Lack of Radiation Dose or Quality Dependence of Epithelial-to-Mesenchymal Transition (EMT) Mediated by Transforming Growth Factor β

Andarawewa, Kumari L.; Costes, Sylvain V.; Fernandez‐Garcia, Ignacio; Chou, Wen‐Hai; Ravani, Shraddha A.; Park, Howard; Barcellos‐Hoff, Mary Helen

doi:10.1016/j.ijrobp.2010.11.058

Cited by 31 publications

(34 citation statements)

References 27 publications

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“…Even though the RBE values we predict here for MCF10A have not been measured yet, they are in excellent agreement with similar studies. For example, the reported RBE for clonogenic survival of ~2 in primary breast cells exposed to 1 GeV/n Fe ions [4] is very close to the predicted RBE of 1.74 for the immortalized MCF10A line exposed to the same ion and energy. Finally, the shape of RBE for survival predicted here matches well the overkill effect observed in the upper hundreds of keV/µm, but the peak is at a higher LET value than previously reported [42].…”

Section: Discussionsupporting

confidence: 62%

“…In other words, it takes 40 times more dose of X-rays to lead to the same tumor incidence than with HZE Fe. In contrast, in vitro studies for mammalian cell survival have led to much lower RBE with values ~2 for primary human breast epithelial cell survival exposed to 1 GeV/n Fe [4] or between 2 to 10 for chromosomal aberrations for various HZE [5]. There are therefore discrepancies between in vitro and in vivo responses, and mechanistic models may help resolve such discrepancies.…”

Section: Introductionmentioning

confidence: 98%

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Combinatorial DNA Damage Pairing Model Based on X-Ray-Induced Foci Predicts the Dose and LET Dependence of Cell Death in Human Breast Cells

et al. 2014

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In contrast to the classic view of static DNA double strand breaks (DSBs) being repaired at the site of damage, we hypothesize that DSBs move and merge with each other over large distances (µm). As X-ray dose increases, the probability of having DSB clusters increases and so does the probability of misrepair and cell death. Experimental work characterizing the dose dependence of radiation-induced foci (RIF) from X-ray in nonmalignant human mammary epithelial cells (MCF10A) is used here to validate a DSB clustering model. We then use the principles of the local effect model (LEM) to predict the yield of DSB at the sub-micron level. Two mechanisms for DSB clustering are first compared: random coalescence of DSBs versus active movement of DSBs into repair domains. Simulations that best predict both RIF dose dependence and cell survival following X-ray favor the repair domain hypothesis, suggesting the nucleus is divided into an array of regularly spaced repair domains of ~1.55 µm sides. Applying the same approach to high-LET ion tracks, we can predict experimental RIF/µm along tracks with an overall relative error of 12%, for LET ranging between 30 and 350 keV/µm and for three different ions. Finally, cell death is predicted by assuming an exponential dependence on the total number of DSBs and of all possible combinations of paired DSBs within each simulated RIF. RBE predictions for cell survival of MCF10A exposed to high-LET show an LET dependence that matches previous experimental results for similar cell types. Overall, this work suggests that microdosimetric properties of ion tracks at the sub-micron level are sufficient to explain both RIF data and survival curves for any LET, similarly to the LEM assumption. On the other hand, high-LET death mechanism does not have to infer linear-quadratic dose formalism as done in the LEM. In addition, the size of repair domains derived in our model are based on experimental RIF and are three times larger than the hypothetical LEM voxel used to fit survival curves. Our model is therefore an alternative to previous approaches by providing a testable biological mechanism (i.e. RIF). More generally, DSB pairing will help develop more accurate alternatives to the simplistic linear cancer risk model (LNT) currently used for regulating exposure to very low levels of ionizing radiation.Vadhavkar et al.

