Showing papers by "Guido Kroemer published in 2011"
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TL;DR: The probable cause and effect relationship between perturbed autophagy and aging is discussed, as well as possible molecular mechanisms that may mediate the anti-aging effects of Autophagy.
1,845 citations
TL;DR: It is demonstrated that autophagy, which is often disabled in cancer, is dispensable for chemotherapy-induced cell death but required for its immunogenicity, and increased extracellular ATP concentrations improve the efficacy of antineoplastic chemotherapies when Autophagy is disabled.
Abstract: Antineoplastic chemotherapies are particularly efficient when they elicit immunogenic cell death, thus provoking an anticancer immune response. Here we demonstrate that autophagy, which is often disabled in cancer, is dispensable for chemotherapy-induced cell death but required for its immunogenicity. In response to chemotherapy, autophagy-competent, but not autophagy-deficient, cancers attracted dendritic cells and T lymphocytes into the tumor bed. Suppression of autophagy inhibited the release of adenosine triphosphate (ATP) from dying tumor cells. Conversely, inhibition of extracellular ATP-degrading enzymes increased pericellular ATP in autophagy-deficient tumors, reestablished the recruitment of immune cells, and restored chemotherapeutic responses but only in immunocompetent hosts. Thus, autophagy is essential for the immunogenic release of ATP from dying cells, and increased extracellular ATP concentrations improve the efficacy of antineoplastic chemotherapies when autophagy is disabled.
1,139 citations
University of Graz1, Joanneum Research2, Institute of Molecular Biotechnology3, Research Institute of Molecular Pathology4, University of Natural Resources and Life Sciences, Vienna5, Foundation for Research & Technology – Hellas6, Austrian Academy of Sciences7, University of Salzburg8, University of Basel9, University of St Andrews10
TL;DR: Administration of spermidine markedly extended the lifespan of yeast, flies and worms, and human immune cells and inhibited oxidative stress in ageing mice, and found that enhanced autophagy is crucial for polyamine-induced suppression of necrosis and enhanced longevity.
Abstract: Ageing results from complex genetically and epigenetically programmed processes that are elicited in part by noxious or stressful events that cause programmed cell death Here, we report that administration of spermidine, a natural polyamine whose intracellular concentration declines during human ageing, markedly extended the lifespan of yeast, flies and worms, and human immune cells In addition, spermidine administration potently inhibited oxidative stress in ageing mice In ageing yeast, spermidine treatment triggered epigenetic deacetylation of histone H3 through inhibition of histone acetyltransferases (HAT), suppressing oxidative stress and necrosis Conversely, depletion of endogenous polyamines led to hyperacetylation, generation of reactive oxygen species, early necrotic death and decreased lifespan The altered acetylation status of the chromatin led to significant upregulation of various autophagy-related transcripts, triggering autophagy in yeast, flies, worms and human cells Finally, we found that enhanced autophagy is crucial for polyamine-induced suppression of necrosis and enhanced longevity
974 citations
TL;DR: In this paper, a combination of mitochondrial dysfunction and insufficient autophagy may contribute to multiple aging-associated pathologies, which can cause degenerative diseases in which deficient quality control results in inflammation and the death of cell populations.
Abstract: Alterations of mitochondrial functions are linked to multiple degenerative or acute diseases. As mitochondria age in our cells, they become progressively inefficient and potentially toxic, and acute damage can trigger the permeabilization of mitochondrial membranes to initiate apoptosis or necrosis. Moreover, mitochondria have an important role in pro-inflammatory signaling. Autophagic turnover of cellular constituents, be it general or specific for mitochondria (mitophagy), eliminates dysfunctional or damaged mitochondria, thus counteracting degeneration, dampening inflammation, and preventing unwarranted cell loss. Decreased expression of genes that regulate autophagy or mitophagy can cause degenerative diseases in which deficient quality control results in inflammation and the death of cell populations. Thus, a combination of mitochondrial dysfunction and insufficient autophagy may contribute to multiple aging-associated pathologies.
962 citations
01 Jan 2011
TL;DR: A combination of mitochondrial dysfunction and insufficient autophagy may contribute to multiple aging-associated pathologies.
734 citations
TL;DR: The disruption of mitotic catastrophe precipitates tumorigenesis and cancer progression, and its induction constitutes a therapeutic endpoint.
