. Front Oncol. 2022 ;12 1070243
    The prospect of tumor microenvironment-modulating therapeutical strategies.
    Dirk Eulberg, Anna Frömming, Kfir Lapid, Aram Mangasarian, Avital Barak.
      Multiple mechanisms promote tumor prosperity, which does not only depend on cell-autonomous, inherent abnormal characteristics of the malignant cells that facilitate rapid cell division and tumor expansion. The neoplastic tissue is embedded in a supportive and dynamic tumor microenvironment (TME) that nurtures and protects the malignant cells, maintaining and perpetuating malignant cell expansion. The TME consists of different elements, such as atypical vasculature, various innate and adaptive immune cells with immunosuppressive or pro-inflammatory properties, altered extracellular matrix (ECM), activated stromal cells, and a wide range of secreted/stroma-tethered bioactive molecules that contribute to malignancy, directly or indirectly. In this review, we describe the various TME components and provide examples of anti-cancer therapies and novel drugs under development that aim to target these components rather than the intrinsic processes within the malignant cells. Combinatory TME-modulating therapeutic strategies may be required to overcome the resistance to current treatment options and prevent tumor recurrence.
    Keywords:  angiogenesis; cancer immunology; chemokines; cytokines; precision oncology; tumor microenvironment; vasculogenesis
    DOI:  https://doi.org/10.3389/fonc.2022.1070243
  5. Front Oncol. 2022 ;12 1093941
    Editorial: Microbiota and metabolites in cancer immunotherapy.
    Giandomenico Roviello, Martina Catalano.
      
    Keywords:  cytotoxic T-lymphocyte antigen (CTLA-4); gut microbiota; immune checkpoint inhibitors; immunotherapy; programmed death/ligand-1
    DOI:  https://doi.org/10.3389/fonc.2022.1093941
  6. Asian Pac J Cancer Prev. 2022 Dec 01. pii: 90398. [Epub ahead of print]23(12): 4079-4084
    Relapsed Childhood Acute Myeloid Leukemia: Experience from a Single Tertiary Center in Thailand.
    Natsaruth Songthawee, Pornpun Sripornsawan, Shevachut Chavananon, Edward B McNeil, Thirachit Chotsampancharoen.
       BACKGROUND: Few studies have examined survival outcomes in relapsed childhood acute myeloid leukemia (AML) in resource-limited countries. This study aimed to evaluate the prognostic factors and survival outcomes of relapsed childhood AML in Thailand.
    METHODS: The medical records of AML patients aged 0-15 years treated in a major tertiary center in Southern Thailand between December 1979 and December 2019 were reviewed retrospectively. The overall survival (OS) was calculated using the Kaplan-Meier method.
    RESULTS: A total of 316 AML patients were included and relapse occurred in 98 (31%) patients. Of these, 57 (58.2%) and 41 (41.8%) patients had early [≤1 year from first complete remission (CR1)] and late (>1 year from CR1) relapses, respectively. Only 54 (55.1%) patients received chemotherapy after relapse. The 3-year OS of all relapsed patients was 3.5%. The 3-year OS of patients with early and late relapse were 0% and 8.5%, respectively (p=0.002). The 3-year OS of patients who received chemotherapy and those who did not were 6.5% and 0%, respectively (p <0.0001). The median survival time of patients who did not receive chemotherapy was 1.7 months. The 3-year OS of patients who achieved second complete remission (CR2) and those who did not were 12.6% and 0%, respectively (p <0.001).
    CONCLUSION: The relapsed AML rate was 31% and the survival outcome was poor with a 3-year OS of 3.5%. The adverse prognostic factors were early relapse, failure to achieve CR2 and those who did not receive chemotherapy after relapse.
    Keywords:  relapsed childhood acute myeloid leukemia; resource-limited countries; survival outcome
    DOI:  https://doi.org/10.31557/APJCP.2022.23.12.4079
  7. Biomed Pharmacother. 2022 Dec 26. pii: S0753-3322(22)01539-6. [Epub ahead of print]158 114150
    Bypassing anti-PD-(L)1 therapy: Mechanisms and management strategies.
