bims-stacyt Biomed News
on Metabolism and the paracrine crosstalk between cancer and the organism
Issue of 2022–04–10
nine papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge
  1. Macropinocytosis and Cancer: From Tumor Stress to Signaling Pathways.
  2. CXCL8 in Tumor Biology and Its Implications for Clinical Translation.
  3. Microbial Metabolism Activates Immune-Suppressive Tumor Macrophages.
  4. Reduction of tumor hypoxia by anti-PD-1 therapy assessed using pimonidazole and [18F]FMISO.
  5. Obesity: A Chronic Low-Grade Inflammation and Its Markers.
  6. GDF-15 in tumor-derived exosomes promotes muscle atrophy via Bcl-2/caspase-3 pathway.
  7. The Influence of Mitochondrial Energy and 1C Metabolism on the Efficacy of Anticancer Drugs - Exploring Potential Mechanisms of Resistance.
  8. Tumor-derived exosomes in hypoxic microenvironment: release mechanism, biological function and clinical application.
  9. Regulation of inflammation by VEGF/BDNF signaling in mouse retinal Müller glial cells exposed to high glucose.
  1. Subcell Biochem. 2022 ;98 15-40
    Macropinocytosis and Cancer: From Tumor Stress to Signaling Pathways.
    Guillem Lambies, Cosimo Commisso.
      Macropinocytosis is an evolutionarily conserved endocytic pathway that mediates the nonselective acquisition of extracellular material via large endocytic vesicles known as macropinosomes. In addition to other functions, this uptake pathway supports cancer cell metabolism through the uptake of nutrients. Cells harboring oncogene or tumor suppressor mutations are known to display heightened macropinocytosis, which confers to the cancer cells the ability to survive and proliferate despite the nutrient-scarce conditions of the tumor microenvironment. Thus, macropinocytosis is associated with cancer malignancy. Macropinocytic uptake can be induced in cancer cells by different stress stimuli, acting as an adaptive mechanism for the cells to resist stresses in the tumor milieu. Here, we review the cellular stresses that are known to promote macropinocytosis, as well as the underlying molecular mechanisms that drive this process.
    Keywords:  Cancer malignancy; Cell metabolism; Macropinocytosis; Nutrient scarcity; Nutrient uptake; Stress stimuli
    DOI:  https://doi.org/10.1007/978-3-030-94004-1_2
  2. Front Mol Biosci. 2022 ;9 723846
    CXCL8 in Tumor Biology and Its Implications for Clinical Translation.
    Xingyu Xiong, Xinyang Liao, Shi Qiu, Hang Xu, Shiyu Zhang, Sheng Wang, Jianzhong Ai, Lu Yang.
      The chemokine CXCL8 has been found to play an important role in tumor progression in recent years. CXCL8 activates multiple intracellular signaling pathways by binding to its receptors (CXCR1/2), and plays dual pro-tumorigenic roles in the tumor microenvironment (TME) including directly promoting tumor survival and affecting components of TME to indirectly facilitate tumor progression, which include facilitating tumor cell proliferation and epithelial-to-mesenchymal transition (EMT), pro-angiogenesis, and inhibit anti-tumor immunity. More recently, clinical trials indicate that CXCL8 can act as an independently predictive biomarker in patients receiving immune checkpoint inhibitions (ICIs) therapy. Preclinical studies also suggest that combined CXCL8 blockade and ICIs therapy can enhance the anti-tumor efficacy, and several clinical trials are being conducted to evaluate this therapy modality.
    Keywords:  CXCL8; immunotherapy; tumor immune suppression; tumor microenvironment; tumor progression
    DOI:  https://doi.org/10.3389/fmolb.2022.723846
  3. Cancer Discov. 2022 Apr 01. 12(4): 883
    Microbial Metabolism Activates Immune-Suppressive Tumor Macrophages.
      Microbial metabolites promote pancreatic tumor growth through effects on macrophage polarization.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2022-028
  4. Nucl Med Biol. 2022 Mar 24. pii: S0969-8051(22)00030-0. [Epub ahead of print]108-109 85-92
    Reduction of tumor hypoxia by anti-PD-1 therapy assessed using pimonidazole and [18F]FMISO.
