bims-stacyt Biomed News
on Metabolism and the paracrine crosstalk between cancer and the organism
Issue of 2022–02–20
seven papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge
  1. The Good, the Bad, and the Ugly: Neutrophils, Angiogenesis, and Cancer.
  2. The ambiguous role of obesity in oncology by promoting cancer but boosting antitumor immunotherapy.
  3. Glioblastoma invasiveness and collagen secretion are enhanced by vitamin C.
  4. VEGF-Independent Angiogenic Factors: Beyond VEGF/VEGFR2 Signaling.
  5. Tumor-Derived Extracellular Vesicles Induce CCL18 Production by Mast Cells: A Possible Link to Angiogenesis.
  6. ATF-4 and hydrogen sulfide signalling mediate longevity in response to inhibition of translation or mTORC1.
  7. Pleiotropic, Unique and Shared Responses Elicited by IL-6 Family Cytokines in Human Vascular Endothelial Cells.
  1. Cancers (Basel). 2022 Jan 21. pii: 536. [Epub ahead of print]14(3):
    The Good, the Bad, and the Ugly: Neutrophils, Angiogenesis, and Cancer.
    Irem Ozel, Inga Duerig, Maksim Domnich, Stephan Lang, Ekaterina Pylaeva, Jadwiga Jablonska.
      Angiogenesis, the formation of new blood vessels from already existing vasculature, is tightly regulated by pro- and anti-angiogenic stimuli and occurs under both physiological and pathological conditions. Tumor angiogenesis is central for tumor development, and an "angiogenic switch" could be initiated by multiple immune cells, such as neutrophils. Tumor-associated neutrophils promote tumor angiogenesis by the release of both conventional and non-conventional pro-angiogenic factors. Therefore, neutrophil-mediated tumor angiogenesis should be taken into consideration in the design of novel anti-cancer therapy. This review recapitulates the complex role of neutrophils in tumor angiogenesis and summarizes neutrophil-derived pro-angiogenic factors and mechanisms regulating angiogenic activity of tumor-associated neutrophils. Moreover, it provides up-to-date information about neutrophil-targeting therapy, complementary to anti-angiogenic treatment.
    Keywords:  cancer; neutrophils; tumor angiogenesis; tumor vasculature
    DOI:  https://doi.org/10.3390/cancers14030536
  2. J Biomed Sci. 2022 Feb 14. 29(1): 12
    The ambiguous role of obesity in oncology by promoting cancer but boosting antitumor immunotherapy.
    José Antônio Fagundes Assumpção, Gabriel Pasquarelli-do-Nascimento, Mariana Saldanha Viegas Duarte, Martín Hernan Bonamino, Kelly Grace Magalhães.
      Obesity is nowadays considered a pandemic which prevalence's has been steadily increasingly in western countries. It is a dynamic, complex, and multifactorial disease which propitiates the development of several metabolic and cardiovascular diseases, as well as cancer. Excessive adipose tissue has been causally related to cancer progression and is a preventable risk factor for overall and cancer-specific survival, associated with poor prognosis in cancer patients. The onset of obesity features a state of chronic low-grade inflammation and secretion of a diversity of adipocyte-derived molecules (adipokines, cytokines, hormones), responsible for altering the metabolic, inflammatory, and immune landscape. The crosstalk between adipocytes and tumor cells fuels the tumor microenvironment with pro-inflammatory factors, promoting tissue injury, mutagenesis, invasion, and metastasis. Although classically established as a risk factor for cancer and treatment toxicity, recent evidence suggests mild obesity is related to better outcomes, with obese cancer patients showing better responses to treatment when compared to lean cancer patients. This phenomenon is termed obesity paradox and has been reported in different types and stages of cancer. The mechanisms underlying this paradoxical relationship between obesity and cancer are still not fully described but point to systemic alterations in metabolic fitness and modulation of the tumor microenvironment by obesity-associated molecules. Obesity impacts the response to cancer treatments, such as chemotherapy and immunotherapy, and has been reported as having a positive association with immune checkpoint therapy. In this review, we discuss obesity's association to inflammation and cancer, also highlighting potential physiological and biological mechanisms underlying this association, hoping to clarify the existence and impact of obesity paradox in cancer development and treatment.
    Keywords:  Adipose tissue; Cancer; Immunotherapy; Inflammation; Obesity
    DOI:  https://doi.org/10.1186/s12929-022-00796-0
  3. Antioxid Redox Signal. 2022 Feb 15.
    Glioblastoma invasiveness and collagen secretion are enhanced by vitamin C.
