bims-stacyt Biomed News
on Paracrine crosstalk between cancer and the organism
Issue of 2020‒08‒23
nine papers selected by
Cristina Muñoz Pinedo
L’Institut d’Investigació Biomèdica de Bellvitge


  1. Cells. 2020 Aug 12. pii: E1892. [Epub ahead of print]9(8):
    Al-Rashed F, Sindhu S, Arefanian H, Al Madhoun A, Kochumon S, Thomas R, Al-Kandari S, Alghaith A, Jacob T, Al-Mulla F, Ahmad R.
      Repetitive intermittent hyperglycemia (RIH) is an independent risk factor for complications associated with type-2 diabetes (T2D). Glucose fluctuations commonly occur in T2D patients with poor glycemic control or following intensive therapy. Reducing blood glucose as well as glucose fluctuations is critical to the control of T2D and its macro-/microvascular complications. The interferon regulatory factor (IRF)-5 located downstream of the nutrient sensor toll-like receptor (TLR)-4, is emerging as a key metabolic regulator. It remains unclear how glucose fluctuations may alter the IRF5/TLR4 expression and inflammatory responses in monocytes/macrophages. To investigate this, first, we determined IRF5 gene expression by real-time qRT-PCR in the white adipose tissue samples from 39 T2D and 48 nondiabetic individuals. Next, we cultured THP-1 macrophages in hypo- and hyperglycemic conditions and compared, at the protein and transcription levels, the expressions of IRF5, TLR4, and M1/M2 polarization profile and inflammatory markers against control (normoglycemia). Protein expression was assessed using flow cytometry, ELISA, Western blotting, and/or confocal microscopy. IRF5 silencing was achieved by small interfering RNA (siRNA) transfection. The data show that adipose IRF5 gene expression was higher in T2D than nondiabetic counterparts (P = 0.006), which correlated with glycated hemoglobin (HbA1c) (r = 0.47/P < 0.001), homeostatic model assessment of insulin resistance (HOMA-IR) (r = 0.23/P = 0.03), tumor necrosis factor (TNF)-α (r = 0.56/P < 0.0001), interleukin (IL)-1β (r = 0.40/P = 0.0009), and C-C motif chemokine receptor (CCR)-2 (r = 0.49/P < 0.001) expression. IRF5 expression in macrophages was induced/upregulated (P < 0.05) by hypoglycemia (3 mM/L), persistent hyperglycemia (15 mM/L-25 mM/L), and RIH/glucose fluctuations (3-15 mM/L) as compared to normoglycemia (5 mM/L). RIH/glucose fluctuations also induced M1 polarization and an inflammatory profile (CD11c, IL-1β, TNF-α, IL-6, and monocyte chemoattractant protein (MCP)-1) in macrophages. RIH/glucose fluctuations also drove the expression of matrix metalloproteinase (MMP)-9 (P < 0.001), which is a known marker for cardiovascular complication in T2D patients. Notably, all these changes were counteracted by IRF5 silencing in macrophages. In conclusion, RIH/glucose fluctuations promote the M1 polarization and inflammatory responses in macrophages via the mechanism involving TLR4-IRF5 pathway, which may have significance for metabolic inflammation.
    Keywords:  IRF5; TLR4; glucose fluctuations; macrophages; metabolic inflammation; repetitive intermittent hyperglycemia; type-2 diabetes
    DOI:  https://doi.org/10.3390/cells9081892
  2. Cells. 2020 Aug 21. pii: E1935. [Epub ahead of print]9(9):
    Bachmann J, Ehlert E, Becker M, Otto C, Radeloff K, Blunk T, Bauer-Kreisel P.
      Adipose-derived stromal/stem cells (ASCs) have been shown to exert regenerative functions, which are mainly attributed to the secretion of trophic factors. Upon transplantation, ASCs are facing an ischemic environment characterized by oxygen and nutrient deprivation. However, current knowledge on the secretion capacity of ASCs under such conditions is limited. Thus, the present study focused on the secretory function of ASCs under glucose and oxygen deprivation as major components of ischemia. After exposure to glucose/oxygen deprivation, ASCs maintained distinct viability, but the metabolic activity was greatly reduced by glucose limitation. ASCs were able to secrete a broad panel of factors under glucose/oxygen deprivation as revealed by a cytokine antibody array. Quantification of selected factors by ELISA demonstrated that glucose deprivation in combination with hypoxia led to markedly higher secretion levels of the angiogenic and anti-apoptotic factors IL-6, VEGF, and stanniocalcin-1 as compared to the hypoxic condition alone. A conditioned medium of glucose/oxygen-deprived ASCs promoted the viability and tube formation of endothelial cells, and the proliferation and migration of fibroblasts. These findings indicate that ASCs are stimulated by ischemia-like stress conditions to secrete trophic factors and would be able to exert their beneficial function in an ischemic environment.
