bims-stacyt Biomed News
on Paracrine crosstalk between cancer and the organism
Issue of 2019‒12‒15
eleven papers selected by
Cristina Muñoz Pinedo
L’Institut d’Investigació Biomèdica de Bellvitge

  1. Am J Physiol Regul Integr Comp Physiol. 2019 Dec 11.
    Daou HN.
      Cancer cachexia is a complicated disorder of extreme, progressive skeletal muscle.wasting. It is directed by metabolic alterations and systemic inflammation dysregulation. Numerous studies have demonstrated that increased systemic inflammation promotes this type of cachexia and have suggested that cytokines are implicated in the skeletal muscle loss. Exercise is firmly established as an anti-inflammatory therapy that can attenuate or even reverse the process of muscle wasting in cancer cachexia. The interleukin IL-6 is generally considered to be a key player in the development of the microenvironment of malignancy; it promotes tumor growth and metastasis by acting as a bridge between chronic inflammation and cancerous tissue and it also induces skeletal muscle atrophy and protein breakdown. Paradoxically, a beneficial role for IL-6 has also been identified recently, and that is its status as a "founding member" of the myokine class of proteins. Skeletal muscle is an important source of circulating IL-6 in persons who participate in exercise training. IL-6 acts as an anti-inflammatory myokine by inhibiting TNF-α and improving glucose uptake through the stimulation of AMPK signaling. This review discusses the action of IL-6 in skeletal muscle tissue dysfunction and the role of IL-6 as an "exercise factor" that modulates the immune system. This review also sheds light on the main considerations related to the treatment of muscle wasting in cancer cachexia.
    Keywords:  Interleukin-6; cancer cachexia; exercise; inflammation; muscle wasting therapy
  2. Asian Pac J Allergy Immunol. 2019 Dec 14.
    Manuprasert W, Leelahavanichkul A, Kanjanabuch S, Ruangvejvorachai P, Manotham K, Sanguanrungsirikul S, Kanjanabuch T.
      BACKGROUND: Due to the high prevalence of both obstructive sleep apnea syndrome (OSA) and end-stage renal disease (ESRD), the co-existence of both conditions in peritoneal dialysis is demonstrated. Because OSA-induced chronic intermittent hypoxia is well-known, the hypoxia might worsen peritoneal membrane.OBJECTIVE: We tested the influence of chronic intermittent hypoxia upon peritoneal membrane in a Sprague-Dawley rat model.
    METHODS: Normal saline or 3.86% glucose peritoneal dialysis fluid (PDF) were intra-peritoneally administered twice a day as negative (NSS group) and positive controls (PDF group), respectively. Intermittent hypoxia was induced by using a hypoxic chamber with 10% O2 for 8 hours a day plus twice-daily NSS injection (IH group).
    RESULTS: At 12 weeks of the experiments, high serum TNF-α and IL-6 (but not IL-10) with normal renal and liver functions were demonstrated in the IH group (but not the PDF group). In parallel, local cytokines (TNF-α, IL-6, and IL10 in peritoneal membrane) and peritoneal membrane thickness were increased whereas peritoneal membrane hypoxia (hypoxyprobeTM and hypoxia-inducible factor-1α; HIF-1α) was induced in both PDF and IH groups (more prominent in the PDF group). However, the increased vascular density in submesothelial area was established only in the PDF group.
    CONCLUSION: Intermittent hypoxia model induced local peritoneal membrane inflammation and enhanced peritoneal membrane thickness, at least in part, through a mechanism of hypoxia-induced HIF-1α. Although peritoneal membrane alterations from PDF were more prominent than intermittent hypoxia, the combination between intermittent hypoxia with PDF utilization might facilitate peritoneal membrane failure, which will need more study.
  3. Sci Immunol. 2019 Dec 13. pii: eaax8189. [Epub ahead of print]4(42):
    Halaby MJ, Hezaveh K, Lamorte S, Ciudad MT, Kloetgen A, MacLeod BL, Guo M, Chakravarthy A, Medina TDS, Ugel S, Tsirigos A, Bronte V, Munn DH, Pugh TJ, De Carvalho DD, Butler MO, Ohashi PS, Brooks DG, McGaha TL.
