bims-stacyt Biomed News
on Paracrine crosstalk between cancer and the organism
Issue of 2020‒02‒09
twelve papers selected by
Cristina Muñoz Pinedo
L’Institut d’Investigació Biomèdica de Bellvitge


  1. J Cell Commun Signal. 2020 Feb 07.
    Masoumi-Dehghi S, Babashah S, Sadeghizadeh M.
      Paracrine signaling between tumor and surrounding stromal cells is critical for the maintenance of tumor microenvironment during ovarian cancer progression. Small extracellular vesicles (sEVs; exosomes in particular) are nano-sized vesicles secreted actively by many cells including tumor cells and are found to have fundamental roles in intercellular communication through shuttling functional RNAs. Although microRNAs (also called miRNAs or miRs), small non-coding RNAs regulating gene expression, are selectively accumulated in tumor sEVs and can mediate intercellular communication, the exact biological mechanisms underlying the functions of exosomal miRNAs in ovarian tumor angiogenesis remain unclear. In this study, sEVs were isolated from conditioned medium of the human ovarian carcinoma cell line SKOV-3 using ExoQuick Exosome Precipitation Solution, and characterized by scanning electron microscopy, dynamic light scattering, and immunoblotting. To elucidate the possible paracrine effects on ovarian tumor cell-derived sEVs (TD-sEVs), we investigated the angiogenesis-related signaling events triggered by TD-sEVs in endothelial cells. Due to the possible role in ovarian tumor pathogenesis, we focused on miR-141-3p which was detected to be enriched in TD-sEVs compared with their corresponding donor cells. We identified that sEV transfer of miR-141-3p considerably reduced the expression levels of cytokine-inducible suppressors of cytokine signaling (SOCS)-5 leading to up-regulated JAK-STAT3 pathway in endothelial cells. We also observed that sEV-shuttled miR-141-3p may up-regulate the expression of VEGFR-2 in endothelial cells which leads to promoting endothelial cell migration and angiogenesis. The putative role of miR-141-3p shuttled by TD-sEVs in regulating VEGFR-2 expression was demonstrated by the ability of anti-miR-141-3p to rescue the promoting effects of TD-sEVs on the expression of VEGFR-2 in endothelial cells. Our results also revealed that TD-sEVs trigger the intracellular reactive oxygen species (ROS)-dependent activation of NF-κB signaling in endothelial cells. Taken together, our findings propose a novel model in which sEV transfer of epithelial ovarian cancer-secreted miR-141-3p plays as a significant mediator of intercellular communication, promoting endothelial cell angiogenesis.
    Keywords:  JAK-STAT3 pathway; Ovarian cancer-secreted miR-141-3p; Small extracellular vesicles; Tumor angiogenesis
    DOI:  https://doi.org/10.1007/s12079-020-00548-5
  2. Adv Exp Med Biol. 2020 ;1223 69-80
    Bazzichetto C, Conciatori F, Falcone I, Ciuffreda L.
      The mammalian target of rapamycin (mTOR) represents a critical hub for the regulation of different processes in both normal and tumor cells. Furthermore, it is now well established the role of mTOR in integrating and shaping different environmental paracrine and autocrine stimuli in tumor microenvironment (TME) constituents. Recently, further efforts have been employed to understand how the mTOR signal transduction mechanisms modulate the sensitivity and resistance to targeted therapies, also for its involvement of mTOR also in modulating angiogenesis and tumor immunity. Indeed, interest in mTOR targeting was increased to improve immune response against cancer and to develop new long-term efficacy strategies, as demonstrated by clinical success of mTOR and immune checkpoint inhibitor combinations. In this chapter, we will describe the role of mTOR in modulating TME elements and the implication in its targeting as a great promise in clinical trials.
    Keywords:  Angiogenesis; Cancer; Combination therapy; Immunotherapy; TME; Targeted therapy; Tumor–stroma interactions; mTOR pathway; mTORC1; mTORC2
    DOI:  https://doi.org/10.1007/978-3-030-35582-1_4
  3. Cancers (Basel). 2020 Jan 10. pii: E171. [Epub ahead of print]12(1):
    Lucchetti D, Ricciardi Tenore C, Colella F, Sgambato A.
      A better understanding of the mechanisms of cell communication between cancer cells and the tumor microenvironment is crucial to develop personalized therapies. It has been known for a while that cancer cells are metabolically distinct from other non-transformed cells. This metabolic phenotype is not peculiar to cancer cells but reflects the characteristics of the tumor microenvironment. Recently, it has been shown that extracellular vesicles are involved in the metabolic switch occurring in cancer and tumor-stroma cells. Moreover, in an immune system, the metabolic programs of different cell subsets are distinctly associated with their immunological function, and extracellular vesicles could be a key factor in the shift of cell fate modulating cancer immunity. Indeed, during tumor progression, tumor-associated immune cells and fibroblasts acquire a tumor-supportive and anti-inflammatory phenotype due to their interaction with tumor cells and several findings suggest a role of extracellular vesicles in this phenomenon. This review aims to collect all the available evidence so far obtained on the role of extracellular vesicles in the modulation of cell metabolism and immunity. Moreover, we discuss the possibility for extracellular vesicles of being involved in drug resistance mechanisms, cancer progression and metastasis by inducing immune-metabolic effects on surrounding cells.
