| 1. |
- Block, Keith I., et al.
(författare)
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Designing a broad-spectrum integrative approach for cancer prevention and treatment
- 2015
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Ingår i: Seminars in Cancer Biology. - : Academic Press. - 1044-579X .- 1096-3650. ; 35, s. S276-S304
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Forskningsöversikt (refereegranskat)abstract
- Targeted therapies and the consequent adoption of "personalized" oncology have achieved notable successes in some cancers; however, significant problems remain with this approach. Many targeted therapies are highly toxic, costs are extremely high, and most patients experience relapse after a few disease-free months. Relapses arise from genetic heterogeneity in tumors, which harbor therapy-resistant immortalized cells that have adopted alternate and compensatory pathways (i.e., pathways that are not reliant upon the same mechanisms as those which have been targeted). To address these limitations, an international task force of 180 scientists was assembled to explore the concept of a low-toxicity "broadspectrum" therapeutic approach that could simultaneously target many key pathways and mechanisms. Using cancer hallmark phenotypes and the tumor microenvironment to account for the various aspects of relevant cancer biology, interdisciplinary teams reviewed each hallmark area and nominated a wide range of high-priority targets (74 in total) that could be modified to improve patient outcomes. For these targets, corresponding low-toxicity therapeutic approaches were then suggested, many of which were phytochemicals. Proposed actions on each target and all of the approaches were further reviewed for known effects on other hallmark areas and the tumor microenvironment Potential contrary or procarcinogenic effects were found for 3.9% of the relationships between targets and hallmarks, and mixed evidence of complementary and contrary relationships was found for 7.1%. Approximately 67% of the relationships revealed potentially complementary effects, and the remainder had no known relationship. Among the approaches, 1.1% had contrary, 2.8% had mixed and 62.1% had complementary relationships. These results suggest that a broad-spectrum approach should be feasible from a safety standpoint. This novel approach has potential to be relatively inexpensive, it should help us address stages and types of cancer that lack conventional treatment, and it may reduce relapse risks. A proposed agenda for future research is offered. (C) 2015 The Authors. Published by Elsevier Ltd.
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| 2. |
- Sideridou, Maria, et al.
(författare)
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Cdc6 expression represses E-cadherin transcription and activates adjacent replication origins
- 2011
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Ingår i: Journal of Cell Biology. - : Rockefeller University Press. - 0021-9525 .- 1540-8140. ; 195:7, s. 1123-1140
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Tidskriftsartikel (refereegranskat)abstract
- E-cadherin (CDH1) loss occurs frequently in carcinogenesis, contributing to invasion and metastasis. We observed that mouse and human epithelial cell lines overexpressing the replication licensing factor Cdc6 underwent phenotypic changes with mesenchymal features and loss of E-cadherin. Analysis in various types of human cancer revealed a strong correlation between increased Cdc6 expression and reduced E-cadherin levels. Prompted by these findings, we discovered that Cdc6 repressed CDH1 transcription by binding to the E-boxes of its promoter, leading to dissociation of the chromosomal insulator CTCF, displacement of the histone variant H2A.Z, and promoter heterochromatinization. Mutational analysis identified the Walker B motif and C-terminal region of Cdc6 as essential for CDH1 transcriptional suppression. Strikingly, CTCF displacement resulted in activation of adjacent origins of replication. These data demonstrate that Cdc6 acts as a molecular switch at the E-cadherin locus, linking transcriptional repression to activation of replication, and provide a telling example of how replication licensing factors could usurp alternative programs to fulfill distinct cellular functions.
