NRF2 and the Hallmarks of Cancer Rojo de la Vega, Montserrat; Chapman, Eli; Zhang, Donna D.
Cancer cell,
07/2018, Volume:
34, Issue:
1
Journal Article
Peer reviewed
Open access
The transcription factor NRF2 is the master regulator of the cellular antioxidant response. Though recognized originally as a target of chemopreventive compounds that help prevent cancer and other ...maladies, accumulating evidence has established the NRF2 pathway as a driver of cancer progression, metastasis, and resistance to therapy. Recent studies have identified new functions for NRF2 in the regulation of metabolism and other essential cellular functions, establishing NRF2 as a truly pleiotropic transcription factor. In this review, we explore the roles of NRF2 in the hallmarks of cancer, indicating both tumor suppressive and tumor-promoting effects.
The transcription factor NRF2 is the master regulator of the cellular antioxidant response. Though recognized originally as a target of chemopreventive compounds that help prevent cancer and other maladies, accumulating evidence has established the NRF2 pathway as a driver of cancer progression, metastasis, and resistance to therapy. Recent studies have identified new functions for NRF2 in the regulation of metabolism and other essential cellular functions, establishing NRF2 as a truly pleiotropic transcription factor. In this Review, we explore the roles of NRF2 in the hallmarks of cancer, indicating both tumor suppressive and tumor promoting effects.
Leading researchers and clinicians join forces to explain how malignant melanoma develops from its benign precursor cell type. The authors focus on the molecular mechanisms involved in melanogenesis, ...in the malignant transformation of melanocytes, and in the further progression of primary melanomas into invasive and metastatic melanomas. They also review recent advances in our understanding of the basic biology of melanocytes and the development, migration, and differentiation of melanoblasts into melanocytes. The book provides an up-to-date understanding of the progressive mechanisms of oncological development in malignant melanoma, a likely model of malignant progress for other types of cancer, and the ongoing development of novel therapeutics.
Summary
Integration of Agrobacterium tumefaciens transferred DNA (T‐DNA) into the plant genome is the last step required for stable plant genetic transformation. The mechanism of T‐DNA integration ...remains controversial, although scientists have proposed the participation of various nonhomologous end‐joining (NHEJ) pathways. Recent evidence suggests that in Arabidopsis, DNA polymerase θ (PolQ) may be a crucial enzyme involved in T‐DNA integration.
We conducted quantitative transformation assays of wild‐type and polQ mutant Arabidopsis and rice, analyzed T‐DNA/plant DNA junction sequences, and (for Arabidopsis) measured the amount of integrated T‐DNA in mutant and wild‐type tissue.
Unexpectedly, we were able to generate stable transformants of all tested lines, although the transformation frequency of polQ mutants was c. 20% that of wild‐type plants. T‐DNA/plant DNA junctions from these transformed rice and Arabidopsis polQ mutants closely resembled those from wild‐type plants, indicating that loss of PolQ activity does not alter the characteristics of T‐DNA integration events. polQ mutant plants show growth and developmental defects, perhaps explaining previous unsuccessful attempts at their stable transformation.
We suggest that either multiple redundant pathways function in T‐DNA integration, and/or that integration requires some yet unknown pathway.
See also the Commentary on this article by Faure, 229: 2386–2388.
This book gathers renowned researchers and policymakers from all continents who have accompanied Dirk Messner’s professional life in science and policy advice. Their articles and essays cover topics ...related to the ideational spheres and practice-oriented spaces which have consistently characterised Dirk Messner’s career. These include steps at the national, regional or global level to effectively accelerate the shift towards planetary sustainability; measures to forge or strengthen cross-sectoral, transboundary, multi-actor alliances for sustainable transformation; and key elements of universal ethics and shared norms which foster transnational cooperation for the global common good. With contributions by Manish Bapna, Lilian Busse, Ani Dasgupta, J. Carlos Domínguez, Ottmar Edenhofer, Jörg Faust, Thomas Fues, Hans Haake, Medelina K. Hendytio, Ariel Macaspac Hernandez, Anna-Katharina Hornidge, Adolf Kloke-Lesch, Claus Leggewie, Siddharth Mallavarapu, Simon Maxwell, Dirk Meyer, Nebojsa Nakicenovic, Sabine Nallinger, Andrew Norton, Franz Nuscheler, Jiahua Pan Jürgen Renn, Enrique Saravia, Sabine Schlacke, Uwe Schneidewind, Imme Scholz, Svenja Schulze, Zita Sebesvari, Wolfgang Seidel, Elizabeth Sidiropoulos, Achim Steiner, Franziska Wehinger and Heidemarie Wieczorek-Zeul.
The transformation-induced plasticity (TRIP) in advanced high-strength steels (AHSS) is reviewed, where the main concepts and the recent progress in the processing and properties of AHSS are ...introduced. The metastable austenitic stainless and multiphase TRIP-assisted steels, as well as the more recent third generation AHSS grades, namely the medium-Mn and quenching and partitioning (Q&P) steels, are critically discussed. These steels utilize the TRIP effect and the enhanced work-hardening rate through the transformation of (retained) austenite in their microstructures to martensite during plastic deformation for the improvement of strength-ductility balance, which make them especially suitable for the automotive industry to be used in the lightweight car body for addressing the safety, fuel consumption, and air pollution issues. The kinetics of strain-induced martensitic transformation (SIMT) as well as the effects of chemical composition, grain size, deformation temperature, strain rate, and deformation mode on the austenite stability are reviewed. The effects of holding temperature and time during the isothermal bainitic transformation (IBT) in TRIP-aided steels, during the austenite-reverted-transformation (ART) annealing in medium-Mn steels, and during the quenching and partitioning steps in the Q&P steels are critically discussed towards enhancement of the amount of retained austenite and optimization of strength-ductility trade off. The alternative thermomechanical processing routes as well as the modified grades such as δ-TRIP and quenching-partitioning-tempering steels are also introduced.
