bims-almceb 2021-10-03 papers

bims-almceb

Biomed News

on Acute Leukemia Metabolism and Cell Biology

Issue of 2021–10–03
eight papers selected by
Camila Kehl Dias, Federal University of Rio Grande do Sul

Recreating the Bone Marrow Microenvironment to Model Leukemic Stem Cell Quiescence.
Characteristics and clinical correlation of TIM-3 and PD-1/PD-L1 expressions in leukemic cells and tumor microenvironment in newly diagnosed acute myeloid leukemia.
Can the Mitochondrial Metabolic Theory Explain Better the Origin and Management of Cancer than Can the Somatic Mutation Theory?
Glucose and Amino Acid Metabolic Dependencies Linked to Stemness and Metastasis in Different Aggressive Cancer Types.
Glucocorticoid and PD-1 Cross-Talk: Does the Immune System Become Confused?
Macrophages and cancer stem cells: a malevolent alliance.
The multifaceted roles of mitochondria at the crossroads of cell life and death in cancer.
Oncogenes, Proto-Oncogenes, and Lineage Restriction of Cancer Stem Cells.

Front Cell Dev Biol. 2021 ;9 662868

Recreating the Bone Marrow Microenvironment to Model Leukemic Stem Cell Quiescence.

Eimear O'Reilly, Hojjat Alizadeh Zeinabad, Caoimhe Nolan, Jamileh Sefy, Thomas Williams, Marina Tarunina, Diana Hernandez, Yen Choo, Eva Szegezdi.

  The main challenge in the treatment of acute myeloid leukemia (AML) is relapse, as it has no good treatment options and 90% of relapsed patients die as a result. It is now well accepted that relapse is due to a persisting subset of AML cells known as leukemia-initiating cells or leukemic stem cells (LSCs). Hematopoietic stem cells (HSCs) reside in the bone marrow microenvironment (BMM), a specialized niche that coordinates HSC self-renewal, proliferation, and differentiation. HSCs are divided into two types: long-term HSCs (LT-HSCs) and short-term HSCs, where LT-HSCs are typically quiescent and act as a reserve of HSCs. Like LT-HSCs, a quiescent population of LSCs also exist. Like LT-HSCs, quiescent LSCs have low metabolic activity and receive pro-survival signals from the BMM, making them resistant to drugs, and upon discontinuation of therapy, they can become activated and re-establish the disease. Several studies have shown that the activation of quiescent LSCs may sensitize them to cytotoxic drugs. However, it is very difficult to experimentally model the quiescence-inducing BMM. Here we report that culturing AML cells with bone marrow stromal cells, transforming growth factor beta-1 and hypoxia in a three-dimensional system can replicate the quiescence-driving BMM. A quiescent-like state of the AML cells was confirmed by reduced cell proliferation, increased percentage of cells in the G0 cell cycle phase and a decrease in absolute cell numbers, expression of markers of quiescence, and reduced metabolic activity. Furthermore, the culture could be established as co-axial microbeads, enabling high-throughput screening, which has been used to identify combination drug treatments that could break BMM-mediated LSC quiescence, enabling the eradication of quiescent LSCs.

Keywords:  acute myeloid leukemia; bone marrow microenvironment; leukemic stem cell; quiescence; three-dimensional model

DOI:  https://doi.org/10.3389/fcell.2021.662868
Leuk Lymphoma. 2021 Sep 29. 1-7

Characteristics and clinical correlation of TIM-3 and PD-1/PD-L1 expressions in leukemic cells and tumor microenvironment in newly diagnosed acute myeloid leukemia.

Thunyamon Chajuwan, Patsita Kansuwan, Sirorat Kobbuaklee, Chantiya Chanswangphuwana.

  Dual targeting of TIM-3 and PD-1/PD-L1 pathways is currently under investigation for cancer immunotherapy. The interaction of these immune checkpoints remains unclear in the leukemic microenvironment of acute myeloid leukemia (AML). We performed an immunophenotypic study of bone marrow in 37 newly diagnosed AML patients. High levels of TIM-3 expression on AML blasts were correlated with first 7 + 3 induction failure (CR 16.2% vs. non-CR 36.4%, p = .038). In contrast, high TIM-3 levels on natural killer (NK) cells were associated with complete remission (CR) status after induction (CR 24.7% vs. non-CR 6.5%, p = .035). Few PD-L1 positive AML blasts and PD-1 or PD-L1 positive NK cells were observed. Although the exhausted PD-1 expressing T cells were detected in 28.3% of T cells, the double positive of PD-1 and TIM-3 T cells were rarely detected. In summary, the TIM-3 levels on AML blasts and NK cells are potentially the prognostic biomarkers in AML.

Keywords:  Acute myeloid leukemia; T cell immunoglobulin and mucin-domain containing-3; immune checkpoint; programmed cell death 1; programmed cell death ligand 1

DOI:  https://doi.org/10.1080/10428194.2021.1984454
Metabolites. 2021 Aug 25. pii: 572. [Epub ahead of print]11(9):

Can the Mitochondrial Metabolic Theory Explain Better the Origin and Management of Cancer than Can the Somatic Mutation Theory?