    Eder Ramírez, Nery Jara, Luciano Ferrada, Katterine Salazar, Fernando Martínez, María José Oviedo, Joanna Tereszczuk, Sebastían Ramírez-Carbonell, Arabel Vollmann, Peter Hau, Francisco Nualart.
       AIMS: Glioblastoma is one of the most aggressive brain tumors. These tumors modify their metabolism, increasing the expression of glucose transporters, GLUTs, which incorporate glucose and the oxidized form of vitamin C, dehydroascorbic acid (DHA). We hypothesized that glioblastoma cells preferentially take up DHA, which is intracellularly reduced and compartmentalized into the endoplasmic reticulum (ER), promoting collagen biosynthesis and an aggressive phenotype.
    RESULTS: Our results showed that glioblastoma cells take up DHA using GLUT1, while GLUT3 and sodium-dependent vitamin C transporter 2 (SVCT2), are preferably intracellular. Using a baculoviral system and reticulum-enriched extracts, we determined that SVCT2 is mainly located in the ER and corresponds to a short isoform. AA was compartmentalized, stimulating collagen IV secretion and increasing in vitro and in situ cell migration. Finally, orthotopic xenografts induced in immunocompetent guinea pigs showed that vitamin C deficiency retained collagen, reduced blood vessel invasion, and affected glomeruloid vasculature formation, all pathological conditions associated with malignancy. Innovation and conclusion: We propose a functional role for vitamin C in glioblastoma development and progression. Vitamin C is incorporated into the ER of glioblastoma cells, where it favors the synthesis of collagen, thus impacting tumor development. Collagen secreted by tumor cells favors the formation of the glomeruloid vasculature and enhances perivascular invasion.
    DOI:  https://doi.org/10.1089/ars.2021.0089
  4. J Vasc Res. 2022 Feb 11. 1-12
    VEGF-Independent Angiogenic Factors: Beyond VEGF/VEGFR2 Signaling.
    Ryoji Eguchi, Jun-Ichi Kawabe, Ichiro Wakabayashi.
      Tumors induce angiogenesis to acquire oxygen and nutrition from their adjacent microenvironment. Tumor angiogenesis has been believed to be induced primarily by the secretion of vascular endothelial growth factor-A (VEGF-A) from various tumors. VEGF-A binds to VEGF receptor 2 (VEGFR2), resulting in subsequent activation of cellular substances regulating cell proliferation, survival, and angiogenesis. Antiangiogenic therapies targeting the VEGF-A/VEGFR2 axis, including bevacizumab and ramucirumab, humanized monoclonal antibodies against VEGF-A and VEGFR2, respectively, have been proposed as a promising strategy aimed at preventing tumor growth, invasion, and metastasis. Phase III clinical trials using bevacizumab and ramucirumab have shown that not all tumor patients benefit from such antiangiogenic agents, and that some patients who initially benefit subsequently become less responsive to these antibodies, suggesting the possible existence of VEGF-independent angiogenic factors. In this review, we focus on VEGF-independent and VEGFR2-dependent tumor angiogenesis, as well as VEGFR2-independent tumor angiogenesis. Additionally, we discuss VEGF-independent angiogenic factors which have been reported in previous studies. Various molecular targeting drugs are currently being evaluated as potential antitumor therapies. We expect that precision medicine will permit the development of innovative antiangiogenic therapies targeting individual angiogenic factors selected on the basis of the genetic screening of tumors.
    Keywords:  Angiogenesis; Bevacizumab; Ramucirumab; VEGF receptor 2; Vascular endothelial growth factor
    DOI:  https://doi.org/10.1159/000521584
  5. Cells. 2022 Jan 21. pii: 353. [Epub ahead of print]11(3):
    Tumor-Derived Extracellular Vesicles Induce CCL18 Production by Mast Cells: A Possible Link to Angiogenesis.
    Irit Shefler, Pazit Salamon, Tali Zitman-Gal, Yoseph A Mekori.