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Section: Discussionsupporting

confidence: 62%

Section: Introductionmentioning

confidence: 98%

Combinatorial DNA Damage Pairing Model Based on X-Ray-Induced Foci Predicts the Dose and LET Dependence of Cell Death in Human Breast Cells

et al. 2014

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“…Previously reported characteristics for the EMT process, such as changes in cell shape, size, intercellular communication and expression of cell differentiation markers (Câmara and Jarai, 2010;Jia et al, 2014;Prahlad et al, 1998), were observed in both cell lines at the applied TGF-β concentrations. The lack of radiation-induced EMT was contrary to previously published observations with other cell types where radiation was able to enhance the TGF-β-induced EMT in dose-and quality-independent way (Andarawewa et al, 2007;Andarawewa et al, 2011;Wang et al, 2012a;Wang et al, 2012b). Cell typespecific dissimilarities in the TGF-β production, response and use of various radiation qualities may explain the controversial results.…”

Section: Discussioncontrasting

confidence: 86%

“…Cell typespecific dissimilarities in the TGF-β production, response and use of various radiation qualities may explain the controversial results. The doses applied for both low and high LET exposures in this study were comparable to doses used by other research groups (Andarawewa et al, 2007;Andarawewa et al, 2011). Even though we used lower concentration of TGF-β (0.1-0.2 ng/ml) than in the other studies (0.4 ng/ml Andarawewa et al, 2007;Andarawewa et al, 2011), it is possible that the lung epithelial cell lines used in our study are highly sensitive to TGF-β and this can mask the potential minor effect of radiation exposure to EMT enhancement.…”

Section: Discussionsupporting

confidence: 77%

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Lack of epithelial-to-mesenchymal transition induction in two bronchial epithelial cell lines after alpha and gamma irradiation

Acheva

Eklund

Lemola

et al. 2015

IJLR

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Abstract:The induction of epithelial-to-mesenchymal transition (EMT) in human lung epithelial cell lines was investigated after α-particle and γ-radiation exposures. We applied TGF-β treatment of cells as positive EMT-controls and tested in parallel if radiation has a potentiating effect on the EMT induction. BEAS-2B and HBEC-3KT cells were irradiated with 5.4 MeV α-particles or γ-rays ( 60 Co, 1.13-1.15 Gy/min) with or without of TGF-β. The cells were harvested three days post treatment and the EMT markers vimentin, fibronectin and E-cadherin were analysed by immunofluorescence staining and Western blotting. The TGF-β treatment-induced EMT in both cell lines in the applied concentrations. We could not prove any clear EMT induction with low or moderate doses of α-particles and γ-rays. No significant additive effect with radiation and TGF-β was observed. We suggest that there might be a different mechanism induced by radiation in bronchial cells after radon and medical exposures that does not involve direct EMT changes.

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Role of the extracellular matrix in cancer‐associated epithelial to mesenchymal transition phenomenon

Tzanakakis

Kavasi

Voudouri

et al. 2017

Developmental Dynamics

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The epithelial to mesenchymal transition (EMT) program is a crucial component in the processes of morphogenesis and embryonic development. The transition of epithelial to mesenchymal phenotype is associated with numerous structural and functional changes, including loss of cell polarity and tight cell-cell junctions, the acquisition of invasive abilities, and the expression of mesenchymal proteins. The switch between the two phenotypes is involved in human pathology and is crucial for cancer progression. Extracellular matrices (ECMs) are multi-component networks that surround cells in tissues. These networks are obligatory for cell survival, growth, and differentiation as well as tissue organization. Indeed, the ECM suprastructure, in addition to its supportive role, can process and deliver a plethora of signals to cells, which ultimately regulate their behavior. Importantly, the ECM derived signals are critically involved in the process of EMT during tumorigenesis. This review discusses the multilayer interaction between the ECM and the EMT process, focusing on contributions of discrete mediators, a strategy that may identify novel potential target molecules. Developmental Dynamics 247:368-381, 2018. V C 2017 Wiley Periodicals, Inc.

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Lack of Radiation Dose or Quality Dependence of Epithelial-to-Mesenchymal Transition (EMT) Mediated by Transforming Growth Factor β

Cited by 31 publications

References 27 publications

Combinatorial DNA Damage Pairing Model Based on X-Ray-Induced Foci Predicts the Dose and LET Dependence of Cell Death in Human Breast Cells

Combinatorial DNA Damage Pairing Model Based on X-Ray-Induced Foci Predicts the Dose and LET Dependence of Cell Death in Human Breast Cells

Lack of epithelial-to-mesenchymal transition induction in two bronchial epithelial cell lines after alpha and gamma irradiation

Role of the extracellular matrix in cancer‐associated epithelial to mesenchymal transition phenomenon

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