Cell Stress最新文献

{"title":"Fine intercellular connections in development: TNTs, cytonemes, or intercellular bridges?","authors":"Olga Korenkova,&nbsp;Anna Pepe,&nbsp;Chiara Zurzolo","doi":"10.15698/cst2020.02.212","DOIUrl":"https://doi.org/10.15698/cst2020.02.212","url":null,"abstract":"<p><p>Intercellular communication is a fundamental property of multicellular organisms, necessary for their adequate responses to changing environment. Tunneling nanotubes (TNTs) represent a novel means of intercellular communication being a long cell-to-cell conduit. TNTs are actively formed under a broad range of stresses and are also proposed to exist under physiological conditions. Development is a physiological condition of particular interest, as it requires fine coordination. Here we discuss whether protrusions shown to exist during embryonic development of different species could be TNTs or if they represent other types of cell structure, like cytonemes or intercellular bridges, that are suggested to play an important role in development.</p>","PeriodicalId":36371,"journal":{"name":"Cell Stress","volume":null,"pages":null},"PeriodicalIF":6.4,"publicationDate":"2020-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6997949/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37630157","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Kynurenine: an oncometabolite in colon cancer.","authors":"Niranjan Venkateswaran,&nbsp;Maralice Conacci-Sorrell","doi":"10.15698/cst2020.01.210","DOIUrl":"https://doi.org/10.15698/cst2020.01.210","url":null,"abstract":"<p><p>Tryptophan is one of the eight essential amino acids that must be obtained from the diet. Interestingly, tryptophan is the least abundant amino acid in most proteins, a large portion of cellular tryptophan is converted into metabolites of the serotonin and kynurenine pathways. In a recent study, (Venkateswaran, Lafita-Navarro et al., 2019, Genes Dev), we discovered that colon cancer cells display greater uptake and processing of tryptophan than normal colonic cells and tissues. This process is mediated by the oncogenic transcription factor MYC that promotes the expression of the tryptophan importers SLC1A5 and SLC7A5 and the tryptophan metabolizing enzyme AFMID. The metabolism of tryptophan in colon cancer cells generates kynurenine, a biologically active metabolite necessary to maintain continuous cell proliferation. Our results indicate that kynurenine functions as an oncometabolite, at least in part, by activating the transcription factor AHR, which then regulates growth promoting genes in cancer cells. We propose that blocking kynurenine production or activity can be an efficient approach to specifically limit the growth of colon cancer cells. Here, we describe our findings and new questions for future studies targeted at understanding AHR-independent function of kynurenine, as well as interfering with the enzyme AFMID as a new strategy to target the kynurenine pathway.</p>","PeriodicalId":36371,"journal":{"name":"Cell Stress","volume":null,"pages":null},"PeriodicalIF":6.4,"publicationDate":"2020-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6946015/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37530150","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Necroptosis, tumor necrosis and tumorigenesis.","authors":"Zheng-Gang Liu,&nbsp;Delong Jiao","doi":"10.15698/cst2020.01.208","DOIUrl":"https://doi.org/10.15698/cst2020.01.208","url":null,"abstract":"<p><p>Necroptosis, known as programmed necrosis, is a form of caspase-independent, finely regulated cell death with necrotic morphology. Tumor necrosis, foci of necrotic cell death, occurs in advanced solid tumors and is often associated with poor prognosis of cancer patients. While it is well documented that apoptosis plays a key role in tumor regression and the inactivation of apoptosis is pivotal to tumor development, the role of necroptosis in tumorigenesis is still not fully understood as recent studies have reported both tumor-promoting and tumor-suppressing effects of necroptosis. In this short review, we will discuss some recent studies about the role of necroptosis in tumorigenesis and speculate the implications of these findings in future research and potential novel cancer therapy targeting necroptosis.</p>","PeriodicalId":36371,"journal":{"name":"Cell Stress","volume":null,"pages":null},"PeriodicalIF":6.4,"publicationDate":"2019-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6946014/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37530149","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fatty acids - from energy substrates to key regulators of cell survival, proliferation and effector function.","authors":"Danilo Cucchi, Dolores Camacho-Muñoz, Michelangelo Certo, Valentina Pucino, Anna Nicolaou, Claudio Mauro","doi":"10.15698/cst2020.01.209","DOIUrl":"10.15698/cst2020.01.209","url":null,"abstract":"<p><p>Recent advances in immunology and cancer research show that fatty acids, their metabolism and their sensing have a crucial role in the biology of many different cell types. Indeed, they are able to affect cellular behaviour with great implications for pathophysiology. Both the catabolic and anabolic pathways of fatty acids present us with a number of enzymes, receptors and agonists/antagonists that are potential therapeutic targets, some of which have already been