    Kohei Nakajima, Mitsunori Homma, Motofumi Suzuki, Yuta Yokouchi, Takuma Matsuda, Hideo Takakura, Kenji Hirata, Yuji Kuge, Mikako Ogawa.
       INTRODUCTION: Hypoxia is common in solid tumors and creates an immunosuppressive environment that leads to resistance to immunotherapy, such as an anti-programmed death receptor-1 (PD-1) therapy. It has been suggested that anti-PD-1 therapy may reduce tumor hypoxia by remodeling the tumor vasculature; however, it is unclear how anti-PD-1 therapy reduces hypoxia over time. Therefore, we investigated the relationship between hypoxia and immune activation by anti-PD-1 therapy in murine cancer models.
    METHODS: Anti-PD-1 antibody was injected to CT26- and MC38-tumor-bearing mice on days 0 and 5. Tumor hypoxia was non-invasively evaluated using positron emission tomography (PET) with [18F]fluoromisonidazole ([18F]FMISO) on days 3 and 7. Histological analysis was conducted to investigate the infiltration of immune cells in [18F]FMISO-accumulated hypoxic area. In addition, the immune cell population in tumors and the percentages of cancer and immune cells under hypoxic conditions were analyzed at single-cell level using flow cytometry.
    RESULTS: Flow cytometric analysis of CT26 tumors on day 3 showed that anti-PD-1 therapy reduced hypoxia without inhibition of tumor growth. In addition, the infiltration of CD8+ T cells was increased in treated tumors. In contrast to CT26 tumors, the percentage of hypoxic cells in MC38 tumors did not change on days 3 and 7, and there was minimal immune activation induced by anti-PD-1 antibody. Changes in hypoxia in CT26 tumors were not detected by [18F]FMISO-PET, but autoradiogram showed that [18F]FMISO accumulated in immunosuppressed areas, where the infiltration of immune cells was relatively low.
    CONCLUSION: Reduction of hypoxia was induced in CT26 tumor, in which adequate immune response to anti-PD-1 therapy was exhibited, at an early time point before suppression of tumor growth. Our findings suggest that anti-PD-1 therapy can create a tumor microenvironment that facilitates immune activation by reducing hypoxia.
    Keywords:  Cancer imaging; Hypoxia; Immune checkpoint blockade; PD-1; [(18)F]FMISO
    DOI:  https://doi.org/10.1016/j.nucmedbio.2022.03.005
  5. Cureus. 2022 Feb;14(2): e22711
    Obesity: A Chronic Low-Grade Inflammation and Its Markers.
    Deepesh Khanna, Siya Khanna, Pragya Khanna, Payal Kahar, Bhavesh M Patel.
      As the prevalence of obesity continues to rise, the world is facing a major public health concern. Obesity is a complex disease associated with an increase in several inflammatory markers, leading to chronic low-grade inflammation. Of multifactorial etiology, it is often used as a measurement of morbidity and mortality. There remains much unknown regarding the association between obesity and inflammation. This review seeks to compile scientific literature on obesity and its associated inflammatory markers in chronic disease and further discusses the role of adipose tissue, macrophages, B-cells, T-cells, fatty acids, amino acids, adipokines, and hormones in obesity. Data were obtained using PubMed and Google Scholar. Obesity, inflammation, immune cells, hormones, fatty acids, and others were search words used to acquire relevant articles. Studies suggest brown adipose tissue is negatively associated with body mass index (BMI) and body fat percentage. Researchers also found the adipose tissue of lean individuals predominantly secretes anti-inflammatory markers, while in obese individuals more pro-inflammatory markers are secreted. Many studies found that adipose tissue in obese individuals showed a shift in immune cells from anti-inflammatory M2 macrophages to pro-inflammatory M1 macrophages, which was also correlated with insulin resistance. Obese individuals generally present with higher levels of hormones such as leptin, visfatin, and resistin. With obesity on the rise globally, it is predicted that severe obesity will become most common amongst low-income adults, black individuals, and women by 2030, making the need for intervention urgent. Further investigation into the association between obesity and inflammation is required to understand the mechanism behind this disease.