    Keywords:  adipose-derived stromal/stem cells (ASCs); glucose starvation; hypoxia; ischemia; regenerative medicine; secretion; trophic factors
    DOI:  https://doi.org/10.3390/cells9091935
  3. Int J Mol Sci. 2020 Aug 19. pii: E5951. [Epub ahead of print]21(17):
    Patras L, Fens MHAM, Vader P, Barendrecht A, Sesarman A, Banciu M, Schiffelers R.
      Extracellular vesicles (EV) secreted in the tumour microenvironment (TME) are emerging as major antagonists of anticancer therapies by orchestrating the therapeutic outcome through altering the behaviour of recipient cells. Recent evidence suggested that chemotherapeutic drugs could be responsible for the EV-mediated tumour-stroma crosstalk associated with cancer cell drug resistance. Here, we investigated the capacity of tumour EV (TEV) secreted by normoxic and hypoxic (1% oxygen) C26 cancer cells after doxorubicin (DOX) treatment to alter the response of naïve C26 cells and RAW 264.7 macrophages to DOX. We observed that C26 cells were less responsive to DOX treatment under normoxia compared to hypoxia, and a minimally cytotoxic DOX concentration that mounted distinct effects on cell viability was selected for TEV harvesting. Homotypic and heterotypic pretreatment of naïve hypoxic cancer and macrophage-like cells with normoxic DOX-elicited TEV rendered these cells slightly less responsive to DOX treatment. The observed effects were associated with strong hypoxia-inducible factor 1-alpha (HIF-1α) induction and B-cell lymphoma-extra-large anti-apoptotic protein (Bcl-xL)-mediated anti-apoptotic response in normoxic DOX-treated TEV donor cells, being also tightly connected to the DOX-TEV-mediated HIF-1α induction, as well as Bcl-xL levels increasing in recipient cells. Altogether, our results could open new perspectives for investigating the role of chemotherapy-elicited TEV in the colorectal cancer TME and their modulatory actions on promoting drug resistance.
    Keywords:  colon cancer; doxorubicin; extracellular vesicles; hypoxia; macrophages; normoxia
    DOI:  https://doi.org/10.3390/ijms21175951
  4. Cancer Immunol Res. 2020 Jul 27.
    Rodrigues Mantuano N, Stanczak MA, Oliveira IA, Kirchhammer N, Filardy AA, Monaco G, Santos RC, Fonseca AC, Fontes M, Bastos CS, Dias WB, Zippelius A, Todeschini AR, Läubli H.
      Diabetes mellitus (DM) significantly increases the risk for cancer and cancer progression. Hyperglycemia is the defining characteristic of DM and tightly correlates with a poor prognosis in patients with cancer. The hexosamine biosynthetic pathway (HBP) is emerging as a pivotal cascade linking high glucose, tumor progression, and impaired immune function. Here we show that enhanced glucose flow through the HBP drives cancer progression and immune evasion by increasing O-GlcNAcylation in tumor-associated macrophages (TAM). Increased O-GlcNAc skewed macrophage polarization to a M2-like phenotype supporting tumor progression. Finally, we found an upregulation of M2 markers on TAMs in DM2 patients with colorectal cancer compared with nondiabetic normoglycemic patients. Our results provide evidence for a new and targetable mechanism of cancer immune evasion in patients with hyperglycemia, advocating for strict control of hyperglycemia in patients with cancer.
    DOI:  https://doi.org/10.1158/2326-6066.CIR-19-0904
  5. Arch Oral Biol. 2020 Aug 01. pii: S0003-9969(20)30236-3. [Epub ahead of print]118 104858
    Zhou T, Huang WK, Xu QY, Zhou X, Shao LQ, Song B.
