bims-stacyt Biomed news
on Paracrine crosstalk between cancer and the organism
Issue of 2019‒03‒17
eight papers selected by
Cristina Muñoz Pinedo
L’Institut d’Investigació Biomèdica de Bellvitge

  1. Oncogene. 2019 Mar 12.
    Park JE, Dutta B, Tse SW, Gupta N, Tan CF, Low JK, Yeoh KW, Kon OL, Tam JP, Sze SK.
      Developing tumors rapidly outgrow their oxygen supply and are subject to hypoxia, which stimulates hypersecretion of tumor-derived exosomes that promote angiogenesis, metastasis, and immunosuppression, but the molecular mediators of these pathological effects remain poorly defined. Using quantitative proteomics, we identified that exosomes produced by hypoxic tumor cells are highly enriched in immunomodulatory proteins and chemokines including CSF-1, CCL2, FTH, FTL, and TGFβ. Modeling exosome effects on tumor-infiltrating immune cells, we observed a potent ability of these hypoxia-induced vesicles to influence macrophage recruitment and promote M2-like polarization both in vitro and in vivo. In addition, hypoxic, but not normoxic, tumor exosomes enhanced oxidative phosphorylation in bone marrow-derived macrophages via transfer of let-7a miRNA, resulting in suppression of the insulin-Akt-mTOR signaling pathway. Together, these data demonstrate that hypoxia promotes tumor secretion of biomolecule-loaded exosomes that can modify the immunometabolic profile of infiltrating monocyte-macrophages to better evade host immunity and enhance tumor progression.
  2. Cell Metab. 2019 Mar 04. pii: S1550-4131(19)30069-5. [Epub ahead of print]
    Hu CM, Tien SC, Hsieh PK, Jeng YM, Chang MC, Chang YT, Chen YJ, Chen YJ, Lee EYP, Lee WH.
      KRAS mutations are the earliest events found in approximately 90% of pancreatic ductal adenocarcinomas (PDACs). However, little is known as to why KRAS mutations preferentially occur in PDACs and what processes/factors generate these mutations. While abnormal carbohydrate metabolism is associated with a high risk of pancreatic cancer, it remains elusive whether a direct relationship between KRAS mutations and sugar metabolism exists. Here, we show that under high-glucose conditions, cellular O-GlcNAcylation is significantly elevated in pancreatic cells that exhibit lower phosphofructokinase (PFK) activity than other cell types. This post-translational modification specifically compromises the ribonucleotide reductase (RNR) activity, leading to deficiency in dNTP pools, genomic DNA alterations with KRAS mutations, and cellular transformation. These results establish a mechanistic link between a perturbed sugar metabolism and genomic instability that induces de novo oncogenic KRAS mutations preferentially in pancreatic cells.
    Keywords:  KRAS mutation; O-GlcNAcylation; PFK; RNR; RRM1; high glucose; nucleotide imbalance
  3. Theranostics. 2019 ;9(4): 1001-1014
    Deng F, Zhou R, Lin C, Yang S, Wang H, Li W, Zheng K, Lin W, Li X, Yao X, Pan M, Zhao L.
