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ABSTRACT: Tetraploid cells-cells that contain twice the normal amount of DNA-are more prone to neoplastic transformation than their normal, diploid counterparts since they are genomically unstable and frequently undergo asymmetric, multipolar cell divisions. Similar to many other genomic aberrations, tetraploidization is normally avoided by multiple, nonredundant cell-intrinsic mechanisms that are tied to cell cycle checkpoints. Unexpectedly, tetraploidization is also under the control of a cell-extrinsic mechanism determined by the immune system. Indeed, oncogene- or carcinogen-induced cancers developing in immunodeficient mice contain cells with a higher DNA content than similar tumors growing in immunocompetent hosts. Moreover, cancer cell lines that have been rendered tetraploid in vitro grow normally in immunodeficient mice, yet almost fail to generate tumors in immunocompetent animals. One of the mechanisms whereby the immune system recognizes tetraploid cells originates from tetraploidy causing an endoplasmic reticulum (ER) stress response that culminates in the exposure of the ER protein calreticulin on the cell surface. Hence, tetraploidy exemplifies a potentially oncogenic alteration that is repressed by a combination of cell-autonomous mechanisms and immunosurveillance. Oncogenesis and tumor progression require the simultaneous failure of both such control systems.
Annals of the New York Academy of Sciences 05/2013; 1284(1):57-61. · 3.15 Impact Factor
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Sylvie Rusakiewicz,
Michaela Semeraro,
Matthieu Sarabi,
Mélanie Desbois,
Clara Locher,
Rosa Mendez,
Nadege Vimond,
Angel Concha,
Federico Garrido,
Nicolas Isambert, [......],
Frederic Commo,
Philippe Terrier,
Paule Opolon,
Jean-Francois Emile,
Jean-Michel Coindre, Guido Kroemer,
Nathalie Chaput,
Axel Le Cesne,
Jean-Yves Blay,
Laurence Zitvogel
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ABSTRACT: Cancer immunosurveillance relies on effector/memory tumor infiltrating CD8+T cells with a Th1 profile. Evidence for an NK cell-based control of human malignancies is still largely missing. The KIT tyrosine kinase inhibitor imatinib mesylate (IM) markedly prolongs the survival of patients with gastrointestinal stromal tumors (GIST) by direct effects on tumor cells, as well as by indirect immunostimulatory effects on T and NK cells. Here, we investigated the prognostic value of tumor-infiltrating lymphocytes expressing CD3, Foxp3 or NKp46 (NCR1) in a cohort of patients with localized GIST. We found that CD3+ TIL were highly activated in GIST and were especially enriched in areas of the tumor that conserve class I MHC expression in spite of IM treatment. High densities of CD3+ TIL predicted progression-free survival (PFS) in multivariate analyses. Moreover, GIST were infiltrated by a homogeneous subset of cytokine secreting -CD56bright (NCAM1) NK cells that accumulated in tumor foci after IM treatment. The density of the NK infiltrate independently predicted PFS and added prognostic information to the Miettinen score, as well as to the KIT mutational status. NK and T lymphocytes preferentially distributed to distinct areas of tumor sections and probably contributed independently to GIST immunosurveillance. These findings encourage the prospective validation of immune biomarkers for optimal risk stratification of GIST patients.
Cancer Research 04/2013; · 7.86 Impact Factor
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ABSTRACT: Inflammation can be either beneficial or detrimental for the liver, depending on multiple factors. Mild (i.e., limited in intensity and destined to resolved) inflammatory responses have indeed been shown to exert consistent hepatoprotective effects, contributing to tissue repair and promoting the reestablishment of homeostasis. Conversely, excessive (i.e., disproportionate in intensity and permanent) inflammation may induce a massive loss of hepatocytes and hence exacerbate the severity of various hepatic conditions, including ischemia-reperfusion injury, systemic metabolic alterations (e.g., obesity, diabetes, non-alcoholic fatty liver disorders), alcoholic hepatitis, intoxication by xenobiotics and infection, de facto being associated with irreversible liver damage, fibrosis and carcinogenesis. Both liver-resident cells (e.g., Kupffer cells, hepatic stellate cells, sinusoidal endothelial cells) and cells that are recruited in response to injury (e.g., monocytes, macrophages, dendritic cells, natural killer cells) emit pro-inflammatory signals including - but not limited to - cytokines, chemokines, lipid messengers and reactive oxygen species that contribute to the apoptotic or necrotic demise of hepatocytes. In turn, dying hepatocytes release damage-associated molecular patterns that - upon binding to evolutionary conserved pattern recognition receptors - activate cells of the innate immune system to further stimulate inflammatory responses, resulting in the establishment of a highly hepatotoxic feedforward cycle of inflammation and cell death. In this review, we discuss the cellular and molecular mechanisms that account for the most deleterious effect of hepatic inflammation at the cellular level, that is, the initiation of a massive cell death response among hepatocytes.
