bims-stacyt Biomed News
on Paracrine crosstalk between cancer and the organism
Issue of 2022‒01‒09
twelve papers selected by
Cristina Muñoz Pinedo
L’Institut d’Investigació Biomèdica de Bellvitge
  1. The Metabolism Symbiosis Between Pancreatic Cancer and Tumor Microenvironment.
  2. Clinical development of metabolic inhibitors for oncology.
  3. Diet, lipids, and antitumor immunity.
  4. The "Dialogue" Between Central and Peripheral Immunity After Ischemic Stroke: Focus on Spleen.
  5. IL-6/STAT3 Is a Promising Therapeutic Target for Hepatocellular Carcinoma.
  6. Extracellular ATP is increased by release of ATP-loaded microparticles triggered by nutrient deprivation.
  7. Unfolded protein response activated by endoplasmic reticulum stress in pancreatic cancer: potential therapeutical target.
  8. Serum Exosomal mir-340-5p Promotes Angiogenesis in Brain Microvascular Endothelial Cells During Oxygen-Glucose Deprivation.
  9. UDCA Inhibits Hypoxic Hepatocellular Carcinoma Cell-Induced Angiogenesis Through Suppressing HIF-1α/VEGF/IL-8 Intercellular Signaling.
  10. Targeting Metabolic Pathways of Myeloid Cells Improves Cancer Immunotherapy.
  11. Lipid Accumulation and IL-6 Production in L02 Hepatocytes Induced by Sodium Oleate: Dose and Time Dependence.
  12. Evidence for the effect of soluble uric acid in augmenting endoplasmic reticulum stress markers in human peripheral blood mononuclear cells.
  1. Front Oncol. 2021 ;11 759376
    The Metabolism Symbiosis Between Pancreatic Cancer and Tumor Microenvironment.
    Ying Li, Ju Zhang, Jie Xu, Shanglong Liu.
      Complex interactions occur between tumor cells and the tumor microenvironment. Studies have focused on the mechanism of metabolic symbiosis between tumors and the tumor microenvironment. During tumor development, the metabolic pattern undergoes significant changes, and the optimal metabolic mode of the tumor is selected on the basis of its individual environment. Tumor cells can adapt to a specific microenvironment through metabolic adjustment to achieve compatibility. In this study, the effects of tumor glucose metabolism, lipid metabolism, and amino acid metabolism on the tumor microenvironment and related mechanisms were reviewed. Selective targeting of tumor cell metabolic reprogramming is an attractive direction for tumor therapy. Understanding the mechanism of tumor metabolic adaptation and determining the metabolism symbiosis mechanism between tumor cells and the surrounding microenvironment may provide a new approach for treatment, which is of great significance for accelerating the development of targeted tumor metabolic drugs and administering individualized tumor metabolic therapy.
    Keywords:  crosstalk; metabolic remodeling; metabolism symbiosis; pancreatic cancer; tumor microenvironment
    DOI:  https://doi.org/10.3389/fonc.2021.759376
  2. J Clin Invest. 2022 Jan 04. pii: e148550. [Epub ahead of print]132(1):
    Clinical development of metabolic inhibitors for oncology.
    Kathryn M Lemberg, Sadakatali S Gori, Takashi Tsukamoto, Rana Rais, Barbara S Slusher.
      Metabolic inhibitors have been used in oncology for decades, dating back to antimetabolites developed in the 1940s. In the past 25 years, there has been increased recognition of metabolic derangements in tumor cells leading to a resurgence of interest in targeting metabolism. More recently there has been recognition that drugs targeting tumor metabolism also affect the often acidic, hypoxic, immunosuppressive tumor microenvironment (TME) and non-tumor cell populations within it, including immune cells. Here we review small-molecule metabolic inhibitors currently in clinical development for oncology applications. For each agent, we evaluate the preclinical studies demonstrating antitumor and TME effects and review ongoing clinical trials. The goal of this Review is to provide an overview of the landscape of metabolic inhibitors in clinical development for oncology.
    DOI:  https://doi.org/10.1172/JCI148550
  3. Cell Mol Immunol. 2022 Jan 05.
    Diet, lipids, and antitumor immunity.
    Hannah Prendeville, Lydia Lynch.