    Keywan Mortezaee, Jamal Majidpoor, Sajad Najafi, Davood Tasa.
      Resistance to immune checkpoint inhibitors (ICIs) is a major issue of the current era in cancer immunotherapy. Immune evasion is a multi-factorial event, which occurs generally at a base of cold immunity. Despite advances in the field, there are still unsolved challenges about how to combat checkpoint hijacked by tumor cells and what are complementary treatment strategies to render durable anti-tumor outcomes. A point is that anti-programed death-1 receptor (PD-1)/anti-programmed death-ligand 1 (PD-L1) is not the solo path of immune escape, and responses in many types of solid tumors to the PD-1/PD-L1 inhibitors are not satisfactory. Thus, seeking mechanisms inter-connecting tumor with its immune ecosystem nearby unravel more about resistance mechanisms so as to develop methods for sustained reinvigoration of immune activity against cancer. In this review, we aimed to discuss about common and specific paths taken by tumor cells to evade immune surveillance, describing novel detection strategies, as well as suggesting some approaches to recover tumor sensitivity to the anti-PD-(L)1 therapy based on the current knowledge.
    Keywords:  CD8(+) T cell; Immune checkpoint inhibitor (ICI); Major histocompatibility complex class I (MHC-I); Programed death-1 receptor (PD-1); Programmed death-ligand 1 (PD-L1); Resistance; Transforming growth factor (TGF)
    DOI:  https://doi.org/10.1016/j.biopha.2022.114150
  8. Front Immunol. 2022 ;13 1046755
    Targeting T-cell metabolism to boost immune checkpoint inhibitor therapy.
    Haohao Li, Alison Zhao, Menghua Li, Lizhi Shi, Qiuju Han, Zhaohua Hou.
      Immune checkpoint inhibitors (ICIs) have shown promising therapeutic effects in the treatment of advanced solid cancers, but their overall response rate is still very low for certain tumor subtypes, limiting their clinical scope. Moreover, the high incidence of drug resistance (including primary and acquired) and adverse effects pose significant challenges to the utilization of these therapies in the clinic. ICIs enhance T cell activation and reverse T cell exhaustion, which is a complex and multifactorial process suggesting that the regulatory mechanisms of ICI therapy are highly heterogeneous. Recently, metabolic reprogramming has emerged as a novel means of reversing T-cell exhaustion in the tumor microenvironment; there is increasing evidence that T cell metabolic disruption limits the therapeutic effect of ICIs. This review focuses on the crosstalk between T-cell metabolic reprogramming and ICI therapeutic efficacy, and summarizes recent strategies to improve drug tolerance and enhance anti-tumor effects by targeting T-cell metabolism alongside ICI therapy. The identification of potential targets for altering T-cell metabolism can significantly contribute to the development of methods to predict therapeutic responsiveness in patients receiving ICI therapy, which are currently unknown but would be of great clinical significance.
    Keywords:  T cell metabolism; immune checkpoint; immune checkpoints inhibitor; metabolic reprogramming; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2022.1046755
  9. Leukemia. 2022 Dec 26.
    Proteogenomic analysis of acute myeloid leukemia associates relapsed disease with reprogrammed energy metabolism both in adults and children.
    Svea Stratmann, Mattias Vesterlund, Husen M Umer, Saeed Eshtad, Aron Skaftason, Morten Krogh Herlin, Christer Sundström, Anna Eriksson, Martin Höglund, Josefine Palle, Jonas Abrahamsson, Kirsi Jahnukainen, Monica Cheng Munthe-Kaas, Bernward Zeller, Katja Pokrovskaja Tamm, Cecilia Lindskog, Lucia Cavelier, Janne Lehtiö, Linda Holmfeldt.