Abstract: The improper distribution of chromosomes during mitosis compromises cellular functions and can reduce cellular fitness or contribute to malignant transformation. As a countermeasure, higher eukaryotes have developed strategies for eliminating mitosis-incompetent cells, one of which is mitotic catastrophe. Mitotic catastrophe is driven by a complex and poorly understood signalling cascade but, from a functional perspective, it can be defined as an oncosuppressive mechanism that precedes (and is distinct from) apoptosis, necrosis or senescence. Accordingly, the disruption of mitotic catastrophe precipitates tumorigenesis and cancer progression, and its induction constitutes a therapeutic endpoint.
696 citations
TL;DR: It is surmised that immune-relevant biomarkers may guide personalized therapeutic interventions including compensatory measures to restore or improve anticancer immune responses.
Abstract: The outcome of chemotherapy can be influenced by the host immune system at multiple levels. Chemotherapy can kill cancer cells by causing them to elicit an immune response or alternatively, by increasing their susceptibility to immune attack. In addition, chemotherapy can stimulate anticancer immune effectors either in a direct fashion or by subverting immunosuppressive mechanisms. Beyond cancer-cell-intrinsic factors that determine the cytotoxic or cytostatic response, as well as the potential immunogenicity of tumor cells, the functional state of the host immune system has a major prognostic and predictive impact on the fate of cancer patients treated with conventional or targeted chemotherapies. In this Review, we surmise that immune-relevant biomarkers may guide personalized therapeutic interventions including compensatory measures to restore or improve anticancer immune responses.
586 citations
TL;DR: Approaches to accurately quantify distinct cell death pathways are described, their advantages and pitfalls are discussed, and those techniques that are amenable to HTS are focused on.
Abstract: Cell death has an important role in many human diseases, and strategies aimed at modulating the associated pathways have been successfully applied to treat various disorders. Indeed, several clinically promising cytotoxic and cytoprotective agents with potential applications in cancer, ischaemic and neurodegenerative diseases have recently been identified by high-throughput screening (HTS), based on appropriate cell death assays. Given that different cell death modalities may be dysregulated in different diseases, it is becoming increasingly clear that such assays need to not only quantify the extent of cell death, but they must also be able to distinguish between the various pathways. Here, we systematically describe approaches to accurately quantify distinct cell death pathways, discuss their advantages and pitfalls, and focus on those techniques that are amenable to HTS.
520 citations
TL;DR: The acetylase inhibitor spermidine and the sirtuin-1 activator resveratrol disrupt the antagonistic network of acetylases and deacetylases that regulate autophagy.
Abstract: Autophagy protects organelles, cells, and organisms against several stress conditions. Induction of autophagy by resveratrol requires the nicotinamide adenine dinucleotide–dependent deacetylase sirtuin 1 (SIRT1). In this paper, we show that the acetylase inhibitor spermidine stimulates autophagy independent of SIRT1 in human and yeast cells as well as in nematodes. Although resveratrol and spermidine ignite autophagy through distinct mechanisms, these compounds stimulate convergent pathways that culminate in concordant modifications of the acetylproteome. Both agents favor convergent deacetylation and acetylation reactions in the cytosol and in the nucleus, respectively. Both resveratrol and spermidine were able to induce autophagy in cytoplasts (enucleated cells). Moreover, a cytoplasm-restricted mutant of SIRT1 could stimulate autophagy, suggesting that cytoplasmic deacetylation reactions dictate the autophagic cascade. At doses at which neither resveratrol nor spermidine stimulated autophagy alone, these agents synergistically induced autophagy. Altogether, these data underscore the importance of an autophagy regulatory network of antagonistic deacetylases and acetylases that can be pharmacologically manipulated.
426 citations
TL;DR: Improved methods for the automation of immunohistochemistry and digitalized image analyses will pave the way to an improved understanding of the complex interplay between cancer parenchyma, stroma, and immune effectors, as well as to the routine evaluation of immune-related parameters to the clinical management of cancer patients.