      OBJECTIVES: This research aimed to study whether necrostain-1 (Nec-1) could alleviate inflammatory injury induced by high glucose upon THP-1 derived macrophages through RIP1.DESIGN: Firstly, THP-1 derived macrophages were incubated with 5.5 mM glucose (normal glucose, NG), 25 mM glucose (high glucose, HG), and mannitol as the high osmotic pressure group (5.5 mM glucose+19.5 mM mannitol) for 24, 48, and 72 h respectively. TNF-α, IL-1β, IL-6, and IL-8 levels were measured by ELISA. Secondly, macrophages were exposed to NG, HG, or HG plus 5 μM necrostatin-1 (Nec-1) for 72 h. mRNA expression of inflammatory cytokine was measured by RT-PCR, and protein levels of inflammatory cytokines and LDH leakage were determined by ELISA. RIP1 expression was determined by RT-PCR and WB. Thirdly, macrophages were transfected with si-RIP1 or negative control (si-NC). Wild type and RIP1-silenced macrophages were incubated with NG or HG, and TNF-α, IL-1β, IL-6, IL-8, and LDH levels were measured again by ELISA.
    RESULTS: 1) TNF-α, IL-1β, IL-6, and IL-8 levels were elevated in the HG group, as compared with that the NG group. Inflammation remained unchanged in the mannitol group. 2) Inflammatory response and LDH levels in the HG plus Nec-1 group were remarkably lower than in the HG group. 3) Inflammatory injury in the si-NC group was more severe than in the si-RIP1 group.
    CONCLUSIONS: Current results indicated that Nec-1 could alleviate HG-caused inflammatory injury on THP-1 derived macrophages by regulating RIP1. These findings could help cast light on the relationships between diabetes and periodontitis.
    Keywords:  Diabetes; Inflammatory injury; Nec-1; Periodontitis; RIP1
    DOI:  https://doi.org/10.1016/j.archoralbio.2020.104858
  6. Int J Mol Sci. 2020 Aug 14. pii: E5840. [Epub ahead of print]21(16):
    Olejarz W, Kubiak-Tomaszewska G, Chrzanowska A, Lorenc T.
      Angiogenesis is the process through which new blood vessels are formed from pre-existing ones. Exosomes are involved in angiogenesis in cancer progression by transporting numerous pro-angiogenic biomolecules like vascular endothelial growth factor (VEGF), matrix metalloproteinases (MMPs), and microRNAs. Exosomes promote angiogenesis by suppressing expression of factor-inhibiting hypoxia-inducible factor 1 (HIF-1). Uptake of tumor-derived exosomes (TEX) by normal endothelial cells activates angiogenic signaling pathways in endothelial cells and stimulates new vessel formation. TEX-driven cross-talk of mesenchymal stem cells (MSCs) with immune cells blocks their anti-tumor activity. Effective inhibition of tumor angiogenesis may arrest tumor progression. Bevacizumab, a VEGF-specific antibody, was the first antiangiogenic agent to enter the clinic. The most important clinical problem associated with cancer therapy using VEGF- or VEFGR-targeting agents is drug resistance. Combined strategies based on angiogenesis inhibitors and immunotherapy effectively enhances therapies in various cancers, but effective treatment requires further research.
    Keywords:  angiogenesis; anti-angiogenic therapy; exosomes; extracellular vesicles
    DOI:  https://doi.org/10.3390/ijms21165840
  7. Int J Mol Sci. 2020 Aug 14. pii: E5845. [Epub ahead of print]21(16):
    Bleve A, Durante B, Sica A, Consonni FM.
      Cancer progression generates a chronic inflammatory state that dramatically influences hematopoiesis, originating different subsets of immune cells that can exert pro- or anti-tumor roles. Commitment towards one of these opposing phenotypes is driven by inflammatory and metabolic stimuli derived from the tumor-microenvironment (TME). Current immunotherapy protocols are based on the reprogramming of both specific and innate immune responses, in order to boost the intrinsic anti-tumoral activity of both compartments. Growing pre-clinical and clinical evidence highlights the key role of metabolism as a major influence on both immune and clinical responses of cancer patients. Indeed, nutrient competition (i.e., amino acids, glucose, fatty acids) between proliferating cancer cells and immune cells, together with inflammatory mediators, drastically affect the functionality of innate and adaptive immune cells, as well as their functional cross-talk. This review discusses new advances on the complex interplay between cancer-related inflammation, myeloid cell differentiation and lipid metabolism, highlighting the therapeutic potential of metabolic interventions as modulators of anticancer immune responses and catalysts of anticancer immunotherapy.