      Tumour growth and dissemination is largely dependent on nutrient availability. It has recently emerged that the tumour microenvironment is rich in a diverse array of lipids that increase in abundance with tumour progression and play a role in promoting tumour growth and metastasis. Here, we describe the pro-tumorigenic roles of lipid uptake, metabolism and synthesis and detail the therapeutic potential of targeting lipid metabolism in cancer. Additionally, we highlight new insights into the distinct immunosuppressive effects of lipids in the tumour microenvironment. Lipids threaten an anti-tumour environment whereby metabolic adaptation to lipid metabolism is linked to immune dysfunction. Finally, we describe the differential effects of commondietary lipids on cancer growth which may uncover a role for specific dietary regimens in association with traditional cancer therapies. Understanding the relationship between dietary lipids, tumour, and immune cells is important in the context of obesity which may reveal a possibility to harness the diet in the treatment of cancers.
    Keywords:  Lipids; anti-tumour immunity; cancer; obesity; β-oxidation
    DOI:  https://doi.org/10.1038/s41423-021-00781-x
  4. Front Immunol. 2021 ;12 792522
    The "Dialogue" Between Central and Peripheral Immunity After Ischemic Stroke: Focus on Spleen.
    Hongchen Yu, Yichen Cai, Aiqin Zhong, Yunsha Zhang, Junping Zhang, Shixin Xu.
      The immune response generated by the body after the incidence of ischemic stroke, runs through the comprehensive process of aftermath. During this process of ischemic stroke, the central neuroinflammation and peripheral immune response seriously affect the prognosis of patients, which has been the focus of research in recent years. As this research scenario progressed, the "dialogue" between central nervous inflammation and peripheral immune response after ischemic stroke has become more closely related. It's worth noting that the spleen, as an important peripheral immune organ, plays a pivotal role in this dialogue. Multiple mechanisms have previously been reported for brain-spleen crosstalk after ischemic stroke. Further, neuroinflammation in the brain can affect the peripheral immune state by activating/inhibiting spleen function. However, the activation of the peripheral immune inflammatory response can work reversibly in the spleen. It further affects intracerebral neuroinflammation through the injured blood-brain barrier. Therefore, paying close attention to the role of spleen as the pivot between central and peripheral immunity in ischemic stroke may help to provide a new target for immune intervention in the treatment of ischemic stroke. In the present review, we reviewed the important role of spleen in central neuroinflammation and peripheral immune response after ischemic stroke. We summarized the relevant studies and reports on spleen as the target of immune intervention which can provide new ideas for the clinical treatment of ischemic stroke.
    Keywords:  brain-spleen crosstalk; immune response; ischemic stroke; neuroinflammation; spleen
    DOI:  https://doi.org/10.3389/fimmu.2021.792522
  5. Front Oncol. 2021 ;11 760971
    IL-6/STAT3 Is a Promising Therapeutic Target for Hepatocellular Carcinoma.
    Junnv Xu, Haifeng Lin, Gang Wu, Mingyue Zhu, Mengsen Li.
      Hepatocellular carcinoma (HCC) is a common malignant tumor of which the occurrence and development, the tumorigenicity of HCC is involving in multistep and multifactor interactions. Interleukin-6 (IL-6), a multifunctional inflammatory cytokine, has increased expression in HCC patients and is closely related to the occurrence of HCC and prognosis. IL-6 plays a role by binding to the IL-6 receptor (IL-6R) and then triggering the Janus kinase (JAK) associated with the receptor, stimulating phosphorylation and activating signal transducer and activator of transcription 3 (STAT3) to initiate downstream signals, participating in the processes of anti-apoptosis, angiogenesis, proliferation, invasion, metastasis, and drug resistance of cancer cells. IL-6/STAT3 signal axes elicit an immunosuppressive in tumor microenvironment, it is important to therapy HCC by blocking the IL-6/STAT3 signaling pathway. Recent, some inhibitors of IL-6/STAT3 have been development, such as S31-201 or IL-6 neutralizing monoclonal antibody (IL-6 mAb), Madindoline A (Inhibits the dimerization of IL-6/IL-6R/gpl30 trimeric complexes), C188-9 and Curcumin (Inhibits STAT3 phosphorylation), etc. for treatment of cancers. Overall, consideration of the IL-6/STAT3 signaling pathway, and its role in the carcinogenesis and progression of HCC will contribute to the development of potential drugs for targeting treatment of liver cancer.
    Keywords:  IL-6 receptor; IL-6/STAT3 signal; hepatocellular carcinoma; malignant transformation; targeted treatment
    DOI:  https://doi.org/10.3389/fonc.2021.760971
  6. Theranostics. 2022 ;12(2): 859-874
    Extracellular ATP is increased by release of ATP-loaded microparticles triggered by nutrient deprivation.