Abstract: Leukocyte infiltrates into or around tumor cell nests are found in the context of protumorigenic inflammation and anticancer immunosurveillance. Hence, the detailed composition, density, architecture, and function of leukocyte infiltrates must be analyzed to understand their prognostic impact. The ectopic presence within tumors of high endothelial venule cells, which are normally characteristic for secondary lymphoid organs, correlates with a more pronounced infiltration by T lymphocytes and has a positive predictive impact on local advanced breast cancer treated with neoadjuvant chemotherapy. Recent progress in the field indicates that immune infiltrates of the primary tumors, as well as of metastases, are not only independent prognostic biomarkers but can also constitute predictive factors, suggesting that the pretherapeutic immune response can determine the efficacy of conventional chemotherapies. Moreover, accumulating evidence indicates that chemotherapy can stimulate anticancer immune responses coupled with an increased intratumoral lymphoid infiltration, which correlates with tumor mass reduction and patient survival. Improved methods for the automation of immunohistochemistry and digitalized image analyses will pave the way to an improved understanding of the complex interplay between cancer parenchyma, stroma, and immune effectors, as well as to the routine evaluation of immune-related parameters to the clinical management of cancer patients.
375 citations
TL;DR: The data suggest that nitrosative stress-mediated protein aggregation in neurodegenerative diseases may be, in part, due to autophagy inhibition.
TL;DR: The combination of ER stress inducers (such as THAPS or tunicamycin) and CDDP effectively induced the translocation of CRT to the plasma membrane, as well as immunogenic cell death, although ER stress or CDDP alone was insufficient to induce CRT exposure and immunogeniccell death.
Abstract: In contrast to other cytotoxic agents including anthracyclins and oxaliplatin (OXP), cisplatin (CDDP) fails to induce immunogenic tumor cell death that would allow to stimulate an anticancer immune response and hence to amplify its therapeutic efficacy. This failure to induce immunogenic cell death can be attributed to CDDP's incapacity to elicit the translocation of calreticulin (CRT) from the lumen of the endoplasmic reticulum (ER) to the cell surface. Here, we show that, in contrast to OXP, CDDP is unable to activate the protein kinase-like ER kinase (PERK)-dependent phosphorylation of the eukaryotic translation initiation factor 2α (eIF2α). Accordingly, CDDP also failed to stimulate the formation of stress granules and macroautophagy, two processes that only occur after eIF2α phosphorylation. Using a screening method that monitors the voyage of CRT from the ER lumen to the cell surface, we identified thapsigargin (THAPS), an inhibitor of the sarco/ER Ca(2+)-ATPase as a molecule that on its own does not stimulate CRT exposure, yet endows CDDP with the capacity to do so. The combination of ER stress inducers (such as THAPS or tunicamycin) and CDDP effectively induced the translocation of CRT to the plasma membrane, as well as immunogenic cell death, although ER stress or CDDP alone was insufficient to induce CRT exposure and immunogenic cell death. Altogether, our results underscore the contribution of the ER stress response to the immunogenicity of cell death.
TL;DR: IL-17 production by γδ T cells is required for tumor cell infiltration by IFN-γ–producing CD8+ T cells and inhibition of tumor growth in response to anthracyclines.
Abstract: By triggering immunogenic cell death, some anticancer compounds, including anthracyclines and oxaliplatin, elicit tumor-specific, interferon-γ-producing CD8(+) αβ T lymphocytes (Tc1 CTLs) that are pivotal for an optimal therapeutic outcome. Here, we demonstrate that chemotherapy induces a rapid and prominent invasion of interleukin (IL)-17-producing γδ (Vγ4(+) and Vγ6(+)) T lymphocytes (γδ T17 cells) that precedes the accumulation of Tc1 CTLs within the tumor bed. In T cell receptor δ(-/-) or Vγ4/6(-/-) mice, the therapeutic efficacy of chemotherapy was compromised, no IL-17 was produced by tumor-infiltrating T cells, and Tc1 CTLs failed to invade the tumor after treatment. Although γδ T17 cells could produce both IL-17A and IL-22, the absence of a functional IL-17A-IL-17R pathway significantly reduced tumor-specific T cell responses elicited by tumor cell death, and the efficacy of chemotherapy in four independent transplantable tumor models. Adoptive transfer of γδ T cells restored the efficacy of chemotherapy in IL-17A(-/-) hosts. The anticancer effect of infused γδ T cells was lost when they lacked either IL-1R1 or IL-17A. Conventional helper CD4(+) αβ T cells failed to produce IL-17 after chemotherapy. We conclude that γδ T17 cells play a decisive role in chemotherapy-induced anticancer immune responses.