      Angiogenesis is a fundamental process that involves in tumor progression and metastasis. Vascular endothelial growth factor (VEGF) family and their receptors are identified as the most prominent regulators of angiogenesis. However, the clinical efficacy of anti-VEGF/VEGFR therapy is not ideal, prompting the needs to further understand mechanisms behind tumor angiogenesis. Here, we found that Dickkopf associated protein 2 (DKK2), a secretory protein highly expressed in metastatic colorectal cancer tissues, could stimulate angiogenesis via a classic VEGF/VEGFR independent pathway. Methods: DKK2 was screened out from microarray data analyzing gene expression profiles of eight pairs of non-metastatic and metastatic human colorectal cancer (CRC) tissues. Immunofluorescence histochemical staining (IHC) was used to detect the expression of DKK2 and angiogenesis in CRC tissues. Chicken chorioallantoic membrane (CAM) assay and Human umbilical vein endothelial cells (HUVEC) tubule formation assay was used for in vitro and in vivo angiogenesis study, respectively. Lactate and glucose concentration in the culture medium was measured by enzyme-linked immunosorbent assay (ELISA). Luciferase reporter assay was used to verify the interaction between miR-493-5p and the 3'UTR of DKK2. Results: DKK2 could stimulate angiogenesis via accelerating the aerobic glycolysis of CRC cells, through which lactate is produced from glucose and accumulated in tumor microenvironment. Lactate functions as the final executor of DDK2 to stimulate tube formation of endothelial cells, and blockage of lactate secretion by lactate transporter (MCT) inhibitors dramatically neutralize the progression and metastasis of CRC both in vitro and in vivo. DKK2 could cooperate with lipoprotein receptor-related protein 6, which is required for glucose uptake, and activated the downstream mTOR signal pathway to accelerate lactate secretion. In addition, the expression of DKK2 is switched on via the demethylation of miR-493-5p, which allows the dissociated of miR-493-5p from the 3'-UTRs of DKK2 and initiates its stimulatory role on CRC progression in an autocrine or paracrine manner. Conclusion: DKK2 promotes tumor metastasis and angiogenesis through a novel VEGF-independent, but energy metabolism related pathway. DKK2 might be a potential anti-angiogenic target in clinical treatment for the advanced CRC patients.
    Keywords:  Aerobic Glycolysis; Angiogenesis; Colorectal cancer; Dickkopf 2; Vascular endothelial growth factor
  4. Sci Rep. 2019 Mar 11. 9(1): 4034
    Finucane OM, Sugrue J, Rubio-Araiz A, Guillot-Sestier MV, Lynch MA.
      Inflammation and metabolism are intricately linked during inflammatory diseases in which activation of the nucleotide-binding domain-like receptors Family Pyrin Domain Containing 3 (NLRP3) inflammasome, an innate immune sensor, is critical. Several factors can activate the NLRP3 inflammasome, but the nature of the link between NLRP3 inflammasome activation and metabolism remains to be thoroughly explored. This study investigates whether the small molecule inhibitor of the NLRP3 inflammasome, MCC950, modulates the lipopolysaccharide (LPS) -and amyloid-β (Aβ)-induced metabolic phenotype and inflammatory signature in macrophages. LPS + Aβ induced IL-1β secretion, while pre-treatment with MCC950 inhibited this. LPS + Aβ also upregulated IL-1β mRNA and supernatant concentrations of TNFα, IL-6 and IL-10, however these changes were insensitive to MCC950, confirming that MCC950 specifically targets inflammasome activation in BMDMs. LPS + Aβ increased glycolysis and the glycolytic enzyme, PFKFB3, and these effects were decreased by MCC950. These findings suggest that NLRP3 inflammasome activation may play a role in modulating glycolysis. To investigate this further, the effect of IL-1β on glycolysis was assessed. IL-1β stimulated glycolysis and PFKFB3, mimicking the effect of LPS + Aβ and adding to the evidence that inflammasome activation impacts on metabolism. This contention was supported by the finding that the LPS + Aβ-induced changes in glycolysis and PFKFB3 were attenuated in BMDMs from NLRP3-deficient and IL-1R1-deficient mice. Consistent with a key role for PFKFB3 is the finding that the PFKFB3 inhibitor, 3PO, attenuated the LPS + Aβ-induced glycolysis. The data demonstrate that activation of the NLRP3 inflammasome, and the subsequent release of IL-1β, play a key role in modulating glycolysis via PFKFB3. Reinstating metabolic homeostasis by targeting the NLRP3 inflammasome-PFKFB3 axis may provide a novel therapeutic target for treatment of acute and chronic disease.
