bims-stacyt Biomed News
on Metabolism and the paracrine crosstalk between cancer and the organism
Issue of 2022‒12‒18
ten papers selected by
Cristina Muñoz Pinedo
L’Institut d’Investigació Biomèdica de Bellvitge
  1. Targeting lactate metabolism for cancer immunotherapy - a matter of precision.
  2. TRAIL receptors promote constitutive and inducible IL-8 secretion in non-small cell lung carcinoma.
  3. The PI3K/Akt Pathway in Meta-Inflammation.
  4. Muscle metabolic stress determines cancer cachexia severity in mice.
  5. Metabolic crosstalk between thermogenic adipocyte and cancer cell: Dysfunction and therapeutics.
  6. Intermittent fasting increases growth differentiation factor 15 in females with overweight or obesity but not associated with food intake.
  7. Endothelial cells-directed angiogenesis in colorectal cancer: Interleukin as the mediator and pharmacological target.
  8. Increased tumor glycolysis is associated with decreased immune infiltration across human solid tumors.
  9. HSP70 inhibitors upregulate prostaglandin E1-induced synthesis of interleukin-6 in osteoblasts.
  10. Extracellular vesicles derived from fibroblasts induced with or without high glucose exert opposite effects on wound healing and angiogenesis.
  1. Semin Cancer Biol. 2022 Dec 07. pii: S1044-579X(22)00255-3. [Epub ahead of print]88 32-45
    Targeting lactate metabolism for cancer immunotherapy - a matter of precision.
    Christoph Heuser, Kathrin Renner, Marina Kreutz, Luca Gattinoni.
      Immune checkpoint inhibitors and adoptive T cell therapies have been valuable additions to the toolbox in the fight against cancer. These treatments have profoundly increased the number of patients with a realistic perspective toward a return to a cancer-free life. Yet, in a number of patients and tumor entities, cancer immunotherapies have been ineffective so far. In solid tumors, immune exclusion and the immunosuppressive tumor microenvironment represent substantial roadblocks to successful therapeutic outcomes. A major contributing factor to the depressed anti-tumor activity of immune cells in tumors is the harsh metabolic environment. Hypoxia, nutrient competition with tumor and stromal cells, and accumulating noxious waste products, including lactic acid, pose massive constraints to anti-tumor immune cells. Numerous strategies are being developed to exploit the metabolic vulnerabilities of tumor cells in the hope that these would also alleviate metabolism-inflicted immune suppression. While promising in principle, especially in combination with immunotherapies, these strategies need to be scrutinized for their effect on tumor-fighting immune cells, which share some of their key metabolic properties with tumor cells. Here, we provide an overview of strategies that seek to tackle lactate metabolism in tumor or immune cells to unleash anti-tumor immune responses, thereby opening therapeutic options for patients whose tumors are currently not treatable.
    Keywords:  Acidification; Adoptive cell transfer; Checkpoint inhibition; Glycolysis; Immunotherapy; Lactate; Metabolism
    DOI:  https://doi.org/10.1016/j.semcancer.2022.12.001
  2. Cell Death Dis. 2022 Dec 15. 13(12): 1046
    TRAIL receptors promote constitutive and inducible IL-8 secretion in non-small cell lung carcinoma.
    Francesca Favaro, Fedra Luciano-Mateo, Joaquim Moreno-Caceres, Miguel Hernández-Madrigal, Demi Both, Chiara Montironi, Franziska Püschel, Ernest Nadal, Eric Eldering, Cristina Muñoz-Pinedo.