Institut Gustave Roussy1, French Institute of Health and Medical Research2, Centre national de la recherche scientifique3, Paris Descartes University4, Pierre-and-Marie-Curie University5, University of Paris6, Istituto Giannina Gaslini7, University of Genoa8, Ghent University9, Aix-Marseille University10
TL;DR: The genetically determined NKp30 status predicts the clinical outcomes of individuals with GIST independently from KIT mutation, and predominant expression of the immunosuppressiveNKp30c isoform was associated with reduced survival of subjects.
Abstract: The natural killer (NK) cell receptor NKp30 is involved in the recognition of tumor and dendritic cells (DCs). Here we describe the influence of three NKp30 splice variants on the prognosis of gastrointestinal sarcoma (GIST), a malignancy that expresses NKp30 ligands and that is treated with NK-stimulatory KIT tyrosine kinase inhibitors. Healthy individuals and those with GIST show distinct patterns of transcription of functionally different NKp30 isoforms. In a retrospective analysis of 80 individuals with GIST, predominant expression of the immunosuppressive NKp30c isoform (over the immunostimulatory NKp30a and NKp30b isoforms) was associated with reduced survival of subjects, decreased NKp30-dependent tumor necrosis factor-α (TNF-α) and CD107a release, and defective interferon-γ (IFN-γ) and interleukin-12 (IL-12) secretion in the NK-DC cross-talk that could be restored by blocking of IL-10. Preferential NKp30c expression resulted partly from a single-nucleotide polymorphism at position 3790 in the 3' untranslated region of the gene encoding NKp30. The genetically determined NKp30 status predicts the clinical outcomes of individuals with GIST independently from KIT mutation.
TL;DR: IL-18 is defined as an immunosuppressive cytokine in cancer because it promotes the development of NK-controlled metastases in a PD-1-dependent manner and novel clinical implementations of anti-PD-1 antibodies in human malignancies that produce IL-18 are suggested.
Abstract: IL-18 suppresses the crucial role of natural killer cells (NK cells) in supporting tumor immunosurveillance, with implications for clinical strategies to reverse this mechanism of tumoral immune escape.
University of Michigan1, University of Massachusetts Medical School2, University of Toronto3, University of Pittsburgh4, University of Paris-Sud5, Yeshiva University6, University of California, San Francisco7, University of New Mexico8, Weizmann Institute of Science9, University of Helsinki10, University of Texas MD Anderson Cancer Center11, Virginia Commonwealth University12, University of Paris13, University of Texas Southwestern Medical Center14, Yale University15, Tokyo Medical and Dental University16, University of Cambridge17, University of Oslo18, University of Colorado Denver19, University of Göttingen20, Cancer Research UK21
TL;DR: A comprehensive glossary of autophagy-related terms is developed to provide a quick reference for researchers who need a brief reminder of the regulatory effects of transcription factors and chemical agents that induce or inhibit Autophagy.
Abstract: The study of autophagy is rapidly expanding, and our knowledge of the molecular mechanism and its connections to a wide range of physiological processes has increased substantially in the past decade. The vocabulary associated with autophagy has grown concomitantly. In fact, it is difficult for readers--even those who work in the field--to keep up with the ever-expanding terminology associated with the various autophagy-related processes. Accordingly, we have developed a comprehensive glossary of autophagy-related terms that is meant to provide a quick reference for researchers who need a brief reminder of the regulatory effects of transcription factors and chemical agents that induce or inhibit autophagy, the function of the autophagy-related proteins, and the roles of accessory components and structures that are associated with autophagy.
TL;DR: Light is shed on the molecular identity of the factors that are required for cell death to be perceived as immunogenic as they appear on the surface or in the microenvironment of dying cells and the intriguing observations that the most abundant endoplasmic reticulum protein, calreticulin, and themost abundant intracellular metabolite, ATP, can determine whether cell death is immunogenic.