    Valentina Vultaggio-Poma, Simonetta Falzoni, Paola Chiozzi, Alba Clara Sarti, Elena Adinolfi, Anna Lisa Giuliani, Alejandro Sánchez-Melgar, Paola Boldrini, Michele Zanoni, Anna Tesei, Paolo Pinton, Francesco Di Virgilio.
      Rationale: Caloric restriction improves the efficacy of anti-cancer therapy. This effect is largely dependent on the increase of the extracellular ATP concentration in the tumor microenvironment (TME). Pathways for ATP release triggered by nutrient deprivation are largely unknown. Methods: The extracellular ATP (eATP) concentration was in vivo measured in the tumor microenvironment of B16F10-inoculated C57Bl/6 mice with the pmeLuc probe. Alternatively, the pmeLuc-TG-mouse was used. Caloric restriction was in vivo induced with hydroxycitrate (HC). B16F10 melanoma cells or CT26 colon carcinoma cells were in vitro exposed to serum starvation to mimic nutrient deprivation. Energy metabolism was monitored by Seahorse. Microparticle release was measured by ultracentrifugation and by Nanosight. Results: Nutrient deprivation increases eATP release despite the dramatic inhibition of intracellular energy synthesis. Under these conditions oxidative phosphorylation was dramatically impaired, mitochondria fragmented and glycolysis and lactic acid release were enhanced. Nutrient deprivation stimulated a P2X7-dependent release of ATP-loaded, mitochondria-containing, microparticles as well as of naked mitochondria. Conclusions: Nutrient deprivation promotes a striking accumulation of eATP paralleled by a large release of ATP-laden microparticles and of naked mitochondria. This is likely to be a main mechanism driving the accumulation of eATP into the TME.
    Keywords:  P2X7.; extracellular ATP; microparticles; nutrient deprivation; tumor microenvironment
    DOI:  https://doi.org/10.7150/thno.66274
  7. Front Biosci (Landmark Ed). 2021 Dec 30. 26(12): 1689-1696
    Unfolded protein response activated by endoplasmic reticulum stress in pancreatic cancer: potential therapeutical target.
    Di Long, Kai Chen, Yinmo Yang, Xiaodong Tian.
      Pancreatic cancer is still one of the most perilous malignant tumors with a very poor prognosis. Despite the progress in the diagnosis and treatment of pancreatic cancer, the overall 5-year survival rate after diagnosis is less than 10%. The pathogenesis of pancreatic cancer has not been fully clarified, but multiple factors are involved. The poor efficacy of traditional therapies for pancreatic cancer is mainly related to complex tumor microenvironment. In recent years, accumulating studies have demonstrated the role of autophagy and apoptosis triggered by endoplasmic reticulum stress in pancreatic cancer. In particular, unfolded protein response is activated by endoplasmic reticulum stress and plays an important role in the modulation of complex pancreatic tumor microenvironment. Here we summarize recent progress in our understanding of the role of unfolded protein response activated by endoplasmic reticulum stress in tumorigenesis of pancreatic cancer, and highlight the potential of the cascade of unfolded protein response as therapeutic target for pancreatic cancer.
    Keywords:  Apoptosis; Endoplasmic reticulum stress; Pancreatic cancer; Unfolded protein response
    DOI:  https://doi.org/10.52586/5061
  8. Neurochem Res. 2022 Jan 07.
    Serum Exosomal mir-340-5p Promotes Angiogenesis in Brain Microvascular Endothelial Cells During Oxygen-Glucose Deprivation.
    Chuan Xu, Hailong Yu, Beilei Chen, Yuan Ma, Penghua Lv.
      Ischemic stroke (IS) is a cerebrovascular disease with high morbidity, recurrence, and mortality. The purpose of the present study was to investigate the role and mechanism of human serum exosomes on angiogenesis after IS. The middle cerebral artery occlusion (MCAO) in vivo model and oxygen-glucose deprivation (OGD) in vitro model were established. Human serum exosomes from healthy samples (NC-exo) and IS samples (IS-exo) were injected into MCAO mice. Neurobehavioral tests were performed to assess the extent of neurological deficits. The infarct volume was assessed by 2,3,5-triphenyl tetrazolium chloride (TTC) staining, and the levels of inflammatory cytokines were analyzed by enzyme-linked immunosorbent assay (ELISA). In addition, human serum exosomes were cocultured with brain microvascular endothelial cells (BMECs). Cell Counting Kit-8 (CCK-8), Transwell, and tubule formation assays were performed to investigate the proliferation, migration, invasion, length, and branching of BMECs. The miRNA expression profiles of NC-exo and IS-exo were analyzed by high-throughput sequencing and compared. Bioinformatics and luciferase reporter assays were performed to evaluate the relationship between miR-340-5p and CD147. Serum NC-exo and IS-exo had protective effects on IS injury and promoted BMEC angiogenesis. Interestingly, the protective effect of IS-exo was weaker than that of NC-exo. In addition, miR-340-5p was downregulated in IS-exo, and miR-340-5p accelerated angiogenesis of BMECs after OGD. Mechanistically, CD147 was confirmed as a direct target of miR-340-5p. Finally, miR-340-5p promoted angiogenesis by directly targeting CD147. Serum exosome-derived miR-340-5p promote angiogenesis in OGD-induced BMECs by targeting CD147.