      Interleukin-8 (IL-8/CXCL8) is a pro-angiogenic and pro-inflammatory chemokine that plays a role in cancer development. Non-small cell lung carcinoma (NSCLC) produces high amounts of IL-8, which is associated with poor prognosis and resistance to chemo-radio and immunotherapy. However, the signaling pathways that lead to IL-8 production in NSCLC are unresolved. Here, we show that expression and release of IL-8 are regulated autonomously by TRAIL death receptors in several squamous and adenocarcinoma NSCLC cell lines. NSCLC constitutively secrete IL-8, which could be further enhanced by glucose withdrawal or by treatment with TRAIL or TNFα. In A549 cells, constitutive and inducible IL-8 production was dependent on NF-κB and MEK/ERK MAP Kinases. DR4 and DR5, known regulators of these signaling pathways, participated in constitutive and glucose deprivation-induced IL-8 secretion. These receptors were mainly located intracellularly. While DR4 signaled through the NF-κB pathway, DR4 and DR5 both regulated the ERK-MAPK and Akt pathways. FADD, caspase-8, RIPK1, and TRADD also regulated IL-8. Analysis of mRNA expression data from patients indicated that IL-8 transcripts correlated with TRAIL, DR4, and DR5 expression levels. Furthermore, TRAIL receptor expression levels also correlated with markers of angiogenesis and neutrophil infiltration in lung squamous carcinoma and adenocarcinoma. Collectively, these data suggest that TRAIL receptor signaling contributes to a pro-tumorigenic inflammatory signature associated with NSCLC.
    DOI:  https://doi.org/10.1038/s41419-022-05495-0
  3. Int J Mol Sci. 2022 Dec 05. pii: 15330. [Epub ahead of print]23(23):
    The PI3K/Akt Pathway in Meta-Inflammation.
    Maricedes Acosta-Martinez, Maria Zulema Cabail.
      Obesity is a global epidemic representing a serious public health burden as it is a major risk factor for the development of cardiovascular disease, stroke and all-cause mortality. Chronic low-grade systemic inflammation, also known as meta-inflammation, is thought to underly obesity's negative health consequences, which include insulin resistance and the development of type 2 diabetes. Meta-inflammation is characterized by the accumulation of immune cells in adipose tissue, a deregulation in the synthesis and release of adipokines and a pronounced increase in the production of proinflammatory factors. In this state, the infiltration of macrophages and their metabolic activation contributes to complex paracrine and autocrine signaling, which sustains a proinflammatory microenvironment. A key signaling pathway mediating the response of macrophages and adipocytes to a microenvironment of excessive nutrients is the phosphoinositide 3-kinase (PI3K)/Akt pathway. This multifaceted network not only transduces metabolic information but also regulates macrophages' intracellular changes, which are responsible for their phenotypic switch towards a more proinflammatory state. In the present review, we discuss how the crosstalk between macrophages and adipocytes contributes to meta-inflammation and provide an overview on the involvement of the PI3K/Akt signaling pathway, and how its impairment contributes to the development of insulin resistance.
    Keywords:  Akt; PI3K; adipocytes; macrophages; meta-inflammation; obesity
    DOI:  https://doi.org/10.3390/ijms232315330
  4. Front Physiol. 2022 ;13 1033932
    Muscle metabolic stress determines cancer cachexia severity in mice.
    Christiano Alves, Laurie Goodyear, Patricia Brum.
      Objectives: To determine the metabolic effects of cancer-conditioned media on myotube metabolism and to understand whether the variability of these effects is associated with cancer cachexia progression. Materials and methods: We established single-cell clones from murine Lewis lung carcinoma (LLC) cells and generated conditioned media from each clonal line. Differentiated primary mouse myotubes were incubated with conditioned media derived from each individual clonal cell line. After initial analysis, we selected a specific LLC clonal cell line that failed to induce metabolic stress in myotubes for further investigation in vitro and in vivo. Results: Short-term incubation with conditioned media from 10/34 LLC clonal cells failed to affect oxygen consumption rate (OCR) in myotubes. Incubation with parental LLC-conditioned media decreased protein content and changed the expression of key regulators of muscle function in myotubes, but the incubation of conditioned media from a selected clone that failed to affect OCR in myotubes also did not affect protein content and expression of muscle regulators. Mice injected with parental LLC cells had a significantly reduced body mass and muscle wasting compared to the mice injected with cells derived from this selected LLC clone. Conclusion: Factors secreted by LLC cells induce metabolic stress in primary myotubes and induce cancer cachexia in mice. However, a selected clonal LLC cell line that failed to induce metabolic stress in myotubes also promoted weaker catabolism in mice. These novel findings establish that early disruption of muscle oxidative metabolism is associated with cancer cachexia progression.