    Keywords:  cytokines; extracellular vesicles; immune cells; metabolism; tumor microenvironment
    DOI:  https://doi.org/10.3390/cancers12010171
  4. Cancer Sci. 2020 Feb 03.
    Ikeda T, Nishita M, Hoshi K, Honda T, Kakeji Y, Minami Y.
      Bone marrow-derived mesenchymal stem or stromal cells (MSCs) have been shown to be recruited to various types of tumor tissues, where they interact with tumor cells to promote their proliferation, survival, invasion, and metastasis, depending on the type of the tumor. We have previously shown that Ror2 receptor tyrosine kinase and its ligand, Wnt5a, are expressed in MSCs, and Wnt5a-Ror2 signaling in MSCs induces expression of CXCL16, which in turn promotes proliferation of co-cultured MKN45 gastric cancer cells via CXCL16-CXCR6 axis. However, it remains unclear how CXCL16 regulates proliferation of MKN45 cells. Here, we show that knockdown of CXCL16 in MSCs by siRNA suppresses not only proliferation, but also migration of co-cultured MKN45 cells. We also show that MSC-derived CXCL16 or recombinant CXCL16 upregulates expression of Ror1 through activation of STAT3 in MKN45 cells, leading to promotion of proliferation and migration of MKN45 cells in vitro. Furthermore, co-injection of MSCs with MKN45 cells in nude mice promoted tumor formation in a manner dependent on expression of Ror1 in MKN45 cells, and anti-CXCL16 neutralizing antibody suppressed tumor formation of MKN45 cells co-injected with MSCs. These results suggest that CXCL16 produced through Ror2-mediated signaling in MSCs within the tumor microenvironment acts on MKN45 cells in a paracrine manner to activate CXCR6-STAT3 pathway, which in turn induces expression of Ror1 in MKN45 cells, thereby promoting tumor progression.
    Keywords:  Bone marrow-derived mesenchymal stem cells; CXCL16; Ror1; STAT3; gastric cancer
    DOI:  https://doi.org/10.1111/cas.14339
  5. Adv Exp Med Biol. 2020 ;1226 73-86
    Zewdu A, Casadei L, Pollock RE, Braggio D.
      The term "adipose tissue" represents a multicellular and multifunctional organ involved in lipid storage, in hormone and temperature regulation, and in the protection of bones and vital organs from impact-based damage. Emerging evidence now suggests a more malignant role of adipose tissue in promoting cancer onset and progression via the release of secreted factors such as interleukin-6 (IL6) and extracellular vesicles (EVs). These adipose-source factors subsequently affect various aspects of tumorigenesis and/or cancer progression by either directly enhancing the tumor cell oncogenic phenotype or indirectly by the stimulating adjacent normal cells to adopt a more pro-cancer phenotype. Due to the recent growing interest in the role of IL6 and EVs released by adipose tissue in cancer promotion and progression, we are focusing on the protumorigenic impact of fat tissue via IL6 and EV secretion.
    Keywords:  Adipocytes; Adipokines; Adipose tumor; Cancer; Cell-to-cell communication; Extracellular vesicles; Fibroblasts; Glycoprotein 130; Inflammation; Interleukin-6; Liposarcoma; Macrophages; Preadipocytes; Signal transduction; Tumor microenvironment
    DOI:  https://doi.org/10.1007/978-3-030-36214-0_6
  6. Biomolecules. 2020 Jan 31. pii: E210. [Epub ahead of print]10(2):
    Tian Y, Li H, Liu X, Xie L, Huang Z, Li W, Li Z, Pan Y, Chen X, Su W.
      Inflammation-induced angiogenesis is closely related to many diseases and has been regarded as a therapeutic target. Caspase-8 has attracted increasing attention for its immune properties and therapeutic potential in inflammatory disorders. The aim of our study is to investigate the clinical application of pharmacological inhibition of caspase-8 and the underlying molecular mechanisms in inflammation-induced angiogenesis in the cornea. A model of alkali burn (AB)-induced corneal neovascularization (CNV) in C57BL/6 wild-type (WT) mice and toll-like receptor 4 knockout (Tlr4-/-) mice was used. We found that AB increased caspase-8 activity and the pharmacological inhibition of caspase-8 exerted substantial inhibitory effects on CNV, with consistent decreases in caspase-8 activity, inflammatory cell infiltration, macrophage recruitment and activation, VEGF-A, TNF-α, IL-1β, MIP-1, and MCP-1 expression in the cornea. In vitro, caspase-8 mediated TLR4-dependent chemokines and VEGF-A production by macrophages. The TLR4 knockout significantly alleviated CNV, suppressed caspase-8 activity and downregulated expression of inflammatory cytokines and chemokines after AB. Taken together, these findings provide the first demonstration that the pharmacological inhibition of caspase-8 suppresses inflammation-induced angiogenesis and support the use of a pharmacological caspase-8 inhibitor as a novel clinical treatment for CNV and other angiogenic disorders.