    Keywords:  adipokine; adipose tissue; browning of white adipose tissue; fatty acid; inflammatory processes/inflammatory markers; nutrition and metabolism .obesity. dietary fiber; obesity and inflammatory markers; obesity: an immune disease; prevalence of obesity; role of hormones in obesity
    DOI:  https://doi.org/10.7759/cureus.22711
  6. Cell Death Discov. 2022 Apr 04. 8(1): 162
    GDF-15 in tumor-derived exosomes promotes muscle atrophy via Bcl-2/caspase-3 pathway.
    Wanli Zhang, Weikuan Sun, Xiaofan Gu, Chunxiao Miao, Lixing Feng, Qiang Shen, Xuan Liu, Xiongwen Zhang.
      Tumor-derived exosomes are emerging mediators of cancer cachexia, a kind of multifactorial syndrome characterized by serious loss of skeletal muscle mass and function. Our previous study had showed that microRNAs in exosomes of C26 colon tumor cells were involved in induction of muscle atrophy. Here, we focus on studying proteins in tumor-derived exosomes which might also contribute to the development of cancer cachexia. Results of comparing the protein profiles of cachexic C26 exosomes and non-cachexic MC38 exosomes suggested that growth differentiation factor 15 (GDF-15) was rich in C26 exosomes. Western blotting analysis confirmed the higher levels of GDF-15 in C26 cells and C26 exosomes, compared with that of MC38 cells. Results of animal study also showed that GDF-15 was rich in tumor tissues, serum exosomes, and gastrocnemius (GA) muscle tissues of C26 tumor-bearing mice. GDF-15 protein could directly induce muscle atrophy of cultured C2C12 myotubes via regulating Bcl-2/caspase-3 pathways. What's more, overexpression of GDF-15 in MC38 cells could increase the potency of MC38 conditioned medium or exosomes in inducing muscle atrophy. Knockdown of GDF-15 in C26 cells decreased the potency of C26 conditioned medium or exosomes in inducing muscle atrophy. These results suggested that GDF-15 in tumor-derived exosomes could contribute to induction of muscle atrophy and also supported the possibility of targeting GDF-15 in treatment of cancer cachexia.
    DOI:  https://doi.org/10.1038/s41420-022-00972-z
  7. Curr Med Chem. 2022 Apr 01.
    The Influence of Mitochondrial Energy and 1C Metabolism on the Efficacy of Anticancer Drugs - Exploring Potential Mechanisms of Resistance.
    Marika Franczak, Isabel Toenshoff, Gerrit Jansen, Ryszard T Smolenski, Elisa Giovannetti, Godefridus J Peters.
      Mitochondria are the main energy factory in living cells. To rapidly proliferate and metastasize, neoplastic cells increase their energy requirements. Thus, mitochondria become one of the most important organelles for them. Indeed, much research shows the interplay between cancer chemoresistance and altered mitochondrial function. In this review we focus on the differences in energy metabolism between cancer and normal cells, to better understand their resistance and how to develop drugs targeting energy metabolism and nucleotide synthesis. One of the differences between cancer and normal cells is the higher nicotinamide adenine dinucleotide (NAD+) level, a cofactor for the tricarboxylic acid cycle (TCA), which enhances their proliferation and helps cancer cells survive under hypoxic conditions. An important change is a metabolic switch, called the Warburg effect. This effect is based on the change of energy harvesting from oxygen-dependent transformation to oxidative phosphorylation (OXPHOS), adapt them to the tumor environment. Another mechanism is the high expression of one carbon (1C) metabolism enzymes. Again, this allows cancer cells to increase proliferation by producing precursors for the synthesis of nucleotides and amino acids. We reviewed drugs in clinical practice and in development targeting NAD+, OXPHOS, and 1C metabolism. Combinations of novel drugs with conventional antineoplastic agents may prove to be a promising new way of anticancer treatment.