      Mast cells (MCs) function as a component of the tumor microenvironment (TME) and have both pro- and anti-tumorigenic roles depending on the tumor type and its developmental stage. Several reports indicate the involvement of MCs in angiogenesis in the TME by releasing angiogenic mediators. Tumor cells and other cells in the TME may interact by releasing extracellular vesicles (EVs) that affect the cells in the region. We have previously shown that tumor-derived microvesicles (TMVs) from non-small-cell lung cancer (NSCLC) cells interact with human MCs and activate them to release several cytokines and chemokines. In the present study, we characterized the MC expression of other mediators after exposure to TMVs derived from NSCLC. Whole-genome expression profiling disclosed the production of several chemokines, including CC chemokine ligand 18 (CCL18). This chemokine is expressed in various types of cancer, and was found to be associated with extensive angiogenesis, both in vitro and in vivo. We now show that CCL18 secreted from MCs activated by NSCLC-TMVs increased the migration of human umbilical cord endothelial cells (HUVECs), tube formation and endothelial- to-mesenchymal transition (EndMT), thus promoting angiogenesis. Our findings support the conclusion that TMVs have the potential to influence MC activity and may affect angiogenesis in the TME.
    Keywords:  CCL18; angiogenesis; extracellular vesicles; lung tumor; mast cell
    DOI:  https://doi.org/10.3390/cells11030353
  6. Nat Commun. 2022 Feb 18. 13(1): 967
    ATF-4 and hydrogen sulfide signalling mediate longevity in response to inhibition of translation or mTORC1.
    Cyril Statzer, Jin Meng, Richard Venz, Monet Bland, Stacey Robida-Stubbs, Krina Patel, Dunja Petrovic, Raffaella Emsley, Pengpeng Liu, Ianessa Morantte, Cole Haynes, William B Mair, Alban Longchamp, Milos R Filipovic, T Keith Blackwell, Collin Y Ewald.
      Inhibition of the master growth regulator mTORC1 (mechanistic target of rapamycin complex 1) slows ageing across phyla, in part by reducing protein synthesis. Various stresses globally suppress protein synthesis through the integrated stress response (ISR), resulting in preferential translation of the transcription factor ATF-4. Here we show in C. elegans that inhibition of translation or mTORC1 increases ATF-4 expression, and that ATF-4 mediates longevity under these conditions independently of ISR signalling. ATF-4 promotes longevity by activating canonical anti-ageing mechanisms, but also by elevating expression of the transsulfuration enzyme CTH-2 to increase hydrogen sulfide (H2S) production. This H2S boost increases protein persulfidation, a protective modification of redox-reactive cysteines. The ATF-4/CTH-2/H2S pathway also mediates longevity and increased stress resistance from mTORC1 suppression. Increasing H2S levels, or enhancing mechanisms that H2S influences through persulfidation, may represent promising strategies for mobilising therapeutic benefits of the ISR, translation suppression, or mTORC1 inhibition.
    DOI:  https://doi.org/10.1038/s41467-022-28599-9
  7. Int J Mol Sci. 2022 Jan 27. pii: 1448. [Epub ahead of print]23(3):
    Pleiotropic, Unique and Shared Responses Elicited by IL-6 Family Cytokines in Human Vascular Endothelial Cells.
    Madelene Lindkvist, Mulugeta M Zegeye, Magnus Grenegård, Liza U Ljungberg.
      Vascular endothelial cells express glycoprotein 130 (gp130), which is utilized as a signaling receptor by cytokines in the interleukin-6 (IL-6) family. Several IL-6 family cytokines can be found in the circulatory system during physiological or pathological conditions, and may influence endothelial function and response. This study evaluated and compared the cellular and molecular responses induced by IL-6 family cytokines in human endothelial cells. A proteomic analysis showed that IL-6 family cytokines induce the release of a range of proteins from endothelial cells, such as C-C motif chemokine ligand 23, hepatocyte growth factor, and IL-6. Pathway analysis indicated that gp130-signaling in endothelial cells regulates several functions related to angiogenesis and immune cell recruitment. The present investigation also disclosed differences and similarities between different IL-6 family cytokines in their ability to induce protein release and regulate gene expression and intracellular signaling, in regards to which oncostatin M showed the most pronounced effect. Further, this study showed that soluble gp130 preferentially blocks trans-signaling-induced responses, but does not affect responses induced by classic signaling. In conclusion, IL-6 family cytokines induce both specific and overlapping molecular responses in endothelial cells, and regulate genes and proteins involved in angiogenesis and immune cell recruitment.
    Keywords:  CCL23; cardiotrophin-1 (CT-1); chemotaxis; ciliary neurotrophic factor (CNTF); hepatocyte growth factor (HGF); interleukin-11 (IL-11); leukemia inhibitory factor (LIF)
    DOI:  https://doi.org/10.3390/ijms23031448
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