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| 3. |
- López Riego, Milagrosa, 1992-
(författare)
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Biomarkers of ionising radiation relevant to carcinogenesis : Dose, dose rate and LET dependency of the responses
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- A better understanding of the relationship between ionising radiation (IR) dose, dose rate and radiation quality, and the risk of stochastic effects would improve risk extrapolation from atomic bomb survivors’ data. Owing to insufficient statistical power of epidemiological studies to detect excess incidence of cancer following low doses of IR delivered at low dose rates (LDLDR), as typically encountered in most common human exposure scenarios, radiobiological experiments are fundamental to describe the biological effectiveness of LDLDR and to define the underlying molecular mechanisms. DNA damage and downstream effects are major contributors to radiation carcinogenesis, and as such, these processes have been investigated in the context of plausible mechanisms of radiation-induced health effects in the studies compiled in this thesis, using different cell models and appropriate radiation sources. In Paper I, we characterized the energy, activity and dose rate of new low activity gamma and alpha sources of IR, expected to promote small-scale radiation protection research, and used to demonstrate that LDLDR led to an increased micronucleus frequency, a marker of DNA damage, in human osteosarcoma cells as compared to control cells. In Paper II, we used blood from patients undergoing radiological imaging procedures, i.e. PET-CT and scintigraphy, to investigate whether candidate IR biomarkers, i.e. ROS, γH2AX, and expression of a panel of radiation-responsive genes, are altered following in vivo low dose exposure as compared to control samples obtained before the diagnostic procedure. We showed that radiological imaging generally induced weak γH2AX, ROS, and gene expression fold changes at the selected timepoints, although few donors presented stronger responses. The observed mild increase in DNA damage was, nevertheless, coherent with a subsequent DNA damage response. This study also indicated that owing to the heterogeneity of the response across individuals, the discrimination of exposed samples might be complicated in the absence of a control for low dose exposures. The current risk assessment approach for mixed beam exposures, as encountered in space and other exposure scenarios, assumes additivity of effects of each radiation quality component, but some reports, which show synergistic effects instead, are in conflict with this assumption and indicate a potential underestimation of the corresponding cancer risk. In Paper III, we investigated the consistency of the interaction between low and high LET IR in two healthy donors who presented the largest inter- and intra-donor variability following mixed beam exposure in a previous study. Based on nine biological replicates, this study confirmed that combined alpha particles and photon radiation led to a higher cytogenetic damage and gene expression responses than those expected based on simple additivity of effects, but that the interaction was prone to seasonal intra-donor and inter-donor variation for both endpoints. This study additionally showed that IR exposure modified alternative transcription of FDXR and MDM2 in a radiation quality-dependent manner, albeit alternative transcription did not coincide with the mode of interaction between the different radiation qualities. In light of these results, we suggest that the possible interaction between low and high LET IR should be considered in calculating uncertainty of risk for mixed exposures. In Paper IV, we investigated the early- and long-term biological effects of LDLDR gamma radiation as compared to the same doses delivered acutely in human AHH-1 lymphoblasts, using relevant endpoints related to carcinogenesis, i.e. cell viability, clonogenic survival, chromosomal aberrations, cell growth and global gene expression. The results presented in this study are coherent with a potential detrimental effect of 100 mGy, delivered either chronically or acutely, with a clear dose rate effect for chromosomal aberrations and gene expression, which may modulate cancer risk by dose rate-dependent mechanisms.
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| 4. |
- Tremi, Ioanna, et al.
(författare)
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Requirements for designing an effective metallic nanoparticle (NP)-boosted radiation therapy (RT)
- 2021
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Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 13:13
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Forskningsöversikt (refereegranskat)abstract
- Many different tumor-targeted strategies are under development worldwide to limit the side effects and improve the effectiveness of cancer therapies. One promising method is to enhance the radiosensitization of the cancer cells while reducing or maintaining the normal tissue complica-tion probability during radiation therapy using metallic nanoparticles (NPs). Radiotherapy with MV photons is more commonly available and applied in cancer clinics than high LET particle radi-otherapy, so the addition of high-Z NPs has the potential to further increase the efficacy of photon radiotherapy in terms of NP radiosensitization. Generally, when using X-rays, mainly the inner electron shells are ionized, which creates cascades of both low and high energy Auger electrons. When using high LET particles, mainly the outer shells are ionized, which give electrons with lower energies than when using X-rays. The amount of the produced low energy electrons is higher when exposing NPs to heavy charged particles than when exposing them to X-rays. Since ions traverse the material along tracks, and therefore give rise to a much more inhomogeneous dose distributions than X-rays, there might be a need to introduce a higher number of NPs when using ions compared to when using X-rays to create enough primary and secondary electrons to get the desired dose escalations. This raises the questions of toxicity. This paper provides a review of the fundamental processes controlling the outcome of metallic NP-boosted photon beam and ion beam radiation therapy and presents some experimental procedures to study the biological effects of NPs’ radio-sensitization. The overview shows the need for more systematic studies of the behavior of NPs when exposed to different kinds of ionizing radiation before applying metallic-based NPs in clinical practice to improve the effect of IR therapy.
