Oncogene-Induced Senescence as a New Mechanism of Disease: The Paradigm of Erdheimâ€“Chester Disease

Cavalli, Giulio; Biavasco, Riccardo; Borgiani, Bruno; Dagna, Lorenzo

doi:10.3389/fimmu.2014.00281

Cited by 42 publications

(35 citation statements)

References 49 publications

(57 reference statements)

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“…The exact aetiology is unknown; however, recent published studies propose occurrence of oncogene-induced senescence and BRAFV600 mutation 9. Recurrent BRAFV600E mutations leading to chronic uncontrolled inflammation have been reported in more than 50% of patients 3.…”

Section: Discussionmentioning

confidence: 99%

Recurrent pericardial effusion and tamponade in a patient with Erdheim-Chester disease (ECD)

et al. 2015

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Erdheim-Chester disease (ECD) is a rare xanthogranulomatous disorder characterised by the proliferation of lipid laden histiocytes along with infiltration of various organs of the body. Although commonly presenting with bone pains secondary to bony infiltration, cardiac involvement in the form of periaortic fibrosis and pericardial involvement may be seen in a subgroup of patients. We report a case of ECD presenting as recurrent pericardial effusion along with pericardial tamponade.

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Section: Discussionmentioning

confidence: 99%

Recurrent pericardial effusion and tamponade in a patient with Erdheim-Chester disease (ECD)

et al. 2015

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“…20 BRAF-mutated histiocytes in ECD activate oncogeneinduced senescence, a protective mechanism against oncogenic events characterized by robust production of pro-inflammatory cytokines, including IL-6. 10,21,22 The pro-inflammatory milieu induced by senescent cells favors the recruitment and activation of histiocytes into ECD lesions. 21 The clinical response observed in Patients 1 and 2 was indeed associated with a decrease or stabilization of these mediators (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…10,21,22 The pro-inflammatory milieu induced by senescent cells favors the recruitment and activation of histiocytes into ECD lesions. 21 The clinical response observed in Patients 1 and 2 was indeed associated with a decrease or stabilization of these mediators (Fig. 3).…”

Section: Discussionmentioning

confidence: 99%

Tocilizumab in patients with multisystem Erdheim–Chester disease

et al. 2017

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Treatment of Erdheim-Chester disease (ECD), a rare non-Langerhans histiocytosis, relies on interferon-a, chemotherapeutic agents such as purine analogs, cytokine-blocking agents and BRAF inhibitors. Since interleukin (IL)-6 levels are elevated in serum and lesions of ECD patients, we evaluated the therapeutic efficacy and safety of IL-6 blockade with tocilizumab. We conducted an open-label, single-arm, phase II, prospective study of tocilizumab in three patients with multisystem ECD and poor tolerance/contraindications to IFN-a. Modifications of symptoms attributed to ECD represented the criteria for evaluation of clinical response. Changes at positron emission tomography scan, computed tomography scan, and magnetic resonance imaging at month 6 represented the main criteria for the evaluation of radiological response.Sustained complete clinical response and partial radiological improvement were observed in two patients, paralleled by modulation of systemic pro-inflammatory mediators. In spite of disease stabilization or improvement at extra-neurological sites, a third patient experienced a radiologic and clinical progression of central nervous system involvement, mirrored by a dramatic increase of circulating IL-6 and related cytokines. These findings indicate that IL-6 inhibition can be effective in ECD, but caution is advisable in patients with neurologic involvement. IL-6 emerges as a central mediator in ECD pathogenesis.

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“…Senescence is commonly defined as a block in cellular proliferation with no cessation in the metabolic activities of cells. Oncogene-induced senescence (OIS) is hypothesized to be a protective mechanism that withdraws the cells from the proliferative pool and thus averts malignant transformation [58]. In human melanoma cells, forced expression of the oncogene BRAF leads to a senescent phenotype with the suppression of PDK1 and simultaneous induction of the PDH-activating enzyme, pyruvate dehydrogenase phosphatase 2 (PDP2).…”

Section: Disparities At the Nuclear Genome Level And Their Role Inmentioning

confidence: 99%

Mitochondrial determinants of cancer health disparities

Choudhury

Singh

2017

Seminars in Cancer Biology

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Mitochondria are involved in the generation of energy, cell growth and differentiation, cellular signaling, cell cycle control, and cell death. To date, the mitochondrial basis of cancer disparities is unknown. The goal of this review is to provide an understanding and a framework of mitochondrial determinants that may contribute to cancer disparities in racially different populations. Mitochondria, which are multi-functional, have been implicated in the initiation and progression of cancers in relation to metabolic alterations in transformed cells. Due to ethnic-based diversity, the mitochondrial genome (mtDNA) could be a basis for inherited racial disparities and for acquired somatic mutations during tumorigenesis. In African Americans, several germline, population-specific haplotype variants in mtDNA as well as depletion of mtDNA have been linked to cancer predisposition and cancer disparities. Indeed, depletion of mtDNA and mutations in mtDNA or nuclear genome (nDNA)-encoded mitochondrial proteins lead to mitochondrial dysfunction and promote resistance to apoptosis, the epithelial-to-mesenchymal transition, and metastatic disease, which in turn can contribute to cancer disparity and tumor aggressiveness related to racial disparities. Ethnic differences at the level of expression or genetic variations in nDNA encoding the mitochondrial proteome, including mitochondria-localized mtDNA replication and repair proteins, miRNA, transcription factors, kinases and phosphatases, and tumor suppressors and oncogenes may underlie susceptibility to high-risk and aggressive cancers found in African Americans and other ethnicities. The mitochondrial retrograde signaling that alters the expression profile of nuclear genes in response to dysfunctional mitochondria is a mechanism for tumorigenesis. In ethnic populations, differences in mitochondrial function may alter the cross talk between mitochondria and the nucleus at epigenetic and genetic levels, which can also contribute to cancer health disparities. Targeting mitochondrial determinants and mitochondrial retrograde signaling could provide a promising strategy for the development of selective anticancer therapy for dealing with cancer disparities. Further, agents that restore mitochondrial function to optimal levels should permit sensitivity to anticancer agents for the treatment of aggressive tumors that occur in racially diverse populations and hence help in reducing racial disparities.

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Oncogene-Induced Senescence as a New Mechanism of Disease: The Paradigm of Erdheimâ€“Chester Disease

Cited by 42 publications

References 49 publications

Recurrent pericardial effusion and tamponade in a patient with Erdheim-Chester disease (ECD)

Recurrent pericardial effusion and tamponade in a patient with Erdheim-Chester disease (ECD)

Tocilizumab in patients with multisystem Erdheim–Chester disease

Mitochondrial determinants of cancer health disparities

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