      General control nonderepressible 2 (GCN2) is an environmental sensor controlling transcription and translation in response to nutrient availability. Although GCN2 is a putative therapeutic target for immuno-oncology, its role in shaping the immune response to tumors is poorly understood. Here, we used mass cytometry, transcriptomics, and transcription factor-binding analysis to determine the functional impact of GCN2 on the myeloid phenotype and immune responses in melanoma. We found that myeloid-lineage deletion of GCN2 drives a shift in the phenotype of tumor-associated macrophages and myeloid-derived suppressor cells (MDSCs) that promotes antitumor immunity. Time-of-flight mass cytometry (CyTOF) and single-cell RNA sequencing showed that this was due to changes in the immune microenvironment with increased proinflammatory activation of macrophages and MDSCs and interferon-γ expression in intratumoral CD8+ T cells. Mechanistically, GCN2 altered myeloid function by promoting increased translation of the transcription factor CREB-2/ATF4, which was required for maturation and polarization of macrophages and MDSCs in both mice and humans, whereas targeting Atf4 by small interfering RNA knockdown reduced tumor growth. Last, analysis of patients with cutaneous melanoma showed that GCN2-dependent transcriptional signatures correlated with macrophage polarization, T cell infiltrates, and overall survival. Thus, these data reveal a previously unknown dependence of tumors on myeloid GCN2 signals for protection from immune attack.
  4. Rep Biochem Mol Biol. 2019 Jul;8(2): 139-146
    Ahmadiankia N, Bagheri M, Fazli M.
      Background: Breast cancer is the leading cause of cancer related death in women worldwide. The development of metastatic cancer is the main factor contributing to mortality. The molecular mechanisms underlying the metastatic process have yet to be clearly elucidated. However, the interplay between the tumor microenvironment and the cancer cells hold a critical role in influencing the progression of cancer metastasis. Within the microenvironment of solid tumors, the lack of sufficient vasculature leads to the development of nutrient deprived conditions. This study aimed to examine how nutrient deprivation influences factors involved in cancer progression and metastasis. Specifically, we examined how nutrient stress changes cancer cell migration, the gene expression, and cytokine production of metastasis-related factors in a human breast cancer cell line.Methods: MCF7 breast cancer cells were cultured in serum-free media for 24, 48, and 72 h. Cell migration was evaluated using a transwell migration assay. The transcriptional expression of metastatic related genes was examined via real-time PCR. Cytokine production was examined via enzyme-linked immunosorbent assay.
    Results: Nutrient deprivation of the MCF7 cells significantly reduced cell migration after 24 h. However, following 72 h of nutrient deprivation, there was significant increase in cell migration compared to the 24 h group. Transcriptional expression of markers involved in migration including, β-catenin, twist, vimentin, fibronectin, ICAM1, VCAM1, and VEGF were up regulated after 72 h of nutrient deprivation. The cytokines TGFβ1, IL-8, and MCP1 were differentially secreted.
    Conclusion: Nutrient deprivation is an environmental stress factor that can influence the behavior of cancer cells. Current treatments implement nutrient deprivation as a potential cancer treatment. Under short periods of nutrient deprivation, cancer cell migration is inhibited. However, our findings show that following extended lengths of nutrient deprivation, cancer cells are capable of adapting themselves to the environmental condition and restoring their migratory abilities. This, in part, may be a result of increased expression of metastasis-related genes. Further research is required to accurately identify how the expression of metastasis-related genes is modulated and controlled in response to nutrient deprivation and environmental stress.
    Keywords:  Cancer cell migration; Epithelial mesenchymal transition; Nutrient deprivation
  5. Pharmacol Ther. 2019 Dec 10. pii: S0163-7258(19)30203-7. [Epub ahead of print] 107451
    Brown T, Ganapathy V.
      Reprogramming of biochemical pathways is a hallmark of cancer cells, and generation of lactic acid from glucose/glutamine represents one of the consequences of such metabolic alterations. Cancer cells export lactic acid out to prevent intracellular acidification, not only increasing lactate levels but also creating an acidic pH in extracellular milieu. Lactate and protons in tumor microenvironment are not innocuous bystander metabolites but have special roles in promoting tumor-cell proliferation and growth. Lactate functions as a signaling molecule by serving as an agonist for the G-protein-coupled receptor GPR81, involving both autocrine and paracrine mechanisms. In the autocrine pathway, cancer cell-generated lactate activates GPR81 on cancer cells; in the paracrine pathway, cancer cell-generated lactate activates GPR81 on immune cells, endothelial cells, and adipocytes present in tumor stroma. The end result of GPR81 activation is promotion of angiogenesis, immune evasion, and chemoresistance. The acidic pH creates an inwardly directed proton gradient across the cancer-cell plasma membrane, which provides driving force for proton-coupled transporters in cancer cells to enhance supply of selective nutrients. There are several molecular targets in the pathways involved in the generation of lactic acid by cancer cells and its role in tumor promotion for potential development of novel anticancer therapeutics.
