bims-stacyt Biomed News
on Paracrine crosstalk between cancer and the organism
Issue of 2019‒06‒16
six papers selected by
Cristina Muñoz Pinedo
L’Institut d’Investigació Biomèdica de Bellvitge


  1. J Exp Clin Cancer Res. 2019 Jun 07. 38(1): 241
    Offer S, Menard JA, Pérez JE, de Oliveira KG, Chandran VI, Johansson MC, Bång-Rudenstam A, Siesjö P, Ebbesson A, Hedenfalk I, Sundgren PC, Darabi A, Belting M.
      BACKGROUND: Primary brain tumors, in particular glioblastoma (GBM), remain among the most challenging cancers. Like most malignant tumors, GBM is characterized by hypoxic stress that triggers paracrine, adaptive responses, such as angiogenesis and macrophage recruitment, rescuing cancer cells from metabolic catastrophe and conventional oncological treatments. The unmet need of strategies to efficiently target tumor "stressness" represents a strong clinical motivation to better understand the underlying mechanisms of stress adaptation. Here, we have investigated how lipid loading may be involved in the paracrine crosstalk between cancer cells and the stromal compartment of the hypoxic tumor microenvironment.METHODS: Regions from patient GBM tumors with or without the lipid loaded phenotype were isolated by laser capture microdissection and subjected to comparative gene expression analysis in parallel with cultured GBM cells with or without lipid loading. The potential involvement of extracellular lipids in the paracrine crosstalk with stromal cells was studied by immunoprofiling of the secretome and functional studies in vitro as well as in various orthotopic GBM mouse models, including hyperlipidemic ApoE-/- mice. Statistical analyses of quantitative experimental methodologies were performed using unpaired Student's T test. For survival analyses of mouse experiments, log-rank test was used, whereas Kaplan-Meier was performed to analyze patient survival.
    RESULTS: We show that the lipid loaded niche of GBM patient tumors exhibits an amplified hypoxic response and that the acquisition of extracellular lipids by GBM cells can reinforce paracrine activation of stromal cells and immune cells. At the functional level, we show that lipid loading augments the secretion of e.g. VEGF and HGF, and may potentiate the cross-activation of endothelial cells and macrophages. In line with these data, in vivo studies suggest that combined local tumor lipid loading and systemic hyperlipidemia of ApoE-/- mice receiving a high fat diet induces tumor vascularization and macrophage recruitment, and was shown to significantly decrease animal survival.
    CONCLUSIONS: Together, these data identify extracellular lipid loading as a potentially targetable modulator of the paracrine adaptive response in the hypoxic tumor niche and suggest the contribution of the distinct lipid loaded phenotype in shaping the glioma microenvironment.
    Keywords:  Angiogenesis; Glioma; Hypoxia; Lipid metabolism; Macrophages
    DOI:  https://doi.org/10.1186/s13046-019-1228-6
  2. J Immunother Cancer. 2019 Jun 13. 7(1): 152
    Marijt KA, Sluijter M, Blijleven L, Tolmeijer SH, Scheeren FA, van der Burg SH, van Hall T.
      BACKGROUND: T-cell mediated immunotherapy brought clinical success for many cancer patients. Nonetheless, downregulation of MHC class I antigen presentation, frequently occurring in solid cancers, limits the efficacy of these therapies. Unraveling the mechanisms underlying this type of immune escape is therefore of great importance. We here investigated the immunological effects of metabolic stress in cancer cells as a result of nutrient deprivation.METHODS: TC1 and B16F10 tumor cell lines were cultured under oxygen- and glucose-deprivation conditions that mimicked the tumor microenvironment of solid tumors. Presentation of peptide antigens by MHC class I molecules was measured by flow cytometry and via activation of tumor-specific CD8 T cell clones. The proficiency of the IFNy-STAT1 pathway was investigated by Western blots on phosphorylated proteins, transfection of constitutive active STAT1 constructs and qPCR of downstream targets. Kinase inhibitors for PI3K were used to examine its role in IFNy receptor signal transduction.
    RESULTS: Combination of oxygen- and glucose-deprivation resulted in decreased presentation of MHC class I antigens on cancer cells, even in the presence of the stimulatory cytokine IFNy. This unresponsiveness to IFNy was the result of failure to phosphorylate the signal transducer STAT1. Forced expression of constitutive active STAT1 fully rescued the MHC class I presentation. Furthermore, oxygen- and glucose-deprivation increased PI3K activity in tumor cells. Pharmacological inhibition of this pathway not only restored signal transduction through IFNy-STAT1 but also improved MHC class I presentation. Importantly, PI3K inhibitors also rendered tumor cells sensitive for recognition by CD8 T cells in culture conditions of metabolic stress.
    CONCLUSIONS: These data revealed a strong impact of metabolic stress on the presentation of tumor antigens by MHC class I and suggest that this type of tumor escape takes place at hypoxic areas even during times of active T cell immunity and IFNy release.
    Keywords:  Cancer metabolism; Immune-escape; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s40425-019-0627-8
  3. Adv Exp Med Biol. 2019 ;1136 1-18
    Luo W, Wang Y.