    Keywords:  1C Metabolism; Cancer; Mitochondria; NAD+; Oxidative Phosphorylation (OXPHOS); Resistance
    DOI:  https://doi.org/10.2174/0929867329666220401110418
  8. J Cancer. 2022 ;13(5): 1685-1694
    Tumor-derived exosomes in hypoxic microenvironment: release mechanism, biological function and clinical application.
    Da Qian, Yaoyao Xie, Mingyao Huang, Jianfeng Gu.
      Hypoxia is a key feature of solid tumors and is related to disease aggressiveness and adverse outcomes. It is recognized that the two-way communication between cancer cells and their microenvironment is critical to cancer progression. Increasing evidences show that the cellular communication and crosstalk between tumor cells and their microenvironment is not limited to secreted molecules, but also includes exosomes secreted by tumor cells. Exosomes are nano-scale extracellular vesicles (30-100 nm in diameter), which carry the molecular characteristics and cargo of the source cell, participating in intercellular communication through autocrine, paracrine and near-crine pathways. Recent studies have shown that cancer cells produce more exosomes under hypoxic conditions than normoxia conditions. The secretion and function of exosomes could be influenced by hypoxia in various types of cancer. Therefore, in this review, we summarize and discuss the latest research on the physiological mechanism of hypoxia regulating the secretion of exosomes, and the involvement of hypoxic exosomes in cancer progression and immune escape processes, and expounds the potential for targeting hypoxia-induced exosomes for cancer therapy strategies.
    Keywords:  Biological functions; Cancer; Cancer therapy; Exosomes; Hypoxic microenvironment
    DOI:  https://doi.org/10.7150/jca.69278
  9. Cell Tissue Res. 2022 Apr 08.
    Regulation of inflammation by VEGF/BDNF signaling in mouse retinal Müller glial cells exposed to high glucose.
    Minqi Zhu, Na Li, Yanuo Wang, Shuang Gao, Jing Wang, Xi Shen.
      The inflammatory changes seem to play an important role in the development of diabetic retinopathy (DR). Anti-VEGF therapy has been testified to inhibit inflammation in animal models of diabetes, but the detailed mechanisms during this process are not yet clear. Müller glial cells (MGCs) in the mammalian retina are deeply involved in DR, while the BDNF overexpression reduces inflammation in diabetic mice. In this research, we aimed to explore the relationship between VEGF and BDNF in mouse retinal MGCs during inflammation of diabetes. We examined the expression of glutamine-synthetase (GS), glial fibrillary acidic protein (GFAP), vascular-endothelial growth factor (VEGF), interleukin-1beta (IL-1β), and tumor necrosis factor-alpha (TNF-α) at different time points after mouse retinal MGCs exposed to high glucose (25 mM). We also explored changes in the expression of brain-derived neurotrophic factor (BDNF), nuclear factor kappa B (NF-κB), IL-1β, and TNF-α in MGCs after treatments with anti-VEGF, VEGF siRNA, BDNF siRNA, BDNF recombination protein, and NF-κB inhibitor. In mouse retinal MGCs exposed to high glucose, BDNF was increased after treatments with anti-VEGF or VEGF siRNA. BDNF was decreased in MGCs from VEGF overexpressed mice. Moreover, the expressions of NF-κB, IL-1β, and TNF-α changed with BDNF: NF-κB, IL-1β, and TNF-α were increased after treatments with BDNF siRNA; NF-κB, IL-1β, and TNF-α were decreased after treatments with BDNF recombination protein. VEGF may regulate cytokines (IL-1β and TNF-α) by BDNF/NF-κB signaling pathway. The regulation of the VEGF/BDNF/NF-κB signaling pathway may be a significant therapeutic strategy for DR.
    Keywords:  Brain-derived neurotrophic factor; Diabetic retinopathy; High glucose; Müller glial cells; Vascular endothelial growth factor
    DOI:  https://doi.org/10.1007/s00441-022-03622-z
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