    Keywords:  Acidic microenvironment; Angiogenesis; Chemoresistance; Immune evasion; Lactate/GPR81; Nutrient supply
  6. Cancer Res. 2019 Dec 12. pii: canres.3351.2019. [Epub ahead of print]
    Singhal M, Augustin HG.
      Looking beyond tumor angiogenesis, the past decade has witnessed a fundamental change of paradigm with the discovery that the vascular endothelium does not just respond to exogenous cytokines, but exerts active 'angiocrine' gatekeeper roles controling their microenvironment in an instructive manner. While vascular niches host disseminated cancer cells and promote their stemness, endothelial cell-derived angiocrine signals orchestrate a favorable immune milieu to facilitate metastatic growth. Here, we discuss recent advances in the field of tumor microenvironment research and propose angiocrine signals as promising targets of future mechanism-driven anti-metastatic therapies, which may prove useful to synergistically combine with chemotherapy and immunotherapy.
  7. Trends Cancer. 2019 Dec;pii: S2405-8033(19)30200-6. [Epub ahead of print]5(12): 822-834
    Mehla K, Singh PK.
      Macrophages act as scavengers, modulating the immune response against pathogens and maintaining tissue homeostasis. Metabolism governs macrophage differentiation, polarization, mobilization, and the ability to mount an effective antitumor response. However, in cancer, the tumor microenvironment (TME) can actively reprogram macrophage metabolism either by direct exchange of metabolites or through cytokines and other signaling mediators. Thus, metabolic reprogramming holds potential for modulating macrophages and developing new therapeutic approaches. In this review, we provide an overview of macrophage metabolism as it relates to macrophage function and plasticity in cancer.
    Keywords:  M1–M2 macrophage polarization; MUC1; cancer; immunometabolism; metabolic reprogramming; tumor microenvironment; tumor-associated macrophages
  8. Gene. 2019 Dec 07. pii: S0378-1119(19)30936-9. [Epub ahead of print] 144277
    Zhou J, Wang M, Deng D.
      Cerebral ischemia injury is common in cerebral ischemic disease, and treatment options remain limited. Krueppel-like factor 2 (KLF2) is reported to negatively regulate inflammation in several ischemic diseases. Our study aimed to investigate the effects and underlying mechanism of KLF2 in BV2 microglial cells exposed to oxygen and glucose deprivation (OGD). We first found decreased KLF2 and toll-like receptor 2 (TLR2)/TLR4 in these cells. OGD also led to decrease in cell viability and increase in LDH release, apoptosis, the Bax/Bcl-2 ratio, and caspase3/9 expression, as well as production of inflammatory cytokines (e.g., TNFα, IL-1β and IL-6), reactive oxygen species (ROS), and TLR2/TLR4. To examine KLF2's effects on these OGD effects, we infected BV2 microglial cells with an ad-KLF2 or negative control vector, and we found that KLF2 reversed all of the effects of OGD exposure. Furthermore, KLF2 significantly increased levels of BDNF and TrkB in these cells, but these effects were blocked by K252a, a BDNF/TrkB inhibitor. K252a also decreased cell viability and increased apoptosis, inflammatory factors, ROS production, and TLR2/TLR4 expression in OGD-exposed BV2 cells that were treated with KLF2, were implying that K252a could reverse the effects of KLF2 on these cells. Taken together, our study results indicate that KLF2 may protect BV2 microglial cells against OGD injury by activating the BDNF/TrkB pathway.
    Keywords:  BDNF/TrkB; Cerebral ischemia; Kruppel-like factor 2; oxygen and glucose deprivation
  9. Cell Immunol. 2019 Oct 16. pii: S0008-8749(19)30386-7. [Epub ahead of print] 103994
    Frasca D, Diaz A, Romero M, Blomberg BB.