    Keywords:  atrophy; lung carcinoma; muscle wasting; oxidative metabolism; oxidative stress
    DOI:  https://doi.org/10.3389/fphys.2022.1033932
  5. Curr Opin Pharmacol. 2022 Dec 08. pii: S1471-4892(22)00149-7. [Epub ahead of print]68 102322
    Metabolic crosstalk between thermogenic adipocyte and cancer cell: Dysfunction and therapeutics.
    Kai Dong, Gang Wei, Honglin Sun, Di Gu, Junli Liu, Linhui Wang.
      As one of the largest endocrine organs with a wide distribution in organisms, adipose tissue secretes multiple adipokines, cytokines, metabolites, and exosomes to promote tumour development. Elaborating the crosstalk between cancer cells and adipocytes provides a tissue-level perspective of cancer progression, which reflects the heterogeneity and complexity of human tumours. Three main types of adipose tissues, white, brown, and beige adipose tissue, have been described. Thermogenic capacity is a prominent characteristic of brown and beige adipocytes. Most studies so far mainly focus on the contribution of white adipocytes to the tumour microenvironment. However, the role of thermogenic adipose tissue in malignant cancer behaviour has been largely overlooked. Recently, emerging evidence suggests that beige/brown adipocytes play a key role in the development and progression of various cancers. This review focuses on the bidirectional communication between tumour cells and thermogenic adipocytes and the therapeutic strategies to disrupt this interaction.
    Keywords:  Metabolism; Thermogenic adipocyte; Tumour microenvironment
    DOI:  https://doi.org/10.1016/j.coph.2022.102322
  6. Obes Res Clin Pract. 2022 Dec 09. pii: S1871-403X(22)00137-5. [Epub ahead of print]
    Intermittent fasting increases growth differentiation factor 15 in females with overweight or obesity but not associated with food intake.
    Kai Liu, Bo Liu, Gary A Wittert, Campbell H Thompson, Amy T Hutchison, Leonie K Heilbronn.
      Growth differentiation factor 15 (GDF15) increases with acute fast in animals, and high GDF15 reduces food intake in rodents. We explored whether GDF15 was altered following intermittent fasting (IF) versus caloric restriction (CR), and associations with energy intake. Females with obesity received all foods at 70% (IF70 and CR70) or 100% of energy requirements for 8 weeks. IF ate 2-9% less than provided on refeeding days, resulting in greater weight losses. GDF15 was increased 5% more in IF70 versus CR70, but not associated with energy intake. This rise in GDF15 is unlikely to explain restriction of energy intake during IF.
    Keywords:  Calorie restriction; Female; Growth differentiation factor 15; Humans; Intermittent fasting
    DOI:  https://doi.org/10.1016/j.orcp.2022.12.001
  7. Int Immunopharmacol. 2022 Dec 09. pii: S1567-5769(22)01010-4. [Epub ahead of print]114 109525
    Endothelial cells-directed angiogenesis in colorectal cancer: Interleukin as the mediator and pharmacological target.
    Guanglin Cui, Hanzhe Liu, Jann-Birger Laugsand.