      Hypoxia is a hallmark of the tumor microenvironment and contributes to tumor malignant phenotypes. Hypoxia-inducible factor (HIF) is a master regulator of intratumoral hypoxia and controls hypoxia-mediated pathological processes in tumors, including angiogenesis, metabolic reprogramming, epigenetic reprogramming, immune evasion, pH homeostasis, cell migration/invasion, stem cell pluripotency, and therapy resistance. In this book chapter, we reviewed the causes and types of intratumoral hypoxia, hypoxia detection methods, and the oncogenic role of HIF in tumorigenesis and chemo- and radio-therapy resistance.
    Keywords:  Angiogenesis; Cell motility; Epigenetics; HIF; Hypoxia; Hypoxia imaging; Metabolism; Stem cell; Therapy resistance; Tumorigenesis
    DOI:  https://doi.org/10.1007/978-3-030-12734-3_1
  4. Mediators Inflamm. 2019 ;2019 8908960
    Wang P, Chen F, Wang W, Zhang XD.
      Hydrogen sulfide (H2S) has been shown to protect against oxidative stress injury and inflammation in various high glucose-induced insult models. However, it remains unknown whether H2S protects human retinal pigment epithelial cells (RPE cells) from high glucose-induced damage. In the current study, cell viability, proinflammatory cytokines, ROS, and inflammasome markers were compared in a low glucose- and high glucose-induced cell culture system. The antioxidant N-acetylcysteine (NAC), NLRP3 siRNA, and NaHS were used to test RPE cell responses. The results demonstrate that compared with the low-glucose culture, high glucose triggered higher cell death and increased IL-18 and IL-1β mRNA expression and protein production. Furthermore, high glucose increased the mRNA expression levels of NLRP3, ACS, and caspase-1. Notably, NAC, a ROS scavenger, could attenuate high glucose-induced ROS formation and IL-18 and IL-1β mRNA and protein expression and block inflammasome activation. Silencing the NLRP3 gene expression also abolished IL-18 and IL-1β mRNA and protein expression. Intrudingly, H2S could ameliorate high glucose-induced ROS formation, IL-18 and IL-1β expression, and inflammasome activation. Taken together, the findings of the present study have demonstrated that H2S protects cultured RPE cells from high glucose-induced damage through inhibiting ROS formation and NLRP3 inflammasome activation. It might suggest that H2S represents a potential therapeutic target for the treatment of diabetic retinopathy.
    DOI:  https://doi.org/10.1155/2019/8908960
  5. Nat Commun. 2019 Jun 11. 10(1): 2416
    Pascual-García M, Bonfill-Teixidor E, Planas-Rigol E, Rubio-Perez C, Iurlaro R, Arias A, Cuartas I, Sala-Hojman A, Escudero L, Martínez-Ricarte F, Huber-Ruano I, Nuciforo P, Pedrosa L, Marques C, Braña I, Garralda E, Vieito M, Squatrito M, Pineda E, Graus F, Espejo C, Sahuquillo J, Tabernero J, Seoane J.
      Cancer response to immunotherapy depends on the infiltration of CD8+ T cells and the presence of tumor-associated macrophages within tumors. Still, little is known about the determinants of these factors. We show that LIF assumes a crucial role in the regulation of CD8+ T cell tumor infiltration, while promoting the presence of protumoral tumor-associated macrophages. We observe that the blockade of LIF in tumors expressing high levels of LIF decreases CD206, CD163 and CCL2 and induces CXCL9 expression in tumor-associated macrophages. The blockade of LIF releases the epigenetic silencing of CXCL9 triggering CD8+ T cell tumor infiltration. The combination of LIF neutralizing antibodies with the inhibition of the PD1 immune checkpoint promotes tumor regression, immunological memory and an increase in overall survival.
    DOI:  https://doi.org/10.1038/s41467-019-10369-9
  6. Anticancer Res. 2019 Jun;39(6): 3039-3046
    Takahashi H, Sakakura K, Arisaka Y, Tokue A, Kaira K, Tada H, Higuchi T, Okamoto A, Tsushima Y, Chikamatsu K.
      BACKGROUND/AIM: Programmed death-ligand 1 (PD-L1) expression in tumor cells is regulated by a close interrelation between tumor and stromal cells within the tumor microenvironment. Our aim was to evaluate the clinical and biological significance of PD-L1 expression in oral squamous cell carcinoma (OSCC).MATERIALS AND METHODS: PD-L1, cluster of differentiation (CD)4, CD8, and forkhead box P3 (FOXP3) expression in tumor tissues obtained from 77 patients with OSCC was evaluated by immunohistochemical staining, and then analyzed for associations with clinical and biological factors.
    RESULTS: Among the clinicopathological factors tested, only vascular invasion showed a trend toward lower PD-L1 expression (p=0.05). Metabolic tumor volume (MTV), and total lesion glycolysis (TLG) significantly positively correlated with PD-L1 expression (MTV, p=0.04; TLG, p=0.03). In patients with OSCC with high PD-L1 expression, those whose tumors had abundant infiltrating CD4+ T-cells showed a longer progression-free survival than those with low CD4+ T-cell infiltration (p=0.0452).
    CONCLUSION: As regulation of PD-L1 expression is complex, its evaluation combined with other markers may be useful to determine clinical applications of PD-L1 expression.
    Keywords:  18F-FDG-PET; 18F-fluorodeoxyglucose positron-emission tomography; OSCC; PD-L1; glucose metabolism; oral squamous cell carcinoma; tumor immune microenvironment; tumor-infiltrating lymphocyte
    DOI:  https://doi.org/10.21873/anticanres.13437