Journal of Hepatology 04/2013; · 9.26 Impact Factor
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Yuting Ma,
Sandy Adjemian,
Stephen R Mattarollo,
Takahiro Yamazaki,
Laetitia Aymeric,
Heng Yang,
João Paulo Portela Catani,
Dalil Hannani,
Helene Duret,
Kim Steegh, [......],
Nathalie Droin,
Lorenzo Galluzzi,
Roman Krzysiek,
Siamon Gordon,
Philip R Taylor,
Peter Van Endert,
Eric Solary,
Mark J Smyth,
Laurence Zitvogel, Guido Kroemer
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ABSTRACT: The therapeutic efficacy of anthracyclines relies on antitumor immune responses elicited by dying cancer cells. How chemotherapy-induced cell death leads to efficient antigen presentation to T cells, however, remains a conundrum. We found that intratumoral CD11c(+)CD11b(+)Ly6C(hi) cells, which displayed some characteristics of inflammatory dendritic cells and included granulomonocytic precursors, were crucial for anthracycline-induced anticancer immune responses. ATP released by dying cancer cells recruited myeloid cells into tumors and stimulated the local differentiation of CD11c(+)CD11b(+)Ly6C(hi) cells. Such cells efficiently engulfed tumor antigens in situ and presented them to T lymphocytes, thus vaccinating mice, upon adoptive transfer, against a challenge with cancer cells. Manipulations preventing tumor infiltration by CD11c(+)CD11b(+)Ly6C(hi) cells, such as the local overexpression of ectonucleotidases, the blockade of purinergic receptors, or the neutralization of CD11b, abolished the immune system-dependent antitumor activity of anthracyclines. Our results identify a subset of tumor-infiltrating leukocytes as therapy-relevant antigen-presenting cells.
Immunity 04/2013; · 21.64 Impact Factor
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Judith Michels,
Ilio Vitale,
Lorenzo Galluzzi,
Julien Adam,
Ken André Olaussen,
Oliver Kepp,
Laura Senovilla,
Ibtissam Talhaoui,
Justine Guegan,
David Pierre Enot, [......],
Pauline Garcia,
Parviz Behnam-Motlagh,
Kimitoshi Kohno,
Gen Sheng Wu,
Catherine Brenner,
Philippe Dessen,
Murat Saparbaev,
Jean-Charles Soria,
Maria Castedo, Guido Kroemer
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ABSTRACT: Non-small cell lung carcinoma patients are frequently treated with cisplatin (CDDP), most often yielding temporary clinical responses. Here, we show that PARP1 is highly expressed and constitutively hyperactivated in a majority of human CDDP-resistant cancer cells of distinct histologic origin. Cells manifesting elevated intracellular levels of poly(ADP-ribosyl)ated proteins (PAR(high)) responded to pharmacologic PARP inhibitors as well as to PARP1-targeting siRNAs by initiating a DNA damage response that translated into cell death following the activation of the intrinsic pathway of apoptosis. Moreover, PARP1-overexpressing tumor cells and xenografts displayed elevated levels of PAR, which predicted the response to PARP inhibitors in vitro and in vivo more accurately than PARP1 expression itself. Thus, a majority of CDDP-resistant cancer cells appear to develop a dependency to PARP1, becoming susceptible to PARP inhibitor-induced apoptosis. Cancer Res; 73(7); 2271-80. ©2013 AACR.