Thomas N Seyfried, Christos Chinopoulos.

  A theory that can best explain the facts of a phenomenon is more likely to advance knowledge than a theory that is less able to explain the facts. Cancer is generally considered a genetic disease based on the somatic mutation theory (SMT) where mutations in proto-oncogenes and tumor suppressor genes cause dysregulated cell growth. Evidence is reviewed showing that the mitochondrial metabolic theory (MMT) can better account for the hallmarks of cancer than can the SMT. Proliferating cancer cells cannot survive or grow without carbons and nitrogen for the synthesis of metabolites and ATP (Adenosine Triphosphate). Glucose carbons are essential for metabolite synthesis through the glycolysis and pentose phosphate pathways while glutamine nitrogen and carbons are essential for the synthesis of nitrogen-containing metabolites and ATP through the glutaminolysis pathway. Glutamine-dependent mitochondrial substrate level phosphorylation becomes essential for ATP synthesis in cancer cells that over-express the glycolytic pyruvate kinase M2 isoform (PKM2), that have deficient OxPhos, and that can grow in either hypoxia (0.1% oxygen) or in cyanide. The simultaneous targeting of glucose and glutamine, while elevating levels of non-fermentable ketone bodies, offers a simple and parsimonious therapeutic strategy for managing most cancers.

Keywords:  IDH1; chimpanzees; evolution; fermentation; glutaminolysis; glycolysis; ketogenic metabolic therapy; metastasis; mitochondrial substrate level phosphorylation; mutations; oncogenes; respiration

DOI:  https://doi.org/10.3390/metabo11090572
Front Pharmacol. 2021 ;12 723798

Glucose and Amino Acid Metabolic Dependencies Linked to Stemness and Metastasis in Different Aggressive Cancer Types.

Andrea Chisari, Irene Golán, Sabrina Campisano, Caroline Gélabert, Aristidis Moustakas, Patricia Sancho, Laia Caja.

  Malignant cells are commonly characterised by being capable of invading tissue, growing self-sufficiently and uncontrollably, being insensitive to apoptosis induction and controlling their environment, for example inducing angiogenesis. Amongst them, a subpopulation of cancer cells, called cancer stem cells (CSCs) shows sustained replicative potential, tumor-initiating properties and chemoresistance. These characteristics make CSCs responsible for therapy resistance, tumor relapse and growth in distant organs, causing metastatic dissemination. For these reasons, eliminating CSCs is necessary in order to achieve long-term survival of cancer patients. New insights in cancer metabolism have revealed that cellular metabolism in tumors is highly heterogeneous and that CSCs show specific metabolic traits supporting their unique functionality. Indeed, CSCs adapt differently to the deprivation of specific nutrients that represent potentially targetable vulnerabilities. This review focuses on three of the most aggressive tumor types: pancreatic ductal adenocarcinoma (PDAC), hepatocellular carcinoma (HCC) and glioblastoma (GBM). The aim is to prove whether CSCs from different tumour types share common metabolic requirements and responses to nutrient starvation, by outlining the diverse roles of glucose and amino acids within tumour cells and in the tumour microenvironment, as well as the consequences of their deprivation. Beyond their role in biosynthesis, they serve as energy sources and help maintain redox balance. In addition, glucose and amino acid derivatives contribute to immune responses linked to tumourigenesis and metastasis. Furthermore, potential metabolic liabilities are identified and discussed as targets for therapeutic intervention.

Keywords:  GBM-glioblastoma multiforme; HCC-hepatocellular carcinoma; PDAC-pancreatic ductal adenocarcinoma; amino acid; cancer stem cell (CSC); glucose; therapy

DOI:  https://doi.org/10.3389/fphar.2021.723798
Cells. 2021 Sep 06. pii: 2333. [Epub ahead of print]10(9):

Glucocorticoid and PD-1 Cross-Talk: Does the Immune System Become Confused?

Sabrina Adorisio, Lorenza Cannarile, Domenico V Delfino, Emira Ayroldi.

  Programmed cell death protein 1 (PD-1) and its ligands, PD-L1/2, control T cell activation and tolerance. While PD-1 expression is induced upon T cell receptor (TCR) activation or cytokine signaling, PD-L1 is expressed on B cells, antigen presenting cells, and on non-immune tissues, including cancer cells. Importantly, PD-L1 binding inhibits T cell activation. Therefore, the modulation of PD-1/PD-L1 expression on immune cells, both circulating or in a tumor microenvironment and/or on the tumor cell surface, is one mechanism of cancer immune evasion. Therapies that target PD-1/PD-L1, blocking the T cell-cancer cell interaction, have been successful in patients with various types of cancer. Glucocorticoids (GCs) are often administered to manage the side effects of chemo- or immuno-therapy, exerting a wide range of immunosuppressive and anti-inflammatory effects. However, GCs may also have tumor-promoting effects, interfering with therapy. In this review, we examine GC signaling and how it intersects with PD-1/PD-L1 pathways, including a discussion on the potential for GC- and PD-1/PD-L1-targeted therapies to "confuse" the immune system, leading to a cancer cell advantage that counteracts anti-cancer immunotherapy. Therefore, combination therapies should be utilized with an awareness of the potential for opposing effects on the immune system.