    Keywords:  Angiogenesis; CD147; Exosome; IS; miR-340-5p
    DOI:  https://doi.org/10.1007/s11064-021-03492-x
  9. Front Pharmacol. 2021 ;12 755394
    UDCA Inhibits Hypoxic Hepatocellular Carcinoma Cell-Induced Angiogenesis Through Suppressing HIF-1α/VEGF/IL-8 Intercellular Signaling.
    Wanfu Lin, Shu Li, Yongbin Meng, Guokai Huang, Shufang Liang, Juan Du, Qun Liu, Binbin Cheng.
      Background: A hypoxic microenvironment may induce angiogenesis and promote the development of hepatocellular carcinoma (HCC). The aim of this study was to evaluate whether ursodeoxycholic acid (UDCA) may inhibit hypoxic HCC cell-induced angiogenesis and the possible mechanisms. Methods: Tube formation and matrigel plug angiogenesis assays were used to evaluate angiogenesis in vitro and in vivo, respectively. Real-time PCR, enzyme-linked immunosorbent assay, and Western blot were used to evaluate the mRNA and protein expressions of hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF), and IL-8, respectively. Dual-luciferase reporter assay was applied to assess the reporter gene expression of hypoxia-response element (HRE). Results: UDCA antagonized hypoxic Huh 7 cell-induced tube formation of EA.hy 926 cells. In HCC cells, UDCA inhibited hypoxia-induced upregulation of VEGF and IL-8 both in mRNA and protein levels. UDCA also inhibited IL-8-induced angiogenesis in vitro and in vivo through suppressing IL-8-induced phosphorylation of ERK. The levels of HIF-1α mRNA and protein and HRE-driven luciferase activity in HCC cells were upregulated by hypoxia and were all inhibited by UDCA. The proteasome inhibitor MG132 antagonized the effect of UDCA on HIF-1α degradation. In hypoxic condition, the phosphorylation of ERK and AKT was obviously increased in HCC cells, which was suppressed by UDCA. Transfection of the HIF-1α overexpression plasmid reversed the effects of UDCA on hypoxic HCC cell-induced angiogenesis, HRE activity, and expressions of IL-8 and VEGF. Conclusions: Our results demonstrated that UDCA could inhibit hypoxic HCC cell-induced angiogenesis through suppressing HIF-1α/VEGF/IL-8-mediated intercellular signaling between HCC cells and endothelial cells.
    Keywords:  HIF-1α; IL-8; angiogenesis; hepatocellular carcinoma; hypoxia
    DOI:  https://doi.org/10.3389/fphar.2021.755394
  10. Front Cell Dev Biol. 2021 ;9 747863
    Targeting Metabolic Pathways of Myeloid Cells Improves Cancer Immunotherapy.
    Jianying Li, Chelsea Bolyard, Gang Xin, Zihai Li.
      Tumor-infiltrating myeloid cells are a prominent pro-tumorigenic immune cell population that limit host anti-tumor immunity and present a significant obstacle for many cancer immunotherapies. Targeting the mechanisms regulating myeloid cell function within the tumor microenvironment may overcome immunotherapy resistance in some cancers. Recent discoveries in the emerging field of immunometabolism reveal that the metabolic profiles of intratumoral myeloid cells are rewired to adapt to the nutrition-limited tumor microenvironment, and this shapes their pro-tumor phenotypes. Interestingly, metabolic modulation can shift these myeloid cells toward the immune-stimulating anti-tumor phenotype. In this review, we will highlight the roles of specific metabolic pathways in the activation and function of myeloid cells, and discuss the therapeutic value of metabolically reprogramming myeloid cells to augment and improve outcomes with cancer immunotherapy.