Abstract: The success of some chemo- and radiotherapeutic regimens relies on the induction of immunogenic tumor cell death and on the induction of an anticancer immune response. Cells succumbing to immunogenic cell death undergo specific changes in their surface characteristics and release pro-immunogenic factors according to a defined spatiotemporal pattern. This stimulates antigen presenting cells such as dendritic cells to efficiently take up tumor antigens, process them, and cross-prime cytotoxic T lymphocytes, thus eliciting a tumor-specific cognate immune response. Such a response can also target therapy-resistant tumor (stem) cells, thereby leading, at least in some instances, to tumor eradication. In this review, we shed some light on the molecular identity of the factors that are required for cell death to be perceived as immunogenic. We discuss the intriguing observations that the most abundant endoplasmic reticulum protein, calreticulin, the most abundant intracellular metabolite, ATP, and the most abundant non-histone chromatin-binding protein, HMGB1, can determine whether cell death is immunogenic as they appear on the surface or in the microenvironment of dying cells.
TL;DR: An essential role for HMGB1 in autophagic surveillance with important effects on mitochondrial quality control is revealed and heat shock protein beta-1 (HSPB1 or HSP27) is shown to be the downstream mediator of this effect.
TL;DR: The contribution of autophagic malfunctions to the development of several common neurological disorders and the potential benefits of pharmacologically induced autophagy for the avoidance of neurodegeneration are discussed.
French Institute of Health and Medical Research1, Pasteur Institute2, Centre national de la recherche scientifique3, University of Paris-Sud4, University of California, Merced5, Paris Descartes University6, Curie Institute7, Laval University8, Paris Diderot University9, University of Rome Tor Vergata10
TL;DR: Contact with HIV-1 envelope protein elicits release of ATP through pannexin-1 channels on target cells; by activating purinergic receptors and Pyk2 kinase in target cells, this extracellular ATP boosts HIV- 1 infectivity.
Abstract: Extracellular adenosine triphosphate (ATP) can activate purinergic receptors of the plasma membrane and modulate multiple cellular functions. We report that ATP is released from HIV-1 target cells through pannexin-1 channels upon interaction between the HIV-1 envelope protein and specific target cell receptors. Extracellular ATP then acts on purinergic receptors, including P2Y2, to activate proline-rich tyrosine kinase 2 (Pyk2) kinase and transient plasma membrane depolarization, which in turn stimulate fusion between Env-expressing membranes and membranes containing CD4 plus appropriate chemokine co-receptors. Inhibition of any of the constituents of this cascade (pannexin-1, ATP, P2Y2, and Pyk2) impairs the replication of HIV-1 mutant viruses that are resistant to conventional antiretroviral agents. Altogether, our results reveal a novel signaling pathway involved in the early steps of HIV-1 infection that may be targeted with new therapeutic approaches.
TL;DR: There is not a single compound that would induce cell death by autophagy in a high-content screen on a set of cytotoxic agents, underscoring the idea that cell death is rarely, if ever, executed by autophile in human cells.
Abstract: To address the question of whether established or experimental anticancer chemotherapeutics can exert their cytotoxic effects by autophagy, we performed a high-content screen on a set of cytotoxic agents. We simultaneously determined parameters of autophagy, apoptosis and necrosis on cells exposed to -1400 compounds. Many agents induced a 'pure' autophagic, apoptotic or necrotic phenotype, whereas less than 100 simultaneously induced autophagy, apoptosis and necrosis. A systematic analysis of the autophagic flux induced by the most potent 80 inducers of GFP-LC3 puncta among the NCI panel agents showed that 59 among them truly induced autophagy. The remaining 21 compounds were potent inducers of apoptosis or necrosis, yet failed to stimulate an autophagic flux, which were characterized as microtubule inhibitors. Knockdown of ATG7 was efficient in preventing GFP-LC3 puncta, yet failed to attenuate cell death by the agents that induce GFP-LC3 puncta. Thus there is not a single compound that would induce cell death by autophagy in our screening, underscoring the idea that cell death is rarely, if ever, executed by autophagy in human cells.
TL;DR: It is suggested that the mitochondrion constitutes a pivotal target of copper in Wilson disease, and copper-chelating agents reversed mitochondrial accumulation of copper, as well as signs of intra-mitochondrial membrane crosslinking, thereby preserving the functional and structural integrity of mitochondria.