      Leptin is an adipokine secreted primarily by the adipocytes. Leptin has endocrine and immune functions and increases the secretion of pro-inflammatory cytokines by immune cells. Here we show that incubation of B cells from young lean individuals with leptin increases the frequencies of pro-inflammatory B cells and induces intrinsic B cell inflammation, characterized by mRNA expression of pro-inflammatory cytokines (TNF-α and IL-6), chemokines (IL-8), micro-RNAs (miR-155 and miR-16), TLR4 and p16, a cell cycle regulator associated with immunosenescence. We have previously shown that the expression of these pro-inflammatory markers in unstimulated B cells is negatively associated with the response of the same B cells after in vivo or in vitro stimulation. B cells from young lean individuals, after in vitro incubation with leptin, show reduced class switch and influenza vaccine-specific IgG production. Our results altogether show that leptin makes B cells from youn lean individuals similar to those from young obese and elderly lean individuals, suggesting that leptin may be a mechanisms of immunosenescence in human B cells.
    Keywords:  B cells; Immunosenescence; Leptin; Obesity
  10. Cancers (Basel). 2019 Dec 11. pii: E1993. [Epub ahead of print]11(12):
    Yoshikawa N, Saito Y, Manabe H, Nakaoka T, Uchida R, Furukawa R, Muramatsu T, Sugiyama Y, Kimura M, Saito H.
      Cancer cells are strongly dependent on the glycolytic pathway for generation of energy even under aerobic condition through a phenomenon known as the Warburg effect. Rapid proliferation of cancer cells is often accompanied by high glucose consumption and abnormal angiogenesis, which may lead to glucose depletion. In the present study, we investigated how cholangiocarcinoma cells adapt to glucose depletion using a 3D organoid culture system. We cultured organoids derived from cholangiocarcinoma under glucose-free condition and investigated cell proliferation, expression of stem cell markers and resistance to gemcitabine. Cholangiocarcinoma organoids cultured under glucose-free condition showed reduced proliferation but were able to survive. We also observed an increase in the expression of stem cell markers including LGR5 and enhancement of stem cell phenotypic characteristics such as resistance to gemcitabine through AKT phosphorylation and reactive oxygen species. These findings indicate that cholangiocarcinoma cells are able to adapt to glucose depletion through enhancement of their stem cell phenotype in response to changes in microenvironmental conditions.
    Keywords:  AKT phosphorylation; cholangiocarcinoma; gemcitabine resistance; glucose depletion; organoid culture; reactive oxygen species
  11. Basic Res Cardiol. 2019 Dec 10. 115(1): 3
    Billah M, Ridiandries A, Rayner BS, Allahwala UK, Dona A, Khachigian LM, Bhindi R.
      Despite improved treatment options myocardial infarction (MI) is still a leading cause of mortality and morbidity worldwide. Remote ischemic preconditioning (RIPC) is a mechanistic process that reduces myocardial infarction size and protects against ischemia reperfusion (I/R) injury. The zinc finger transcription factor early growth response-1 (Egr-1) is integral to the biological response to I/R, as its upregulation mediates the increased expression of inflammatory and prothrombotic processes. We aimed to determine the association and/or role of Egr-1 expression with the molecular mechanisms controlling the cardioprotective effects of RIPC. This study used H9C2 cells in vitro and a rat model of cardiac ischemia reperfusion (I/R) injury. We silenced Egr-1 with DNAzyme (ED5) in vitro and in vivo, before three cycles of RIPC consisting of alternating 5 min hypoxia and normoxia in cells or hind-limb ligation and release in the rat, followed by hypoxic challenge in vitro and I/R injury in vivo. Post-procedure, ED5 administration led to a significant increase in infarct size compared to controls (65.90 ± 2.38% vs. 41.00 ± 2.83%, p < 0.0001) following administration prior to RIPC in vivo, concurrent with decreased plasma IL-6 levels (118.30 ± 4.30 pg/ml vs. 130.50 ± 1.29 pg/ml, p < 0.05), downregulation of the cardioprotective JAK-STAT pathway, and elevated myocardial endothelial dysfunction. In vitro, ED5 administration abrogated IL-6 mRNA expression in H9C2 cells subjected to RIPC (0.95 ± 0.20 vs. 6.08 ± 1.40-fold relative to the control group, p < 0.05), resulting in increase in apoptosis (4.76 ± 0.70% vs. 2.23 ± 0.34%, p < 0.05) and loss of mitochondrial membrane potential (0.57 ± 0.11% vs. 1.0 ± 0.14%-fold relative to control, p < 0.05) in recipient cells receiving preconditioned media from the DNAzyme treated donor cells. This study suggests that Egr-1 functions as a master regulator of remote preconditioning inducing a protective effect against myocardial I/R injury through IL-6-dependent JAK-STAT signaling.
    Keywords:  Egr-1; Interleukin-6; JAK–STAT; Myocardial Infarction; Remote preconditioning