      Enhanced angiogenesis is a cancer hallmark and critical for colorectal cancer (CRC) invasion and metastasis. Upon exposure to proangiogenic factors, therefore, targeting tumor-associated proangiogenic factors/receptors hold great promise as a therapeutic modality to treat CRC, particularly metastatic CRC. Accumulating evidence from numerous studies suggests that tumor endothelial cells (ECs) are not only the target of proangiogenic factors, but also function as the cellular source of proangiogenic factors. Studies showed that ECs can produce different proangiogenic factors to participate in the regulation of angiogenesis process, in which ECs-derived interleukins (ILs) show a potential stimulatory effect on angiogenesis via either an direct action on their receptors expressed on progenitor of ECs or an indirect way through enhanced production of other proangiogenic factors. Although a great deal of attention is given to the effects of tumor-derived and immune cell-derived ILs, few studies describe the potential effects of vascular ECs-derived ILs on the tumor angiogenesis process. This review provides an updated summary of available information on proangiogenic ILs, such as IL-1, IL-6, IL-8, IL-17, IL-22, IL-33, IL-34, and IL-37, released by microvascular ECs as potential drivers of the tumor angiogenesis process and discusses their potential as a novel candidate for antiangiogenic target for the treatment of CRC patients.
    Keywords:  Angiogenesis; Colorectal cancer; Endothelial cell; Interleukin
    DOI:  https://doi.org/10.1016/j.intimp.2022.109525
  8. Front Immunol. 2022 ;13 880959
    Increased tumor glycolysis is associated with decreased immune infiltration across human solid tumors.
    Ivan J Cohen, Fresia Pareja, Nicholas D Socci, Ronglai Shen, Ashley S Doane, Jazmin Schwartz, Raya Khanin, Elizabeth A Morris, Elizabeth J Sutton, Ronald G Blasberg.
      Response to immunotherapy across multiple cancer types is approximately 25%, with some tumor types showing increased response rates compared to others (i.e. response rates in melanoma and non-small cell lung cancer (NSCLC) are typically 30-60%). Patients whose tumors are resistant to immunotherapy often lack high levels of pre-existing inflammation in the tumor microenvironment. Increased tumor glycolysis, acting through glucose deprivation and lactic acid accumulation, has been shown to have pleiotropic immune suppressive effects using in-vitro and in-vivo models of disease. To determine whether the immune suppressive effect of tumor glycolysis is observed across human solid tumors, we analyzed glycolytic and immune gene expression patterns in multiple solid malignancies. We found that increased expression of a glycolytic signature was associated with decreased immune infiltration and a more aggressive disease across multiple tumor types. Radiologic and pathologic analysis of untreated estrogen receptor (ER)-negative breast cancers corroborated these observations, and demonstrated that protein expression of glycolytic enzymes correlates positively with glucose uptake and negatively with infiltration of CD3+ and CD8+ lymphocytes. This study reveals an inverse relationship between tumor glycolysis and immune infiltration in a large cohort of multiple solid tumor types.
    Keywords:  glycolysis; immune infiltration; immunotherapy; solid tumors; tumor metabolism; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2022.880959
  9. PLoS One. 2022 ;17(12): e0279134
    HSP70 inhibitors upregulate prostaglandin E1-induced synthesis of interleukin-6 in osteoblasts.
    Gen Kuroyanagi, Junko Tachi, Kazuhiko Fujita, Tetsu Kawabata, Go Sakai, Daiki Nakashima, Woo Kim, Kumiko Tanabe, Rie Matsushima-Nishiwaki, Takanobu Otsuka, Hiroki Iida, Osamu Kozawa, Haruhiko Tokuda.
