Necrosis is often viewed as an accidental and unregulated cellular event. However, accumulating evidence suggests that necrosis, like apoptosis, can be executed by regulated mechanisms.
Hitomi et al. ...(2008) now describe an extensive network of genes that mediate a form of programmed necrosis called necroptosis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Besides constituting a first layer of defense against microbial challenges, the detection of cytosolic DNA is fundamental for mammalian organisms to control malignant transformation and tumor ...progression. The accumulation of DNA in the cytoplasm can initiate the proliferative inactivation (via cellular senescence) or elimination (via regulated cell death) of neoplastic cell precursors. Moreover, cytosolic DNA sensing is intimately connected to the secretion of cytokines that support innate and adaptive antitumor immunity. Here, we discuss the molecular mechanisms whereby cytosolic DNA enables cell-intrinsic and -extrinsic oncosuppression, and their relevance for the development of novel therapeutic approaches that reinstate anticancer immunosurveillance.
Besides constituting a first layer of defense against microbial challenges, the detection of cytosolic DNA is fundamental for mammalian organisms to control malignant transformation and tumor progression. The accumulation of DNA in the cytoplasm can initiate the proliferative inactivation (via cellular senescence) or elimination (via regulated cell death) of neoplastic cell precursors. Moreover, cytosolic DNA sensing is intimately connected to the secretion of cytokines that support innate and adaptive antitumor immunity. Here, we discuss the molecular mechanisms whereby cytosolic DNA enables cell-intrinsic and -extrinsic oncosuppression, and their relevance for the development of novel therapeutic approaches that reinstate anticancer immunosurveillance.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
SummaryImmunotherapy is radically changing the clinical management of patients affected by an increasingly wide array of tumours. However, not all patients achieve long-term clinical benefits from ...immunotherapy as a standalone treatment, calling for the development of regimens that combine various interventions. Radiotherapy stands out as a particularly promising candidate in this setting, not only because of its established safety profile, but also because radiotherapy has the potential ability to mediate robust immunostimulatory effects that could synergise with immunotherapy in systemic tumour control. However, optimal radioimmunotherapy regimens might call for the redefinition of conventional radiotherapy doses and fractionation schedules. In this Series paper, we discuss current approaches to improve the efficacy and reduce the toxicity of radioimmunotherapy for the management of cancer.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Conventional chemotherapeutics and targeted antineoplastic agents have been developed based on the simplistic notion that cancer constitutes a cell-autonomous genetic or epigenetic disease. However, ...it is becoming clear that many of the available anticancer drugs that have collectively saved millions of life-years mediate therapeutic effects by eliciting de novo or reactivating pre-existing tumor-specific immune responses. Here, we discuss the capacity of both conventional and targeted anticancer therapies to enhance the immunogenic properties of malignant cells and to stimulate immune effector cells, either directly or by subverting the immunosuppressive circuitries that preclude antitumor immune responses in cancer patients. Accumulating evidence indicates that the therapeutic efficacy of several antineoplastic agents relies on their capacity to influence the tumor-host interaction, tipping the balance toward the activation of an immune response specific for malignant cells. We surmise that the development of successful anticancer therapies will be improved and accelerated by the immunological characterization of candidate agents.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Since the discovery that mitochondrial membrane permeabilization represents a critical step in the regulation of intrinsic apoptosis, mitochondria have been viewed as pluripotent organelles, ...controlling cell death as well as several aspects of cell survival. Mitochondria constitute the most prominent source of ATP and are implicated in multiple anabolic and catabolic circuitries. In addition, mitochondria coordinate cell-wide stress responses, such as autophagy, and control nonapoptotic cell death routines, such as regulated necrosis. Thus, mitochondria seem to regulate a continuum of cellular functions, spanning from physiological metabolism to stress responses and death. The involvement of mitochondria in both vital and lethal processes is crucial for both embryonic and postembryonic development, as well as for the maintenance of adult tissue homeostasis. In line with this notion, primary mitochondrial defects or alterations in the signaling pathways that converge on or emanate from mitochondria underpin a large number of human diseases, including premature aging, neurodegenerative disorders, cardiovascular disorders, and cancer. Here, we provide an overview of the molecular mechanisms that enable mitochondria to sustain cell survival, coordinate stress responses, and mediate cell death, linking these pathways—whenever relevant—to cardiovascular health and disease.
Autophagy is central to the maintenance of organismal homeostasis in both physiological and pathological situations. Accordingly, alterations in autophagy have been linked to clinically relevant ...conditions as diverse as cancer, neurodegeneration and cardiac disorders. Throughout the past decade, autophagy has attracted considerable attention as a target for the development of novel therapeutics. However, such efforts have not yet generated clinically viable interventions. In this Review, we discuss the therapeutic potential of autophagy modulators, analyse the obstacles that have limited their development and propose strategies that may unlock the full therapeutic potential of autophagy modulation in the clinic.
A variety of targeted anticancer agents have been successfully introduced into clinical practice, largely reflecting their ability to inhibit specific molecular alterations that are required for ...disease progression. However, not all malignant cells rely on such alterations to survive, proliferate, disseminate and/or evade anticancer immunity, implying that many tumours are intrinsically resistant to targeted therapies. Radiotherapy is well known for its ability to activate cytotoxic signalling pathways that ultimately promote the death of cancer cells, as well as numerous cytoprotective mechanisms that are elicited by cellular damage. Importantly, many cytoprotective mechanisms elicited by radiotherapy can be abrogated by targeted anticancer agents, suggesting that radiotherapy could be harnessed to enhance the clinical efficacy of these drugs. In this Review, we discuss preclinical and clinical data that introduce radiotherapy as a tool to elicit or amplify clinically actionable signalling pathways in patients with cancer.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The immunosurveillance theory postulates that tumors evolve and progress in an uncontrolled fashion only when anticancer immune responses fail. Natural immunosurveillance clearly influences human ...breast cancer (BC) progression because the prognosis of BC patients is dictated by the density, composition and activity of the tumor immune infiltrate at diagnosis. Moreover, chemotherapeutic and radiotherapeutic regimens commonly employed for the treatment of BC affect the tumor immune infiltrate, and accumulating data suggest that the clinical efficacy of these treatments is largely determined by T cell-dependent tumor-specific immune responses. In addition, the mechanism of action of targeted anticancer therapeutics, such as the erb-b2 receptor tyrosine kinase 2 (ERBB2)-targeting agent trastuzumab, involves the innate and adaptive arms of the immune system. In this Review, we discuss these findings as well as preliminary evidence indicating that immunotherapy constitutes a promising option for the treatment of BC. Moreover, we point out that the successful implementation of immunotherapy to BC management requires the optimization of current immunotherapeutic regimens and the identification of immunological biomarkers that enable improved risk stratification and the design of personalized, dynamic treatment plans.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SBMB, UILJ, UKNU, UL, UM, UPUK
30.
Cell death and senescence Galluzzi, Lorenzo; Myint, Melissa
Journal of translational medicine,
06/2023, Volume:
21, Issue:
1
Journal Article
Peer reviewed
Open access
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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