Abstract: Wilson disease (WD) is a rare hereditary condition that is caused by a genetic defect in the copper-transporting ATPase ATP7B that results in hepatic copper accumulation and lethal liver failure. The present study focuses on the structural mitochondrial alterations that precede clinical symptoms in the livers of rats lacking Atp7b, an animal model for WD. Liver mitochondria from these Atp7b–/– rats contained enlarged cristae and widened intermembrane spaces, which coincided with a massive mitochondrial accumulation of copper. These changes, however, preceded detectable deficits in oxidative phosphorylation and biochemical signs of oxidative damage, suggesting that the ultrastructural modifications were not the result of oxidative stress imposed by copper-dependent Fenton chemistry. In a cell-free system containing a reducing dithiol agent, isolated mitochondria exposed to copper underwent modifications that were closely related to those observed in vivo. In this cell-free system, copper induced thiol modifications of three abundant mitochondrial membrane proteins, and this correlated with reversible intramitochondrial membrane crosslinking, which was also observed in liver mitochondria from Atp7b–/– rats. In vivo, copper-chelating agents reversed mitochondrial accumulation of copper, as well as signs of intra-mitochondrial membrane crosslinking, thereby preserving the functional and structural integrity of mitochondria. Together, these findings suggest that the mitochondrion constitutes a pivotal target of copper in WD.
TL;DR: In this review, the historical evolution of the concept of programmed necrosis and the molecular mechanisms that underlie necroptosis initiation and execution are described and evidence suggesting that necroPTosis represents an ancient and evolutionarily conserved cell death modality that may be targeted for drug development is provided.
Abstract: During the past decade, cell death researchers have witnessed a gradual but deep conceptual revolution: it has been unequivocally shown that necrosis, which for long had been considered as a purely accidental cell death mode, can also be induced by finely regulated signal transduction pathways In particular, when caspases are inhibited by pharmacological or genetic means, the ligation of death receptors such as the tumor necrosis factor receptor 1 (TNFR1) can lead to the assembly of a supramolecular complex containing the receptor-interacting protein kinases 1 and 3 (RIP1 and RIP3) that delivers a pronecrotic signal Such complex has recently been dubbed necrosome and mediates the execution of a specific instance of regulated necrosis, necroptosis Soon, it turned out that programmed necrosis occurs in nonmammalian model organisms and that it is implicated in human diseases including ischemia and viral infection In this review, we first describe the historical evolution of the concept of programmed necrosis and the molecular mechanisms that underlie necroptosis initiation and execution We then provide evidence suggesting that necroptosis represents an ancient and evolutionarily conserved cell death modality that may be targeted for drug development
Oregon Health & Science University1, Providence Portland Medical Center2, University of Pittsburgh3, University of Oslo4, Howard Hughes Medical Institute5, Memorial Sloan Kettering Cancer Center6, Harvard University7, Charles University in Prague8, Goethe University Frankfurt9, Pontifícia Universidade Católica do Rio Grande do Sul10, Cleveland Clinic11, McMaster University12, University of Mainz13, Second Military Medical University14, Peking Union Medical College15, Ohio State University16, University of Michigan17, Vilnius University18, University of Queensland19, University of Pennsylvania20, VU University Amsterdam21, Radboud University Nijmegen22, University of Nottingham23, French Institute of Health and Medical Research24, Alnylam Pharmaceuticals25, University of Tübingen26, Lund University27, University of California, San Francisco28, Celgene29, Bristol-Myers Squibb30, University of Texas MD Anderson Cancer Center31, University of Tokyo32, Johns Hopkins University33, Rush University Medical Center34, Kyoto University35, Keio University36, Charité37, National Institutes of Health38, Karolinska Institutet39, Institut Gustave Roussy40, Université de Montréal41, Vita-Salute San Raffaele University42, Merck KGaA43, Thomas Jefferson University44, University of Navarra45, Leiden University46, University of California, Davis47, University of British Columbia48, University of Pisa49, Loyola University Chicago50, Roswell Park Cancer Institute51, University of Toronto52, Cancer Research Institute53, Ludwig Institute for Cancer Research54, University of Southampton55, Istituto Superiore di Sanità56, Nottingham Trent University57, University of California, Los Angeles58, University of Lausanne59, Tanta University60, Mie University61, Millennium Pharmaceuticals62, University of Copenhagen63, University of Science and Technology of China64, Shandong University65, Ludwig Maximilian University of Munich66, Society for Immunotherapy of Cancer67, Innsbruck Medical University68, University of Chicago69, University of Washington70
TL;DR: The critical hurdles identified by representatives of the collaborating organizations, now organized as the World Immunotherapy Council, are presented and discussed in this report.