      Interleukin-6 (IL-6) is a pro-inflammatory and bone-resorptive cytokine that also regulates bone formation. We previously showed that prostaglandin E1 (PGE1) induces the synthesis of IL-6 by activating p44/p42 mitogen-activated protein kinase (MAPK), stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK), and p38 MAPK in osteoblast-like MC3T3-E1 cells. In the present study, we investigated whether heat shock protein 70 (HSP70), a molecular chaperone that coordinates protein folding and homeostasis, affects PGE1-stimulated IL-6 synthesis in MC3T3-E1 cells through the MAPK activation. The osteoblast-like MC3T3-E1 cells were treated with HSP70 inhibitors-VER-155008 and YM-08-, PD98059, SB203580 or SP600125 and then stimulated with PGE1. IL-6 synthesis was evaluated using an IL-6 enzyme-linked immunosorbent assay kit. IL-6 mRNA expression was measured by real-time RT-PCR. The phosphorylation of p38 MAPK was evaluated by Western blotting. We found that VER-155008, an HSP70 inhibitor, enhanced the PGE1-stimulated IL-6 release and IL-6 mRNA expression. YM-08, another HSP70 inhibitor, also enhanced PGE1-stimulated IL-6 release. PD98059, a p44/p42 MAPK inhibitor, and SP600125, a SAPK/JNK inhibitor, upregulated PGE1-stimulated IL-6 release. On the other hand, SB203580, a p38 MAPK inhibitor, suppressed PGE1-stimulated IL-6 release. YM-08 stimulated the PGE1-induced phosphorylation of p38 MAPK. SB203580 suppressed the amplification by YM-08 of the PGE1-stimulated IL-6 release. Our results suggest that HSP70 inhibitors upregulate the PGE1-stimulated IL-6 synthesis through p38 MAPK in osteoblasts and therefore affect bone remodeling.
    DOI:  https://doi.org/10.1371/journal.pone.0279134
  10. Front Surg. 2022 ;9 1065172
    Extracellular vesicles derived from fibroblasts induced with or without high glucose exert opposite effects on wound healing and angiogenesis.
    Xiaowei Bian, Bingmin Li, Haowen Tang, Qiankun Li, Wenzhi Hu, Qian Wei, Kui Ma, Yuguang Yang, Haihong Li, Xiaobing Fu, Cuiping Zhang.
      Background: Communication between fibroblasts and endothelial cells is essential for skin wound repair and regeneration. Extracellular vesicles (EVs) are crucial for intracellular communication by transporting active molecules. However, whether EVs derived from diabetic fibroblasts can perform the nomal communication function is unclear. Here, we compared the effects of EVs from human skin fibroblasts (HSFs) induced with or without HG on the angiogenic function of endothelial cells and wound healing.Methods: We first collected EVs from HSFs cultured with normal glucose concentration (NG-EVs) or with HG concentration (HG-EVs) and applied them to treat human umbilical vein endothelial cells (HUVECs). The cells were divided into three groups: control group, NG-EVs group, and HG-EVs group. We then examined the proliferation, migration, apoptosis, and tube formation of HUVECs. To illustrate the mechanism, the expression of β-catenin, GSK-3β, and p-GSK-3β was detected by western-blot. Finally, NG-EVs or HG-EVs were used to treat the wounds of mice to determine their role in wound closure.
    Results: By DNA content detection, Annexin V/PI staining, and EdU staining, we found that NG-EVs promoted HUVEC proliferation, while HG-EVs exhibited an opposite effect (p < 0.05). Scratch assay and tube formation assay demonstrated that NG-EV promoted angiogenesis in vitro, while HG-EVs showed negative impact (p < 0.05). The expressions of β-catenin and p-GSK-3β in HUVECs were enhanced by NG-EVs and decreased by HG-EVs (p < 0.05). Additionally, the in vivo experiment demonstrated that NG-EVs effectively promoted wound healing by locally enhancing blood supply and angiogenesis. In contrast, HG-EVs leaded to delayed wound closure and reduced blood supply and angiogenesis (p < 0.05).
    Conclusion: NG-EVs and HG-EVs exert opposite effects on wound healing and angiogenesis possibly by regulating GSK-3β/β-catenin signaling pathway. This research may provide a new treatment strategy for wound healing and illustrate the mechanism for impaired angiogenesis in diabetics.
    Keywords:  angiogenesis; endothelial cells; extracellular vesicles; fibroblasts; high glucose; wound healing
    DOI:  https://doi.org/10.3389/fsurg.2022.1065172
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