Keywords:  PD-1/PD-L1; cancer; glucocorticoids; immune response

DOI:  https://doi.org/10.3390/cells10092333
Mol Med. 2021 Sep 28. 27(1): 121

Macrophages and cancer stem cells: a malevolent alliance.

Paola Allavena, Elisabeth Digifico, Cristina Belgiovine.

  Myeloid cells infiltrating tumors are gaining ever growing attention in the last years because their pro-tumor and immunosuppressive functions are relevant for disease progression and therapeutic responses. The functional ambiguity of tumor-associated macrophages (TAMs), mostly promoting tumor evolution, is a challenging hurdle. This is even more evident in the case of cancer stem cells (CSCs); as active participants in the specialized environment of the cancer stem cell niche, TAMs initiate a reciprocal conversation with CSCs. TAMs contribute to protect CSCs from the hostile environment (exogenous insults, toxic compounds, attacks from the immune cells), and produce several biologically active mediators that modulate crucial developmental pathways that sustain cancer cell stemness. In this review, we have focused our attention on the interaction between TAMs and CSCs; we describe how TAMs impact on CSC biology and, in turn, how CSCs exploit the tissue trophic activity of macrophages to survive and progress. Since CSCs are responsible for therapy resistance and tumor recurrence, they are important therapeutic targets. In view of the recent success in oncology obtained by stimulating the immune system, we discuss some macrophage-targeted therapeutic strategies that may also affect the CSCs and interrupt their malevolent alliance.

Keywords:  Cancer stem cells; GPNMB; Stemness; Tumor associated macrophages

DOI:  https://doi.org/10.1186/s10020-021-00383-3
Free Radic Biol Med. 2021 Sep 28. pii: S0891-5849(21)00744-9. [Epub ahead of print]

The multifaceted roles of mitochondria at the crossroads of cell life and death in cancer.

Fabrizio Fontana, Patrizia Limonta.

  Mitochondria are the cytoplasmic organelles mostly known as the "electric engine" of the cells; however, they also play pivotal roles in different biological processes, such as cell growth/apoptosis, Ca2+ and redox homeostasis, and cell stemness. In cancer cells, mitochondria undergo peculiar functional and structural dynamics involved in the survival/death fate of the cell. Cancer cells use glycolysis to support macromolecular biosynthesis and energy production ("Warburg effect"); however, mitochondrial OXPHOS has been shown to be still active during carcinogenesis and even exacerbated in drug-resistant and stem cancer cells. This metabolic rewiring is associated with mutations in genes encoding mitochondrial metabolic enzymes ("oncometabolites"), alterations of ROS production and redox biology, and a fine-tuned balance between anti-/proapoptotic proteins. In cancer cells, mitochondria also experience dynamic alterations from the structural point of view undergoing coordinated cycles of biogenesis, fusion/fission and mitophagy, and physically communicating with the endoplasmic reticulum (ER), through the Ca2+ flux, at the MAM (mitochondria-associated membranes) levels. This review addresses the peculiar mitochondrial metabolic and structural dynamics occurring in cancer cells and their role in coordinating the balance between cell survival and death. The role of mitochondrial dynamics as effective biomarkers of tumor progression and promising targets for anticancer strategies is also discussed.

Keywords:  Cancer; MAMs; Metabolic rewiring; Mitochondria; OXPHOS; ROS; Structural dynamics

DOI:  https://doi.org/10.1016/j.freeradbiomed.2021.09.024
Int J Mol Sci. 2021 Sep 07. pii: 9667. [Epub ahead of print]22(18):

Oncogenes, Proto-Oncogenes, and Lineage Restriction of Cancer Stem Cells.

Geoffrey Brown.

  In principle, an oncogene is a cellular gene (proto-oncogene) that is dysfunctional, due to mutation and fusion with another gene or overexpression. Generally, oncogenes are viewed as deregulating cell proliferation or suppressing apoptosis in driving cancer. The cancer stem cell theory states that most, if not all, cancers are a hierarchy of cells that arises from a transformed tissue-specific stem cell. These normal counterparts generate various cell types of a tissue, which adds a new dimension to how oncogenes might lead to the anarchic behavior of cancer cells. It is that stem cells, such as hematopoietic stem cells, replenish mature cell types to meet the demands of an organism. Some oncogenes appear to deregulate this homeostatic process by restricting leukemia stem cells to a single cell lineage. This review examines whether cancer is a legacy of stem cells that lose their inherent versatility, the extent that proto-oncogenes play a role in cell lineage determination, and the role that epigenetic events play in regulating cell fate and tumorigenesis.

Keywords:  epigenetics; lineage determination; oncogenes; proto-oncogenes; stem cells

DOI:  https://doi.org/10.3390/ijms22189667