Cancer Research 04/2013; 73(7):2271-2280. · 7.86 Impact Factor
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Mickaël Michaud,
Isabelle Martins,
Abdul Qader Sukkurwala,
Sandy Adjemian,
Yuting Ma,
Patrizia Pellegatti,
Shensi Shen,
Oliver Kepp,
Marie Scoazec,
Grégoire Mignot,
Santiago Rello-Varona,
Maximilien Tailler,
Laurie Menger,
Erika Vacchelli,
Lorenzo Galluzzi,
François Ghiringhelli,
Francesco di Virgilio,
Laurence Zitvogel, Guido Kroemer
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Judith Michels,
Ilio Vitale,
Laura Senovilla,
David P Enot,
Pauline Garcia,
Delphine Lissa,
Ken A Olaussen,
Catherine Brenner,
Jean-Charles Soria,
Maria Castedo, Guido Kroemer
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ABSTRACT: The antineoplastic agent cis-diammineplatinum(II) dichloride (cisplatin, CDDP) is part of the poorly effective standard treatment of non-small cell lung carcinoma (NSCLC). Here, we report a novel strategy to improve the efficacy of CDDP. In conditions in which CDDP alone or either of two PARP inhibitors, PJ34 hydrochloride hydrate or CEP 8983, used as standalone treatments were inefficient in killing NSCLC cells, the combination of CDDP plus PJ34 or that of CDDP plus CEP 8983 were found to kill a substantial fraction of the cells. This cytotoxic synergy could be recapitulated by combining CDDP and the siRNA-mediated depletion of the principal PARP isoform, PARP1, indicating that it is mediated by on-target effects of PJ34 or CEP 8983. CDDP and PARP inhibitors synergized in inducing DNA damage foci, mitochondrial membrane permeabilization leading to cytochrome c release, and dissipation of the inner transmembrane potential, caspase activation, plasma membrane rupture and loss of clonogenic potential in NSCLC cells. Collectively, our results indicate that CDDP can be advantageously combined with PARP inhibitors to kill several NSCLC cell lines, independently from their p53 status. Combined treatment with CDDP and PARP inhibitors elicits the intrinsic pathway of apoptosis.
Cell cycle (Georgetown, Tex.) 02/2013; 12(6). · 5.36 Impact Factor
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ABSTRACT: Significance: Accumulating evidence indicates that the success of some anticancer treatments (select chemotherapies or radiotherapy or trastuzumab) could be related to the stimulation of an anticancer immune response through the induction of an immunogenic tumor cell death (ICD). Recent advances: Preclinical data revealed that dying tumor cells can emit a series of danger signals (so called "cell death associated molecular patterns" (CDAMP) that will dictate the recruitment and activation of specific inflammatory phagocytes. Hence, tumor cells succumbing to ICD are characterized by specific metabolic and molecular changes that will trigger a hierarchy of polarizing cytokine -producing cells culminating in the recruitment and reactivation of antitumor IFNγ-producing-effector T cells contributing to the success of cytotoxic treatments. Critical issues: In this review, we summarize the molecular and cellular bases of this ICD, underscoring the crucial role of high mobility group box 1 protein (HMGB1), and adenosine tri-phosphate (ATP), both released from dying tumor cells during ICD and implicated in the chemotherapy-elicited anticancer immune response. Future directions: We discuss here how such CDAMP could be predictive biomarkers that could discriminate immunogenic from non immunogenic anti-cancer compounds, and in case of deficiency, could be compensated by surrogate products to ameliorate the success rate of conventional anticancer treatment modalities.
Antioxidants & Redox Signaling 02/2013; · 8.20 Impact Factor
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ABSTRACT: Cardiac glycosides (CGs) are natural compounds sharing the ability to operate as potent inhibitors of the plasma membrane Na(+)/K(+)-ATPase, hence promoting-via an indirect mechanism-the intracellular accumulation of Ca(2+) ions. In cardiomyocytes, increased intracellular Ca(2+) concentrations exert prominent positive inotropic effects, that is, they increase myocardial contractility. Owing to this feature, two CGs, namely digoxin and digitoxin, have extensively been used in the past for the treatment of several cardiac conditions, including distinct types of arrhythmia as well as contractility disorders. Nowadays, digoxin is approved by the FDA and indicated for the treatment of congestive heart failure, atrial fibrillation and atrial flutter with rapid ventricular response, whereas the use of digitoxin has been discontinued in several Western countries. Recently, CGs have been suggested to exert potent antineoplastic effects, notably as they appear to increase the immunogenicity of dying cancer cells. In this Trial Watch, we summarize the mechanisms that underpin the unsuspected anticancer potential of CGs and discuss the progress of clinical studies that have evaluated/are evaluating the safety and efficacy of CGs for oncological indications.