successfully pursued. Fatty acids can affect the differentiation of immune cells, particularly T cells, as well as their activation and function, with important consequences for the balance between anti- and pro-inflammatory signals in immune diseases, such as rheumatoid arthritis, psoriasis, diabetes, obesity and cardiovascular conditions. In the context of cancer biology, fatty acids mainly provide substrates for energy production, which is of crucial importance to meet the energy demands of these highly proliferating cells. Fatty acids can also be involved in a broader transcriptional programme as they trigger signals necessary for tumorigenesis and can confer to cancer cells the ability to migrate and generate distant metastasis. For these reasons, the study of fatty acids represents a new research direction that can generate detailed insight and provide novel tools for the understanding of immune and cancer cell biology, and, more importantly, support the development of novel, efficient and fine-tuned clinical interventions. Here, we review the recent literature focusing on the involvement of fatty acids in the biology of immune cells, with emphasis on T cells, and cancer cells, from sensing and binding, to metabolism and downstream effects in cell signalling.</p>","PeriodicalId":36371,"journal":{"name":"Cell Stress","volume":null,"pages":null},"PeriodicalIF":6.4,"publicationDate":"2019-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6946016/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37530151","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Stress granules regulate paraspeckles: RNP granule continuum at work.","authors":"Haiyan An,&nbsp;Tatyana A Shelkovnikova","doi":"10.15698/cst2019.12.207","DOIUrl":"https://doi.org/10.15698/cst2019.12.207","url":null,"abstract":"<p><p>Eukaryotic cells contain several types of RNA-protein membraneless macro-complexes - ribonucleoprotein (RNP) granules that form by liquid-liquid phase separation. These structures represent biochemical microreactors for a variety of cellular processes and also act as highly accurate sensors of changes in the cellular environment. RNP granules share multiple protein components, however, the connection between spatially separated granules remains surprisingly understudied. Paraspeckles are constitutive nuclear RNP granules whose numbers significantly increase in stressed cells. Our recent work using affinity-purified paraspeckles revealed that another type of RNP granule, cytoplasmic stress granule (SG), acts as an important regulator of stress-induced paraspeckle assembly. Our study demonstrates that despite their residency in different cellular compartments, the two RNP granules are closely connected. This study suggests that nuclear and cytoplasmic RNP granules are integral parts of the intracellular \"RNP granule continuum\" and that rapid exchange of protein components within this continuum is important for the temporal control of cellular stress responses. It also suggests that cells can tolerate and efficiently handle a certain level of phase separation, which is reflected in the existence of \"bursts\", or \"waves\", of RNP granule formation. Our study triggers a number of important questions related to the mechanisms controlling the flow of RNP granule components within the continuum and to the possibility of targeting these mechanisms in human disease.</p>","PeriodicalId":36371,"journal":{"name":"Cell Stress","volume":null,"pages":null},"PeriodicalIF":6.4,"publicationDate":"2019-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6883742/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37453675","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metabolism remodeling in pancreatic ductal adenocarcinoma.","authors":"Jin-Tao Li,&nbsp;Yi-Ping Wang,&nbsp;Miao Yin,&nbsp;Qun-Ying Lei","doi":"10.15698/cst2019.12.205","DOIUrl":"https://doi.org/10.15698/cst2019.12.205","url":null,"abstract":"<p><p>Pancreatic ductal adenocarcinoma (PDAC) is predicted to become the second leading cause of death of patients with malignant cancers by 2030. Current options of PDAC treatment are limited and the five-year survival rate is less than 8%, leading to an urgent need to explore innovatively therapeutic strategies. PDAC cells exhibit extensively reprogrammed metabolism to meet their energetic and biomass demands under extremely harsh conditions. The metabolic changes are closely linked to signaling triggered by activation of oncogenes like <i>KRAS</i> as well as inactivation of tumor suppressors. Furthermore, tumor microenvironmental factors including extensive desmoplastic stroma reaction result in series of metabolism remodeling to facilitate PDAC development. In this review, we focus on the dysregulation of metabolism in PDAC and its surrounding microenvironment to explore potential metabolic targets in PDAC therapy.