Abstract: Scientific discoveries that provide strong evidence of antitumor effects in preclinical models often encounter significant delays before being tested in patients with cancer. While some of these delays have a scientific basis, others do not. We need to do better. Innovative strategies need to move into early stage clinical trials as quickly as it is safe, and if successful, these therapies should efficiently obtain regulatory approval and widespread clinical application. In late 2009 and 2010 the Society for Immunotherapy of Cancer (SITC), convened an "Immunotherapy Summit" with representatives from immunotherapy organizations representing Europe, Japan, China and North America to discuss collaborations to improve development and delivery of cancer immunotherapy. One of the concepts raised by SITC and defined as critical by all parties was the need to identify hurdles that impede effective translation of cancer immunotherapy. With consensus on these hurdles, international working groups could be developed to make recommendations vetted by the participating organizations. These recommendations could then be considered by regulatory bodies, governmental and private funding agencies, pharmaceutical companies and academic institutions to facilitate changes necessary to accelerate clinical translation of novel immune-based cancer therapies. The critical hurdles identified by representatives of the collaborating organizations, now organized as the World Immunotherapy Council, are presented and discussed in this report. Some of the identified hurdles impede all investigators; others hinder investigators only in certain regions or institutions or are more relevant to specific types of immunotherapy or first-in-humans studies. Each of these hurdles can significantly delay clinical translation of promising advances in immunotherapy yet if overcome, have the potential to improve outcomes of patients with cancer.
TL;DR: Data indicate that peptide aptamers or peptides that target HSP70 may be considered as novel lead compounds for cancer therapy.
Abstract: The inhibition of heat shock protein 70 (HSP70) is an emerging strategy in cancer therapy. Unfortunately, no specific inhibitors are clinically available. By yeast two-hybrid screening, we have identified multiple peptide aptamers that bind HSP70. When expressed in human tumor cells, two among these peptide aptamers-A8 and A17-which bind to the peptide-binding and the ATP-binding domains of HSP70, respectively, specifically inhibited the chaperone activity, thereby increasing the cells' sensitivity to apoptosis induced by anticancer drugs. The 13-amino acid peptide from the variable region of A17 (called P17) retained the ability to specifically inhibit HSP70 and induced the regression of subcutaneous tumors in vivo after local or systemic injection. This antitumor effect was associated with an important recruitment of macrophages and T lymphocytes into the tumor bed. Altogether, these data indicate that peptide aptamers or peptides that target HSP70 may be considered as novel lead compounds for cancer therapy.
TL;DR: Data now demonstrate that these organelles also regulate the innate immune response by modulating inflammasome-mediated generation of proinflammatory cytokines.
Abstract: During the past few decades, the vital and lethal functions of mitochondria have been investigated extensively. Data now demonstrate that these organelles also regulate the innate immune response by modulating inflammasome-mediated generation of proinflammatory cytokines.
TL;DR: It is speculated that the identification of signaling/metabolic cascades that are required for the survival of tetraploid or aneuploid (but not diploid) cancer cells may pave the way for the development of novel broad-spectrum anticancer agents.
Abstract: Tetraploidy and the depolyploidization of tetraploid cells may contribute to oncogenesis. Several mechanisms have evolved to avoid the generation, survival, proliferation and depolyploidization of tetraploids. Cells that illicitly survive these checkpoints are prone to chromosomal instability and aneuploidization. Along with their replication, tetraploids constantly undergo chromosomal rearrangements that eventually lead to pseudodiploidy by two non-exclusive mechanisms: (i) multipolar divisions and (ii) illicit bipolar divisions in the presence of improper microtubule-kinetochore attachments. Here, we describe the regulation and the molecular mechanisms that underlie such a ‘polyploidization–depolyploidization' cascade, while focusing on the role of oncogenes and tumor suppressor genes in tetraploidy-driven tumorigenesis. We speculate that the identification of signaling/metabolic cascades that are required for the survival of tetraploid or aneuploid (but not diploid) cancer cells may pave the way for the development of novel broad-spectrum anticancer agents.