  5. Carcinogenesis. 2019 Mar 13. pii: bgy138. [Epub ahead of print]
    Wu J, Li H, Xie H, Wu X, Lan P.
      Colorectal cancer (CRC) is a complex and heterogeneous malignant cancer characterized by its high prevalence and poor prognosis. Among different etiologies, impairment of immune surveillance and dysbiosis are important events to mediate the invasion and metastasis of CRC. Although aberrant distribution of macrophages and microbiota exhibits distinct properties to modulate the malignant behaviors of CRC, the crosstalk among macrophages, microbiomes and tumor cells remains unclear. Exosomes are intercellular messengers carrying different cargo to regulate the biological and pathologic changes of recipient cells. CRC-derived exosomes can educate macrophages and facilitate the angiogenesis and establishment of premetastatic niche. Meanwhile, exosomes from macrophages and microbiome can regulate the tumor microenvironment for tumor progression and dissemination. The aim of this review is to highlight the innovative role of exosomes in the pathogenesis of CRC. Theoretical elaboration of the underlying mechanism provides valuable treating targets of CRC.
  6. Clin Exp Immunol. 2019 Mar 15.
    Yu YR, Ho PC.
      Cancer immunotherapy unleashing the power of host immunity on eliminating cancer cells represents a critical advance in cancer treatment; however, effective anti-tumor responses are largely dampened by the immunosuppressive tumor microenvironment (TME). Emerging studies have revealed that physiological features in the TME, including glucose deprivation, hypoxia and low pH, established by the metabolically dysregulated cancer cells restrict anti-tumor immunity by impeding metabolic fitness of tumor-infiltrating cytotoxic CD8+ T cells and NK cells. Furthermore, infiltrating immunomodulatory cells with different metabolic preferences also facilitate the establishment of the immunosuppressive TME. Therefore, deciphering the metabolic crosstalk between immune cells and cancer cells in the TME and elucidating the impact of this process during tumorigenesis are needed to better harness anti-tumor immunity. Herein, we summarize the immunosuppressive features of TME and how these features impair anti-tumor immunity. Moreover, we postulate how immune cells may be involved in shaping the metabolic features of cancer cells and discuss how we might improve anti-tumor functions of tumor-specific T cells by rewiring their metabolic regulations. This article is protected by copyright. All rights reserved.
    Keywords:  Immunometabolism; immunoediting; tumor microenvironment
  7. Cancer Lett. 2019 Mar 07. pii: S0304-3835(19)30131-4. [Epub ahead of print]450 123-131
    Zhang S, Cao L, Li Z, Qu D.
      The causal connections between chronic inflammation and tumorigenesis are well established and supported by a great deal of evidence and research results over recent decades. Still, many mysteries remain in our understanding of tumor metabolism, not to mention inflammatory-oncogenic transformation. In this review, we examined the Warburg effect and the process of inflammation during tumorigenesis and attempted to extend the knowledge about metabolic reprogramming. This review may establish a useful conceptual framework for understanding the complex pathophysiological process of inflammatory-oncogenic transformation from the metabolic perspective.
    Keywords:  Chronic inflammation; Colorectal cancer; Metabolic reprogramming; Oncogenic transformation; Tumorigenesis
  8. Clin Exp Immunol. 2019 Mar 13.
    Lötscher J, Balmer ML.
      Perception of potential threat is key for survival. The immune system constantly patrols the organism scanning for potential pathogenic or malignant danger. Recent evidence suggests that immunosurveillance not only relies on classic receptors (e.g. TLRs or antibodies) but is also based on sensing of the metabolic environment. Metabolites interact in numerous ways with immune cells and are therefore more than just reaction intermediates. This new perspective opens the door for potential, future therapeutic strategies. Here we describe, how immune functionality during infections, cancer or auto-immunity, as exemplified by short-chain fatty acids, lactate and reactive oxygen species (ROS), can be shaped by metabolic intermediates. This article is protected by copyright. All rights reserved.