</p>","PeriodicalId":36371,"journal":{"name":"Cell Stress","volume":null,"pages":null},"PeriodicalIF":6.4,"publicationDate":"2019-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6883744/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37453674","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"LTX-315 – a promising novel antitumor peptide and immunotherapeutic agent","authors":"Dagmar Zweytick","doi":"10.15698/cst2019.11.202","DOIUrl":"https://doi.org/10.15698/cst2019.11.202","url":null,"abstract":"Host defense in mammals, as provided by the innate immune system, comprises proteins such as lactoferrin (LF), a multifunctional iron-binding glycoprotein originally discovered in bovine milk. LF is further pepsin-cleaved to a cationic amphipathic peptide, lactoferricin (LFcin; amino acid 1-45 of LF), which is known for its antimicrobial, antiseptic, antiviral, antitumor and immunomodulatory activities [13]. Bovine LFcin has been shown to inhibit liver and lung metastasis of both murine melanomas and lymphomas [4] and to induce apoptosis in human leukemic and carcinoma cell lines [5, 6]. LTX-315 [7] and LTX-302 [8], which derived of bovine LFcin by structural optimization, contain amongst others the non-coded residue β-diphenylalanine and show increased activity in vivo by peptide induced tumor regression and infiltration of the tumor by immune cells. LTX-315 is effective against multiple tumor types, and is therefore studied as novel immunotherapeutic agent in phase I/II clinical trials in combination with checkpoint inhibitors for treatment of advanced solid tumors, using the ability to reduce tumor growth and to induce de novo T-cell responses [9]. In the current issue of Cell Stress, Pittet and colleagues evaluated LTX-315 in conditional genetic mouse models of melanoma and sarcoma that are so far mainly resistant to standard treatment. Therefore, syngeneic grafts of murine melanoma B16F10, Brafand Pten-driven melanoma as well as Krasand P53-driven soft tissue sarcoma were studied in mice regarding their sensitivity towards LTX-315. These mutations are an ideal model, since they are often found in human patients suffering of these cancer types, as well are these tumor models, as also murine melanoma B16F10, poorly infiltrated by T cells and resistant to immune checkpoint therapy. The authors show a two-phase response in the tumor models triggered by the intratumoral injection with the peptide. The first phase of response is a rapid (within minutes) disruption of tumor vasculature and decrease of tumor burden. This direct antitumor effect seems to occur by induced cell lysis blocking the oxygen and nutrients supply by the tumor vasculature without the help of antitumor lymphocytes. The second phase of response is however as important for the antitumor (longterm) effect of the peptide. It endures over several weeks and is characterized by a tumor infiltration with CD8+ T cells that is normally very poor in the described tumor models and can display antitumor functions. Further, immune cells such as CD4+ T cells and natural killer (NK) cells were shown to migrate into the tumor environment upon treatment with LTX-315. This effect of triggering an antitumor immune response was more pronounced in the melanoma than in the sarcoma models, which might be due to the lower mutational load of the latter. However, this long-term conversion of a poorly to a highly immunogenic tumor promises a long-term antitumor immunity by prevention of tumor regrowth af","PeriodicalId":36371,"journal":{"name":"Cell Stress","volume":null,"pages":null},"PeriodicalIF":6.4,"publicationDate":"2019-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43874510","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Endoplasmic reticulum and Golgi stress in microcephaly.","authors":"Sandrine Passemard,&nbsp;Franck Perez,&nbsp;Pierre Gressens,&nbsp;Vincent El Ghouzzi","doi":"10.15698/cst2019.12.206","DOIUrl":"https://doi.org/10.15698/cst2019.12.206","url":null,"abstract":"<p><p>Microcephaly is a neurodevelopmental condition characterized by a small brain size associated with intellectual deficiency in most cases and is one of the most frequent clinical sign encountered in neurodevelopmental disorders. It can result from a wide range of environmental insults occurring during pregnancy or postnatally, as well as from various genetic causes and represents a highly heterogeneous condition. However, several lines of evidence highlight a compromised mode of division of the cortical precursor cells during neurogenesis, affecting neural commitment or survival as one of the common mechanisms leading to a limited production of neurons and associated with the most severe forms of congenital microcephaly. In this context, the emergence of the endoplasmic reticulum (ER) and the Golgi apparatus as key guardians of cellular homeostasis, especially through the regulation of proteostasis, has raised the hypothesis that pathological ER and/or Golgi stress could contribute significantly to cortical impairments eliciting microcephaly. In this review, we discuss recent findings implicating ER and Golgi stress responses in early brain development and provide an overview of microcephaly-associated genes involved in these pathways.