Cadmium (Cd) is a toxic metal, targeting the lung, liver, kidney, and testes following acute intoxication, and causing nephrotoxicity, immunotoxicity, osteotoxicity and tumors after prolonged ...exposures. Reactive oxygen species (ROS) are often implicated in Cd toxicology. This minireview focused on direct evidence for the generation of free radicals in intact animals following acute Cd overload and discussed the association of ROS in chronic Cd toxicity and carcinogenesis. Cd-generated superoxide anion, hydrogen peroxide, and hydroxyl radicals
in vivo have been detected by the electron spin resonance spectra, which are often accompanied by activation of redox sensitive transcription factors (e.g., NF-κB, AP-1 and Nrf2) and alteration of ROS-related gene expression. It is generally agreed upon that oxidative stress plays important roles in acute Cd poisoning. However, following long-term Cd exposure at environmentally-relevant low levels, direct evidence for oxidative stress is often obscure. Alterations in ROS-related gene expression during chronic exposures are also less significant compared to acute Cd poisoning. This is probably due to induced adaptation mechanisms (e.g., metallothionein and glutathione) following chronic Cd exposures, which in turn diminish Cd-induced oxidative stress. In chronic Cd-transformed cells, less ROS signals are detected with fluorescence probes. Acquired apoptotic tolerance renders damaged cells to proliferate with inherent oxidative DNA lesions, potentially leading to tumorigenesis. Thus, ROS are generated following acute Cd overload and play important roles in tissue damage. Adaptation to chronic Cd exposure reduces ROS production, but acquired Cd tolerance with aberrant gene expression plays important roles in chronic Cd toxicity and carcinogenesis.
Fusions involving the oncogenic gene RET have been observed in thyroid and lung cancers. Here we report RET gene alterations, including amplification, missense mutations, known fusions, novel ...fusions, and rearrangements in breast cancer. Their frequency, oncogenic potential, and actionability in breast cancer are described. Two out of eight RET fusions (NCOA4-RET and a novel RASGEF1A-RET fusion) and RET amplification were functionally characterized and shown to activate RET kinase and drive signaling through MAPK and PI3K pathways. These fusions and RET amplification can induce transformation of non-tumorigenic cells, support xenograft tumor formation, and render sensitivity to RET inhibition. An index case of metastatic breast cancer progressing on HER2-targeted therapy was found to have the NCOA4-RET fusion. Subsequent treatment with the RET inhibitor cabozantinib led to a rapid clinical and radiographic response. RET alterations, identified by genomic profiling, are promising therapeutic targets and are present in a subset of breast cancers.
Tumours most often arise from progression of precursor clones within a single anatomical niche. In the bone marrow, clonal progenitors can undergo malignant transformation to acute leukaemia, or ...differentiate into immune cells that contribute to disease pathology in peripheral tissues
. Outside the marrow, these clones are potentially exposed to a variety of tissue-specific mutational processes, although the consequences of this are unclear. Here we investigate the development of blastic plasmacytoid dendritic cell neoplasm (BPDCN)-an unusual form of acute leukaemia that often presents with malignant cells isolated to the skin
. Using tumour phylogenomics and single-cell transcriptomics with genotyping, we find that BPDCN arises from clonal (premalignant) haematopoietic precursors in the bone marrow. We observe that BPDCN skin tumours first develop at sun-exposed anatomical sites and are distinguished by clonally expanded mutations induced by ultraviolet (UV) radiation. A reconstruction of tumour phylogenies reveals that UV damage can precede the acquisition of alterations associated with malignant transformation, implicating sun exposure of plasmacytoid dendritic cells or committed precursors during BPDCN pathogenesis. Functionally, we find that loss-of-function mutations in Tet2, the most common premalignant alteration in BPDCN, confer resistance to UV-induced cell death in plasmacytoid, but not conventional, dendritic cells, suggesting a context-dependent tumour-suppressive role for TET2. These findings demonstrate how tissue-specific environmental exposures at distant anatomical sites can shape the evolution of premalignant clones to disseminated cancer.
Most tumors exhibit increased glucose metabolism to lactate, however, the extent to which glucose-derived metabolic fluxes are used for alternative processes is poorly understood. Using a ...metabolomics approach with isotope labeling, we found that in some cancer cells a relatively large amount of glycolytic carbon is diverted into serine and glycine metabolism through phosphoglycerate dehydrogenase (PHGDH). An analysis of human cancers showed that PHGDH is recurrently amplified in a genomic region of focal copy number gain most commonly found in melanoma. Decreasing PHGDH expression impaired proliferation in amplified cell lines. Increased expression was also associated with breast cancer subtypes, and ectopic expression of PHGDH in mammary epithelial cells disrupted acinar morphogenesis and induced other phenotypic alterations that may predispose cells to transformation. Our findings show that the diversion of glycolytic flux into a specific alternate pathway can be selected during tumor development and may contribute to the pathogenesis of human cancer.
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