    Keywords:  angiogenesis; caspase-8; corneal neovascularization; macrophage
    DOI:  https://doi.org/10.3390/biom10020210
  7. FEBS J. 2020 Feb 03.
    Ramond E, Petrignani B, Dudzic JP, Boquete JP, Poidevin M, Kondo S, Lemaitre B.
      In animals, growth is regulated by the complex interplay between paracrine and endocrine signals. When food is scarce, tissues compete for nutrients, leading to critical resource allocation and prioritization. Little is known about how the immune system maturation is coordinated with the growth of other tissues. Here, we describe a signaling mechanism that regulates the number of hemocytes (blood cells) according to the nutritional state of the Drosophila larva. Specifically, we found that a secreted protein, NimB5, is produced in the fat body upon nutrient scarcity downstream of metabolic sensors and ecdysone signaling. NimB5 is then secreted and binds to hemocytes to down-regulate their proliferation and adhesion. Blocking this signaling loop results in conditional lethality when larvae are raised on a poor diet, due to excessive hemocyte numbers and insufficient energy storage. Similar regulatory mechanisms shaping the immune system in response to nutrient availability are likely to be widespread in animals.
    Keywords:  Drosophila; Nimrod; Peripheral hematopoiesis; growth; metabolism; organ prioritization; trade-off
    DOI:  https://doi.org/10.1111/febs.15237
  8. Curr Med Chem. 2020 Feb 06.
    Stepka P, Vsiansky V, Raudenska M, Gumulec J, Adam V, Masarik M.
      Metabolic changes driven by the hostile tumor microenvironment surrounding cancer cells and effect of these changes on tumorigenesis and metastatic potential have been known for a long time. The usual point of interest is glucose and changes in its utilization by cancer cells, mainly in the form of the Warburg effect. However, amino acids, both intra- and extracellular, also represent an important aspect of tumour microenvironment, which can have a significant effect on cancer cell metabolism and overall development of the tumor. Namely alterations in metabolism of amino acids glutamine, sarcosine, aspartate, methionine and cysteine have been previously connected to the tumor progression and aggressivity of prostate cancer. The aim of this review is to pinpoint current gaps in our knowledge of the role of amino acids as a part of the tumor microenvironment and to show effect of various amino acids on cancer cell metabolism and metastatic potential. This review shows limitations and exceptions from the traditionally accepted model of Warburg effect in some cancer tissues, with the emphasis on prostate cancer, because the traditional definition of Warburg effect as a metabolic switch to aerobic glycolysis does not always apply. Prostatic tissue both in healthy and transformed state significantly differs in many metabolic aspects, including the metabolisms of glucose and amino acids, from metabolism of other tissues. Findings from different tissues are therefore not always interchangeable and have to be taken into account during experimentation modifying the environment of tumor tissue by amino acid supplementation or depletion, which could potentially serve as a new therapeutic approach.
    Keywords:  Cancer metabolism ; aspartate; glutamine ; metastasis; methionine; sarcosine
    DOI:  https://doi.org/10.2174/0929867327666200207114658
  9. Trends Pharmacol Sci. 2020 Jan 31. pii: S0165-6147(20)30001-8. [Epub ahead of print]
    Kozlova N, Grossman JE, Iwanicki MP, Muranen T.
      The tumor microenvironment (TME) is a complex neighborhood that consists of immune cells, fibroblasts, pericytes, adipocytes, endothelial and neuronal cells, and the extracellular matrix proteins. TME also consists of physical factors, such as oxygen availability, changing pH, interstitial fluid pressure, and tissue stiffness. As cancer progresses, the physical properties and the cells in the TME change significantly, impacting the efficacy of the therapies and modulating drug resistance. This has led to the development of several new treatments targeting the TME. This review focuses on recent advances on the role of TME in drug resistance, with a particular focus on the ongoing clinical trials aiming at disrupting the TME- and the extracellular matrix-mediated protection against therapies.
    Keywords:  cancer-associated fibroblasts; clinical trials; drug resistance; extracellular matrix; stroma-cancer crosstalk; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.tips.2020.01.001
  10. Cancer Sci. 2020 Feb 03.
    Osumi H, Horiguchi H, Kadomatsu T, Tashiro K, Morinaga J, Takahashi T, Ikeda K, Ito T, Suzuki M, Endo M, Oike Y.