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| 5. |
- Wang, Zongwei, et al.
(författare)
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Broad targeting of angiogenesis for cancer prevention and therapy
- 2015
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Ingår i: Seminars in Cancer Biology. - : Elsevier. - 1044-579X .- 1096-3650. ; S1044-579X:15, s. 00002-00004
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Forskningsöversikt (refereegranskat)abstract
- Deregulation of angiogenesis - the growth of new blood vessels from an existing vasculature - is a main driving force in many severe human diseases including cancer. As such, tumor angiogenesis is important for delivering oxygen and nutrients to growing tumors, and therefore considered an essential pathologic feature of cancer, while also playing a key role in enabling other aspects of tumor pathology such as metabolic deregulation and tumor dissemination/metastasis. Recently, inhibition of tumor angiogenesis has become a clinical anti-cancer strategy in line with chemotherapy, radiotherapy and surgery, which underscore the critical importance of the angiogenic switch during early tumor development. Unfortunately the clinically approved anti-angiogenic drugs in use today are only effective in a subset of the patients, and many who initially respond develop resistance over time. Also, some of the anti-angiogenic drugs are toxic and it would be of great importance to identify alternative compounds, which could overcome these drawbacks and limitations of the currently available therapy. Finding "the most important target" may, however, prove a very challenging approach as the tumor environment is highly diverse, consisting of many different cell types, all of which may contribute to tumor angiogenesis. Furthermore, the tumor cells themselves are genetically unstable, leading to a progressive increase in the number of different angiogenic factors produced as the cancer progresses to advanced stages. As an alternative approach to targeted therapy, options to broadly interfere with angiogenic signals by a mixture of non-toxic natural compound with pleiotropic actions were viewed by this team as an opportunity to develop a complementary anti-angiogenesis treatment option. As a part of the "Halifax Project" within the "Getting to know cancer" framework, we have here, based on a thorough review of the literature, identified 10 important aspects of tumor angiogenesis and the pathological tumor vasculature which would be well suited as targets for anti-angiogenic therapy: (1) endothelial cell migration/tip cell formation, (2) structural abnormalities of tumor vessels, (3) hypoxia, (4) lymphangiogenesis, (5) elevated interstitial fluid pressure, (6) poor perfusion, (7) disrupted circadian rhythms, (8) tumor promoting inflammation, (9) tumor promoting fibroblasts and (10) tumor cell metabolism/acidosis. Following this analysis, we scrutinized the available literature on broadly acting anti-angiogenic natural products, with a focus on finding qualitative information on phytochemicals which could inhibit these targets and came up with 10 prototypical phytochemical compounds: (1) oleic acid, (2) tripterine, (3) silibinin, (4) curcumin, (5) epigallocatechin-gallate, (6) kaempferol, (7) melatonin, (8) enterolactone, (9) withaferin A and (10) resveratrol. We suggest that these plant-derived compounds could be combined to constitute a broader acting and more effective inhibitory cocktail at doses that would not be likely to cause excessive toxicity. All the targets and phytochemical approaches were further cross-validated against their effects on other essential tumorigenic pathways (based on the "hallmarks" of cancer) in order to discover possible synergies or potentially harmful interactions, and were found to generally also have positive involvement in/effects on these other aspects of tumor biology. The aim is that this discussion could lead to the selection of combinations of such anti-angiogenic compounds which could be used in potent anti-tumor cocktails, for enhanced therapeutic efficacy, reduced toxicity and circumvention of single-agent anti-angiogenic resistance, as well as for possible use in primary or secondary cancer prevention strategies.
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