      Despite improvement of current treatment strategies and novel targeted drugs, relapse and treatment resistance largely determine the outcome for acute myeloid leukemia (AML) patients. To identify the underlying molecular characteristics, numerous studies have been aimed to decipher the genomic- and transcriptomic landscape of AML. Nevertheless, further molecular changes allowing malignant cells to escape treatment remain to be elucidated. Mass spectrometry is a powerful tool enabling detailed insights into proteomic changes that could explain AML relapse and resistance. Here, we investigated AML samples from 47 adult and 22 pediatric patients at serial time-points during disease progression using mass spectrometry-based in-depth proteomics. We show that the proteomic profile at relapse is enriched for mitochondrial ribosomal proteins and subunits of the respiratory chain complex, indicative of reprogrammed energy metabolism from diagnosis to relapse. Further, higher levels of granzymes and lower levels of the anti-inflammatory protein CR1/CD35 suggest an inflammatory signature promoting disease progression. Finally, through a proteogenomic approach, we detected novel peptides, which present a promising repertoire in the search for biomarkers and tumor-specific druggable targets. Altogether, this study highlights the importance of proteomic studies in holistic approaches to improve treatment and survival of AML patients.
    DOI:  https://doi.org/10.1038/s41375-022-01796-7
  10. iScience. 2023 Jan 20. 26(1): 105719
    Decoding the coupled decision-making of the epithelial-mesenchymal transition and metabolic reprogramming in cancer.
    Madeline Galbraith, Herbert Levine, José N Onuchic, Dongya Jia.
      Cancer metastasis relies on an orchestration of traits driven by different interacting functional modules, including metabolism and epithelial-mesenchymal transition (EMT). During metastasis, cancer cells can acquire a hybrid metabolic phenotype (W/O) by increasing oxidative phosphorylation without compromising glycolysis and they can acquire a hybrid epithelial/mesenchymal (E/M) phenotype by engaging EMT. Both the W/O and E/M states are associated with high metastatic potentials, and many regulatory links coupling metabolism and EMT have been identified. Here, we investigate the coupled decision-making networks of metabolism and EMT. Their crosstalk can exhibit synergistic or antagonistic effects on the acquisition and stability of different coupled metabolism-EMT states. Strikingly, the aggressive E/M-W/O state can be enabled and stabilized by the crosstalk irrespective of these hybrid states' availability in individual metabolism or EMT modules. Our work emphasizes the mutual activation between metabolism and EMT, providing an important step toward understanding the multifaceted nature of cancer metastasis.
    Keywords:  Cancer systems biology; Metabolic flux analysis
    DOI:  https://doi.org/10.1016/j.isci.2022.105719
  11. Int J Hematol. 2022 Dec 29.
    Long-term retrospective study of retinoic acid combined with arsenic and chemotherapy for acute promyelocytic leukemia.
    Xian Zhang, Shulan Wu, Junfang Yang, Gailing Zhang, Yunchao Su, Min Zhang, Jiujiang He, Yanze Shi, Wenqian Li, Peihua Lu, Daopei Lu.
      Chemotherapy, all-trans retinoic acid (ATRA), and arsenic are effective options for acute promyelocytic leukemia (APL). We conducted a 20-year retrospective analysis of newly diagnosed (ND) APL patients treated with arsenic, ATRA and mitoxantrone. After achieving complete remission (CR), patients received 3-5 cycles of chemotherapy followed by AS4S4 maintenance for 3 years. Eighty-eight ND APL patients were treated with either oral AS4S4 (n = 42) or arsenic trioxide (ATO) (n = 46). The 8-year overall survival (OS) rate was 100% in the AS4S4 group and 90% in the ATO group. The disease-free survival (DFS) rates were 100% and 87.1% (p = 0.027), respectively. Patients in the ATO group had more side effects. A subsequent cohort of 33 ND APL patients received triple therapy with oral AS4S4, ATRA, and chemotherapy. The 13-year OS and DFS rates were 100% and 90.9%. Our long-term analyses show that APL patients with oral AS4S4 had better outcomes compared to ATO, with no need for hospitalization.