      We previously revealed that tumor cell-derived angiopoietin-like protein 2 (ANGPTL2) accelerates metastatic capacity of tumors in an autocrine/paracrine manner by activating tumor cell motility and invasiveness and the epithelial-mesenchymal transition (EMT). However, the effects of ANGPTL2 on cancer cell glycolytic metabolism, which is a hallmark of tumor cells, are unknown. Here we report evidence supporting a role for tumor cell-derived ANGPTL2 in establishing a preference for glycolytic metabolism. We report that a highly metastatic lung cancer cell subline expressing abundant ANGPTL2 showed upregulated expression of the glucose transporter GLUT3 as well as enhanced glycolytic metabolism relative to a less metastatic parental line. Most notably, ANGPTL2 overexpression in the less metastatic line activated glycolytic metabolism by increasing GLUT3 expression. Moreover, ANGPTL2 signaling via integrin α5β1 increased GLUT3 expression by increasing TGF-β signaling and expression of the downstream transcription factor ZEB1. Conversely, ANGPTL2 knockdown in the highly metastatic subline decreased TGF-β1, ZEB1, and GLUT3 expression and antagonized glycolytic metabolism. In primary tumor cells from patients with lung cancer, ANGPTL2 expression levels correlated with GLUT3 expression. Overall, this work suggests that tumor cell-derived ANGPTL2 accelerates activities associated with glycolytic metabolism in lung cancer cells by activating TGF-β-ZEB1-GLUT3 signaling.
    Keywords:  ANGPTL2; GLUT3; ZEB1; cancer metabolism; lung cancer
    DOI:  https://doi.org/10.1111/cas.14337
  11. Sci Rep. 2020 Feb 05. 10(1): 1854
    Kang HS, Kwon HY, Kim IK, Ban WH, Kim SW, Kang HH, Yeo CD, Lee SH.
      The purpose of this study was to evaluate whether obstructive sleep apnea (OSA)-related chronic intermittent hypoxia (CIH) influences lung cancer progression and to elucidate the associated mechanisms in a mouse model of lung cancer. C57/BL6 mice in a CIH group were exposed to intermittent hypoxia for two weeks after tumor induction and compared with control mice (room air). Hypoxia inducible factor 1α (HIF-1α), vascular endothelial growth factor (VEGF) and metastasis-related matrix metalloproteinases (MMP) were measured. The expression levels of several hypoxia-related pathway proteins including HIF-1α, Wnt/ß-catenin, the nuclear factor erythroid 2-related factor 2 (Nrf2) and mammalian target of rapamycin-ERK were measured by western blot. The number (P < 0.01) and volume (P < 0.05) of tumors were increased in the CIH group. The activity of MMP-2 was enhanced after CIH treatment. The level of VEGF was increased significantly in the CIH group (p < 0.05). ß-catenin and Nrf2 were translocated to the nucleus and the levels of downstream effectors of Wnt/ß-catenin signaling increased after IH exposure. CIH enhanced proliferative and migratory properties of tumors in a mouse model of lung cancer. ß-catenin and Nrf2 appeared to be crucial mediators of tumor growth.
    DOI:  https://doi.org/10.1038/s41598-020-58906-7
  12. Cancer Immunol Res. 2020 Feb 04. pii: canimm.0504.2019. [Epub ahead of print]
    Ercolano G, Garcia-Garijo A, Salomé B, Gomez-Cadena A, Vanoni G, Mastelic-Gavillet B, Ianaro A, Speiser DE, Romero P, Trabanelli S, Jandus C.
      Innate lymphoid cells (ILCs) are a family of immune cells that are emerging as potent orchestrators of immune responses. In cancer, ILCs display both pro- and antitumorigenic functions depending on the nature of the tumor and the involved ILC subset. Little is known about the ILC-tumor crosstalk in human melanoma. Here, we showed that ILC1s were enriched but functionally impaired in cytokine secretion in both PBMCs and tumor-infiltrated lymph nodes of melanoma patients. These findings were confirmed in vivo in murine cutaneous melanoma. Multiple immunosuppressive mechanisms are described in the melanoma microenvironment. Among others, adenosine and kynurenines were shown suppress antitumor immune responses. By exposing ILCs to adenosine and kynurenines we observed a similar shift towards the ILC1 subset distribution and impairment in pro-inflammatory cytokine production to that of patient samples studied ex-vivo. Thus, we hypothesized that the immunosuppressive microenvironment of malignant melanoma might shape ILC sub-populations. Hence, we provide rational for the use of drugs targeting adenosine and kynurenine pathways in melanoma patients.
    DOI:  https://doi.org/10.1158/2326-6066.CIR-19-0504