TL;DR: It is shown that p53 regulates autophagy through a direct molecular interaction with RB1CC1/FIP200, a protein that is essential for the very apical step of Autophagy initiation.
Abstract: The tumor suppressor protein p53 tonically suppresses autophagy when it is present in the cytoplasm. This effect is phylogenetically conserved from mammals to nematodes, and human p53 can inhibit autophagy in yeast, as we show here. Bioinformatic investigations of the p53 interactome in relationship to the autophagy-relevant protein network underscored the possible relevance of a direct molecular interaction between p53 and the mammalian ortholog of the essential yeast autophagy protein Atg17, namely RB1-inducible coiled-coil protein 1 (RB1CC1), also called FAK family kinase-interacting protein of 200 KDa (FIP200). Mutational analyses revealed that a single point mutation in p53 (K382R) abolished its capacity to inhibit autophagy upon transfection into p53-deficient human colon cancer or yeast cells. In conditions in which wild-type p53 co-immunoprecipitated with RB1CC1/FIP200, p53K382R failed to do so, underscoring the importance of the physical interaction between these proteins for the control of autop...
TL;DR: The yeast genome encodes a functional BH3 domain that induces cell death through phylogenetically conserved mechanisms and displays prolonged chronological and replicative lifespans and resistance to apoptosis induction.
Abstract: Mitochondrial outer membrane permeabilization is a watershed event in the process of apoptosis, which is tightly regulated by a series of pro- and anti-apoptotic proteins belonging to the BCL-2 family, each characteristically possessing a BCL-2 homology domain 3 (BH3). Here, we identify a yeast protein (Ybh3p) that interacts with BCL-XL and harbours a functional BH3 domain. Upon lethal insult, Ybh3p translocates to mitochondria and triggers BH3 domain-dependent apoptosis. Ybh3p induces cell death and disruption of the mitochondrial transmembrane potential via the mitochondrial phosphate carrier Mir1p. Deletion of Mir1p and depletion of its human orthologue (SLC25A3/PHC) abolish stress-induced mitochondrial targeting of Ybh3p in yeast and that of BAX in human cells, respectively. Yeast cells lacking YBH3 display prolonged chronological and replicative lifespans and resistance to apoptosis induction. Thus, the yeast genome encodes a functional BH3 domain that induces cell death through phylogenetically conserved mechanisms.
TL;DR: Functional experiments revealed that pharmacological or genetic inhibition of IKK, Sirtuin and the p53-depleting ubiquitin ligase MDM2 prevented ABT737-induced autophagy, pointing to unexpected and pleiotropic pro-autophagic effects of BH3 mimetics involving the modulation of multiple signalling pathways.
Abstract: The BH3 mimetic ABT737 induces autophagy by competitively disrupting the inhibitory interaction between the BH3 domain of Beclin 1 and the anti-apoptotic proteins Bcl-2 and Bcl-X(L), thereby stimulating the Beclin 1-dependent allosteric activation of the pro-autophagic lipid kinase VPS34. Here, we examined whether ABT737 stimulates other pro-autophagic signal-transduction pathways. ABT737 caused the activating phosphorylation of AMP-dependent kinase (AMPK) and of the AMPK substrate acetyl CoA carboxylase, the activating phosphorylation of several subunits of the inhibitor of NF-κB (IκB) kinase (IKK) and the hyperphosphorylation of the IKK substrate IκB, inhibition of the activity of mammalian target of rapamycin (mTOR) and consequent dephosphorylation of the mTOR substrate S6 kinase. In addition, ABT737 treatment dephosphorylates (and hence likewise inhibits) p53, glycogen synthase kinase-3 and Akt. All these effects were shared by ABT737 and another structurally unrelated BH3 mimetic, HA14-1. Functional experiments revealed that pharmacological or genetic inhibition of IKK, Sirtuin and the p53-depleting ubiquitin ligase MDM2 prevented ABT737-induced autophagy. These results point to unexpected and pleiotropic pro-autophagic effects of BH3 mimetics involving the modulation of multiple signalling pathways.