    Keywords:  AS4S4; Acute promyelocytic leukemia; All-trans retinoic acid; Arsenic trioxide; Chemotherapy
    DOI:  https://doi.org/10.1007/s12185-022-03507-5
  12. Autophagy. 2022 Dec 26. 1-2
    Mitochondria and peroxisomes: partners in autophagy.
    Léa P Wilhelm, Ian G Ganley.
      Mitochondria, often called "the powerhouse" of the cell due to their role as the main energy supplier, regulate numerous complex processes including intracellular calcium homeostasis, reactive oxygen species (ROS) production, regulation of immune responses, and apoptosis. So, mitochondria are a fundamental metabolic hub that also control cell survival and cell death. However, they are not unique in all these functions. Indeed, peroxisomes are small cytoplasmic organelles that also ensure metabolic functions such as fatty acid oxidation and ROS production. This common relationship also extends beyond function as peroxisomes themselves can form from mitochondrial-derived precursors. Given this interconnection between mitochondria and peroxisomes involving biogenesis and function, in our recent work we determined if their turnover was also linked.
    Keywords:  Autophagy; BNIP3L; NIX; mitophagy; pexophagy
    DOI:  https://doi.org/10.1080/15548627.2022.2155368
  13. Health Sci Rep. 2023 Jan;6(1): e996
    Importance of lactate dehydrogenase (LDH) and monocarboxylate transporters (MCTs) in cancer cells.
    Hamed Hatami, Atefe Sajedi, Seyed Mostafa Mir, Mohammad Yousef Memar.
       Background: In most regions, cancer ranks the second most frequent cause of death following cardiovascular disorders.
    Aim: In this article, we review the various aspects of glycolysis with a focus on types of MCTs and the importance of lactate in cancer cells.
    Results and Discussion: Metabolic changes are one of the first and most important alterations in cancer cells. Cancer cells use different pathways to survive, energy generation, growth, and proliferation compared to normal cells. The increase in glycolysis, which produces substances such as lactate and pyruvate, has an important role in metastases and invasion of cancer cells. Two important cellular proteins that play a role in the production and transport of lactate include lactate dehydrogenase and monocarboxylate transporters (MCTs). These molecules by their various isoforms and different tissue distribution help to escape the immune system and expansion of cancer cells under different conditions.
    Keywords:  cancer metabolism; lactate; monocarboxylate transporters
    DOI:  https://doi.org/10.1002/hsr2.996
  14. Front Cell Dev Biol. 2022 ;10 1079076
    Role of CD36 in cancer progression, stemness, and targeting.
    Sandra L Guerrero-Rodríguez, Cecilia Mata-Cruz, Sonia M Pérez-Tapia, Marco A Velasco-Velázquez.
      CD36 is highly expressed in diverse tumor types and its expression correlates with advanced stages, poor prognosis, and reduced survival. In cancer cells, CD36: 1) increases fatty acid uptake, reprogramming lipid metabolism; 2) favors cancer cell proliferation, and 3) promotes epithelial-mesenchymal transition. Furthermore, CD36 expression correlates with the expression of cancer stem cell markers and CD36+ cancer cells display increased stemness functional properties, including clonogenicity, chemo- and radioresistance, and metastasis-initiating capability, suggesting CD36 is a marker of the cancer stem cell population. Thus, CD36 has been pointed as a potential therapeutic target in cancer. At present, at least three different types of molecules have been developed for reducing CD36-mediated functions: blocking monoclonal antibodies, small-molecule inhibitors, and compounds that knock-down CD36 expression. Herein, we review the role of CD36 in cancer progression, its participation in stemness control, as well as the efficacy of reported CD36 inhibitors in cancer cell cultures and animal models. Overall, the evidence compiled points that CD36 is a valid target for the development of new anti-cancer therapies.
    Keywords:  CD36; cancer stem cells; drug development; metastasis; oxLDL
    DOI:  https://doi.org/10.3389/fcell.2022.1079076
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