    Keywords:  immunometabolism; immunotherapy; myeloid cells; myeloid-derived suppressor cells; tumor-associated dendritic cells; tumor-associated macrophages; tumor-associated neutrophils; tumor-infiltrating myeloid cells
    DOI:  https://doi.org/10.3389/fcell.2021.747863
  11. Biomed Environ Sci. 2021 Dec 20. 34(12): 998-1004
    Lipid Accumulation and IL-6 Production in L02 Hepatocytes Induced by Sodium Oleate: Dose and Time Dependence.
    Chen Chen, Jun Sheng Huo, Qin Zhuo, Yan Li, Yan Ma, Jing Bo Wang, Xu Dong Jia.
      To explore interleukin-6 (IL-6) production and characterize lipid accumulation in L02 hepatocytes induced by sodium oleate. L02 hepatocytes were incubated with 0, 37.5, 75, 150, 300, 600, or 1,200 μmol/L sodium oleate for 24 h, and the supernatant was collected to detect the concentration of IL-6. L02 hepatocytes were incubated with 300, 150, 75, or 0 μmol/L sodium oleate for 0-24 h. The supernatant was collected for detection of IL-6 and free fatty acids. L02 hepatocytes treated with 300 μmol/L sodium oleate for 0-24 h were stained with Oil Red O. With extended sodium oleate incubation time, IL-6 levels increased, and free fatty acids decreased. After 24 h incubation, IL-6 levels increased as sodium oleate increased from 37.5 to 300 μmol/L ( P < 0.05 for 37.5 μmol/L, P < 0.01 for 75 μmol/L and P < 0.001 for concentrations 150 μmol/L or higher). Lipid accumulation increased as the sodium oleate concentration and incubation time increased. Oil Red O staining intensified with incubation time extending beyond 2 h. IL-6 production and lipid accumulation in L02 hepatocytes are influenced by sodium oleate in a dose- and time-dependent manner.
    Keywords:  IL-6; L02 hepatocytes; Lipid accumulation; Sodium oleate
    DOI:  https://doi.org/10.3967/bes2021.058
  12. J Physiol Biochem. 2022 Jan 05.
    Evidence for the effect of soluble uric acid in augmenting endoplasmic reticulum stress markers in human peripheral blood mononuclear cells.
    Reyhane Ebrahimi, Parvin Pasalar, Hajar Shokri, Maryam Shabani, Solaleh Emamgholipour.
      There is evidence regarding the association of hyperuricemia with inflammatory disorders. Hence, it has been of particular interest to dissect the exact role of alteration in uric acid (UA) levels in the context of inflammation. Recently, the endoplasmic reticulum (ER) stress pathway has come into the forefront as a possible mechanism linking hyperuricemia to inflammation. Here, we intended to examine the role of UA in the presence or absence of a second stimulus, LPS, in human peripheral blood mononuclear cells (PBMCs), and analyzed ROS production as well as expression of ER stress markers: GRP78 and CHOP, and inflammatory cytokines.PBMCs were isolated using Ficoll gradient centrifugation from healthy volunteers. Cell viability was measured by MTT assay. PBMCs were treated with an increasing concentration of soluble UA (0, 5, 12, and 20 mg/dl) for 20 h, followed by the addition of 100 ng/mL of LPS or vehicle for another 4 h. Real time-PCR was performed to investigate the mRNA expression of GRP78, CHOP, TNF-α, IL-1β, and IL-6, and western blot was used to investigate the protein levels of GRP78 and CHOP. Moreover, ELISA was used to evaluate the protein levels of TNF-α, IL-1β, and IL-6. Finally, intracellular ROS production was determined using fluorescent probes (DCFH-DA).High concentrations of UA either alone or combined with LPS increased the protein levels of GRP78 and CHOP. On the other hand, LPS alone increased the protein levels of GRP78 and CHOP. However, there was no significant difference between the mRNA expression of GRP78, CHOP, TNF-α, IL-1β, and IL-6 when PBMCs were treated with UA. High concentrations of UA augmented LPS-stimulated IL-1β transcript and protein levels as well as TNF-α protein levels in PBMC culture. Moreover, high concentrations of UA along with LPS significantly increased intracellular ROS production.It seems that a high concentration of UA not only induces the protein levels of ER stress markers in PBMCs but also augments the impact of LPS on the levels of pro-inflammatory markers and ROS production.
    Keywords:  Endoplasmic reticulum stress; Inflammation; Reactive oxygen species; Uric acid
    DOI:  https://doi.org/10.1007/s13105-021-00869-y
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