Oncoimmunology. 02/2013; 2(2):e23082.
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Massimo Bonora,
Angela Bononi,
Elena De Marchi,
Carlotta Giorgi,
Magdalena Lebiedzinska,
Saverio Marchi,
Simone Patergnani,
Alessandro Rimessi,
Jan M Suski,
Aleksandra Wojtala,
Mariusz R Wieckowski, Guido Kroemer,
Lorenzo Galluzzi,
Paolo Pinton
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ABSTRACT: The term "mitochondrial permeability transition" (MPT) refers to an abrupt increase in the permeability of the inner mitochondrial membrane to low molecular weight solutes. Due to osmotic forces, MPT is paralleled by a massive influx of water into the mitochondrial matrix, eventually leading to the structural collapse of the organelle. Thus, MPT can initiate mitochondrial outer membrane permeabilization (MOMP), promoting the activation of the apoptotic caspase cascade as well as of caspase-independent cell death mechanisms. MPT appears to be mediated by the opening of the so-called "permeability transition pore complex" (PTPC), a poorly characterized and versatile supramolecular entity assembled at the junctions between the inner and outer mitochondrial membranes. In spite of considerable experimental efforts, the precise molecular composition of the PTPC remains obscure and only one of its constituents, cyclophilin D (CYPD), has been ascribed with a crucial role in the regulation of cell death. Conversely, the results of genetic experiments indicate that other major components of the PTPC, such as voltage-dependent anion channel (VDAC) and adenine nucleotide translocase (ANT), are dispensable for MPT-driven MOMP. Here, we demonstrate that the c subunit of the FO ATP synthase is required for MPT, mitochondrial fragmentation and cell death as induced by cytosolic calcium overload and oxidative stress in both glycolytic and respiratory cell models. Our results strongly suggest that, similar to CYPD, the c subunit of the FO ATP synthase constitutes a critical component of the PTPC.
Cell cycle (Georgetown, Tex.) 01/2013; 12(4). · 5.36 Impact Factor
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Lorenzo Galluzzi,
Aicha Goubar,
Ken André Olaussen,
Ilio Vitale,
Laura Senovilla,
Judith Michels,
Angélique Robin,
Nicolas Dorvault,
Benjamin Besse,
Pierre Validire,
Pierre Fouret,
Carmen Behrens,
Ignacio Ivan Wistuba,
Jean-Charles Soria, Guido Kroemer
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ABSTRACT: Non-small cell lung carcinoma (NSCLC) is the most common form of lung cancer and is associated with a high mortality rate worldwide. The majority of individuals bearing NSCLC are treated with surgery plus adjuvant cisplatin, an initially effective therapeutic regimen that, however, is unable to prevent relapse within 5 y after tumor resection in an elevated proportion of patients. The factors that predict the clinical course of NSCLC and its sensitivity to therapy remain largely obscure. One notable exception is provided by pyridoxal kinase (PDXK), the enzyme that generates the bioactive form of vitamin B6. PDXK has recently been shown to be required for optimal cisplatin responses in vitro and in vivo and to constitute a bona fide prognostic marker in the NSCLC setting. Together with PDXK, 84 additional factors were identified that influence the response of NSCLC cells to cisplatin in vitro including the hepatic lipase LIPC. Here, we report that the intratumoral levels of LIPC, as assessed by immunohistochemistry in two independent cohorts of NSCLC patients, positively correlate with disease outcome. In one out of two cohorts studied, the overall survival of NSCLC patients bearing LIPC (high) lesions was unaffected, if not slightly worsened, by cisplatin-based adjuvant therapy. Conversely, the overall survival of patients with LIPC (low) lesions was prolonged by post-operative cisplatin. Pending validation in appropriate clinical series, these results suggest that LIPC (low) NSCLC patients would be those who mainly benefit from adjuvant cisplatin therapy. Thus, the expression levels of LIPC appear to have an independent prognostic value (and perhaps a predictive potential) in the setting of NSCLC. If these findings were confirmed by additional studies, LIPC expression levels might allow not only for NSCLC patient stratification, but also for the implementation of personalized therapeutic approaches.
Cell cycle (Georgetown, Tex.) 01/2013; 12(4). · 5.36 Impact Factor