</p>","PeriodicalId":36371,"journal":{"name":"Cell Stress","volume":null,"pages":null},"PeriodicalIF":6.4,"publicationDate":"2019-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6883743/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37453676","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"LTX-315 sequentially promotes lymphocyte-independent and lymphocyte-dependent antitumor effects.","authors":"Hsin-Wei Liao, Christopher Garris, Christina Pfirschke, Steffen Rickelt, Sean Arlauckas, Marie Siwicki, Rainer H Kohler, Ralph Weissleder, Vibeke Sundvold-Gjerstad, Baldur Sveinbjørnsson, Øystein Rekdal, Mikael J Pittet","doi":"10.15698/cst2019.11.204","DOIUrl":"10.15698/cst2019.11.204","url":null,"abstract":"<p><p>LTX-315 is an oncolytic peptide that has antitumor efficacy in mice grafted with various tumor cell lines and is currently being tested in phase II clinical trials. Here we aimed to further evaluate LTX-315 in conditional genetic mouse models of cancer that typically resist current treatment options and to better understand the drug's mode of action <i>in vivo</i>. We report LTX-315 mediates profound antitumor effects against <i>Braf-</i> and <i>Pten</i>-driven melanoma and delays the progression of <i>Kras-</i> and <i>P53-</i>driven soft tissue sarcoma in mice. Additionally, we show in melanoma that LTX-315 triggers two sequential phases of antitumor response. The first phase of response, which begins within minutes of drug delivery into tumors, is defined by disrupted tumor vasculature and decreased tumor burden and occurs independently of lymphocytes. The second phase of response, which continues over weeks, is defined by long-term alteration of the tumor microenvironment; the changes induced by LTX-315 are most notably characterized by CD8+ T cell infiltration. We further show that these CD8+ T cells are involved in suppressing melanoma outgrowth in mice and report similar CD8+ T cell infiltration following LTX-315 treatment in melanoma and sarcoma patients. Taken together, these findings reveal LTX-315's multiple antitumor effects, including disrupting the tumor vasculature and promoting the conversion of poorly immunogenic tumors into ones that display antitumor T cell immunity.</p>","PeriodicalId":36371,"journal":{"name":"Cell Stress","volume":null,"pages":null},"PeriodicalIF":6.4,"publicationDate":"2019-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6859426/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46533893","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Anti-regulatory T cells are natural regulatory effector T cells.","authors":"Niels Ødum","doi":"10.15698/cst2019.10.199","DOIUrl":"https://doi.org/10.15698/cst2019.10.199","url":null,"abstract":"It is well established that the immune system uses regulatory immune-suppressive cells to inhibit and terminate immune reactions and maintain immune balance. In the last decade, Andersen and colleagues have discovered that regulatory cells also can have effector capabilities that counteract the many immune-suppressive feedback mechanisms that regulatory cells mediate. These authors have described pro-inflammatory antigen-specific T cells that react towards immune-suppressive cells [1,2]. Indeed, because of their reactive ability against regulatory immune cells, these effector T cells have been designated as antiregulatory T cells or anti-Tregs [3]. Anti-Tregs recognize proteins that regulatory cells express, including PD-L1 [47]. Spontaneous CD8+ and CD4+ T-cell reactivity against PD-L1 has been described in patients with cancer and in healthy individuals. Naturally occurring PD-L1–specific T cells can recognize PD-L1–expressing immune cells and malignant cells [8]. Activation of PD-L1–specific T cells has been described as modulating adaptive immune reactions directly and indirectly. The addition of PD-L1–specific T cells to cultured peripheral blood mononuclear cells (PBMCs) one week after viral antigen stimulation results in an immense increase in virus-specific T cells. Likewise, the co-stimulation of PD-L1 epitopes with viral epitopes results in expansion of virus-specific T cells. Thus, activation of PDL1–specific T cells enhances the effector phase of an ongoing immune response. In the current issue of Cell Stress, Andersen and colleagues further characterize the natural function of PD-L1– specific T cells, showing a direct link between inflammation and expansion of this cell population [9]. PD-L1 is expressed even in very potent antigen-presenting cells early during the inflammatory process. This expression occurs because of induction by both type I and II interferons (IFNs), which are present at the inflammation site. PD-L1 thus plays a central role in the counter-regulation of immune responses. Andersen and colleagues also show that circulating PDL1–specific T cells expand in response to pro-inflammatory mediators, such as IFN- and interleukin-2, in the absence of antigen-specific stimulation. PD-L1–specific T cells therefore expand as a first response to inflammation and can function as helper cells at the inflammation site, where they also can aid in the response to infected cells. Further evidence for these roles is the increased susceptibility of target cells to PD-L1–specific T-cell recognition in the presence of IFN- [4]. In their current work in Cell Stress, Andersen et al. provide further support for the natural regulatory role of PD-L1–specific anti-Tregs, showing that addition of inflammation-induced PD-L1–specific T cells to unstimulated PBMC cultures indeed influences Treg numbers [9]. PD-L1 is not the only target that regulatory immune cells express and that anti-Tregs can recognize. The metabolic enzymes indoleamine-pyrr","PeriodicalId":36371,"journal":{"name":"Cell Stress","volume":null,"pages":null},"PeriodicalIF":6.4,"publicationDate":"2019-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6789433/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41214971","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}