    Keywords:  cancer immunotherapy; cholesterol; fatty acids; lipid metabolism; myeloid-derived suppressor cells (MDSCs); obesity; tumor-associated macrophages (TAMs)
    DOI:  https://doi.org/10.3390/ijms21165845
  8. Biochem Biophys Res Commun. 2020 Aug 13. pii: S0006-291X(20)31384-X. [Epub ahead of print]
    Shibata C, Nakai K, Ozaki M, Koshi R, Tanaka H, Morita T, Maeno M, Kawato T.
      OBJECTIVE: The remodeling of the vascular network and collagen in the extracellular matrix is closely associated with the expansion and dysfunction of adipose tissue. In the present study, we investigated the effects of interleukin (IL)-6 and tumor necrosis factor (TNF)-α on the expression of angiogenic factors, collagen, and collagenase and its endogenous inhibitor in premature and mature adipocytes.METHODS: Premature and mature adipocytes were differentiated from 3T3-L1 cells and stimulated with IL-6 or TNF-α to mimic the early and late phases of obesity development. The levels of expression of angiogenic factors, including vascular endothelial cell growth factor a (Vegfa), hepatocyte growth factor (Hgf), angiopoietin (Angpt)1, and Angpt2, as well as type I collagen, matrix metallopeptidase (Mmp) 13, and tissue inhibitor of Mmp (Timp) 1, were determined using real-time reverse transcription polymerase chain reaction or enzyme-linked immunosorbent assay. Human umbilical vein endothelial cells were grown with the culture supernatant of adipocytes stimulated with/without IL-6 or TNF-α, and the formation of tube structures was evaluated.
    RESULTS: IL-6 and TNF-α induced the expression of Vegfa, Hgf, and Angpt2 and decreased the expression of Angpt1 in premature adipocytes, whereas, they decreased the expression of Vegfa and Hgf in mature adipocytes. The culture supernatant of IL-6- or TNF-α-stimulated premature adipocytes induced the formation of tube structures. IL-6 and TNF-α had no effects on type I collagen expression in both premature and mature adipocytes but suppressed the expression of Mmp13 and Timp1 in mature and premature adipocytes, respectively.
    CONCLUSION: The effects of IL-6 and TNF-α on the expression of angiogenic and collagenolytic factors differed between premature and mature adipocytes. This finding suggests that these inflammatory cytokines induce expansion and dysfunction of adipose tissue via angiogenesis and collagen turnover in premature and mature adipocytes.
    Keywords:  Adipocytes; Angiogenic factors; Collagenolytic factors; Interleukin-6; Tumor necrosis factor-α
    DOI:  https://doi.org/10.1016/j.bbrc.2020.06.162
  9. Sci China Life Sci. 2020 Aug 17.
    Fan C, Zhang S, Gong Z, Li X, Xiang B, Deng H, Zhou M, Li G, Li Y, Xiong W, Zeng Z, Li X.
      Mounting evidence has revealed that the therapeutic efficacy of immunotherapies is restricted to a small portion of cancer patients. A deeper understanding of how metabolic reprogramming in the tumor microenvironment (TME) regulates immunity remains a major challenge to tumor eradication. It has been suggested that metabolic reprogramming in the TME may affect metabolism in immune cells and subsequently suppress immune function. Tumor cells compete with infiltrating immune cells for nutrients and metabolites. Notably, the immunosuppressive TME is characterized by catabolic and anabolic processes that are critical for immune cell function, and elevated inhibitory signals may favor cancer immune evasion. The major energy sources that supply different immune cell subtypes also undergo reprogramming. We herein summarize the metabolic remodeling in tumor cells and different immune cell subtypes and the latest advances underlying the use of metabolic checkpoints in antitumor immunotherapies. In this context, targeting both tumor and immune cell metabolic reprogramming may enhance therapeutic efficacy.
    Keywords:  antitumor immunotherapy; infiltrating immune cells; metabolic reprogramming; tumor immune evasion; tumor microenvironment
    DOI:  https://doi.org/10.1007/s11427-019-1735-4