Radiation and the microenvironment - Tumorigenesis and therapy
ABSTRACT Radiation rapidly and persistently alters the soluble and insoluble components of the tissue microenvironment. This affects the cell phenotype, tissue composition and the physical interactions and signalling between cells. These alterations in the microenvironment can contribute to carcinogenesis and alter the tissue response to anticancer therapy. Examples of these responses and their implications are discussed with a view to therapeutic intervention.
- SourceAvailable from: Per Karlsson
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- "TGFˇwas identified as a critical signal, accelerating carcinogenesis. Such cellular and tissue responses to ionizing radiation can have non-targeted effects on non-irradiated cells, such as induction of genomic instability . Since the mechanisms and timing of breast cancer development are complex and not well understood, most efforts to develop mechanistic cancer models including GI concentrated on colon cancer , including additional pathways for genomic instability     . "
ABSTRACT: The cohort of 17,200 female Swedish hemangioma patients, who had been exposed to ionizing radiation because of skin hemangioma, was analyzed for breast cancer incidence with descriptive excess relative risk models and mechanistic models of carcinogenesis. The dosimetry system has recently been updated, leading to substantially reduced doses for the most highly exposed part of the Stockholm cohort. The follow-up includes persons until December 2009 with 877 breast cancer cases. All models agree on the risk estimates. The excess relative and excess absolute risk at the age of 50 years are 0.48Gy(-1) (95% CI 0.28; 0.69) and 10.4 [Formula: see text] (95% CI 6.1; 14.4), respectively. These risk estimates are about a factor of 2 higher than previous analyses of this cohort as a consequence of the re-evaluation of the dosimetry system. Explicit models incorporating effects of genomic instability were developed and applied to the hemangioma cohort. It was found that a radiation-induced transition towards genomic instability was highly significant. The models indicate that the main effect of radiation-induced genomic instability is to increase the rate of transition of non-initiated cells to initiated cells with a proliferative advantage. The magnitude of such an acceleration cannot be inferred from epidemiological data alone, but must be complemented by radiobiological measurements. Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 03/2015; 7. DOI:10.1016/j.mrfmmm.2015.03.002 · 3.68 Impact Factor
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- "activation of cytokines, growth factors and chemokines can induce persistent remodelling of the extracellular matrix, affecting the overall response of the tissue . "
ABSTRACT: Introduction The kidneys are the dose-limiting organ in some radionuclide therapy regimens. However, the biological impact of internal exposure from radionuclides is still not fully understood. The aim of this study was to examine the effects of dose rate and time after i.v. injection of 177LuCl3 on changes in transcriptional patterns in mouse kidney tissue. Methods To investigate the effect of dose rate, female Balb/c nude mice were i.v. injected with 11, 5.6, 1.6, 0.8, 0.30, and 0 MBq of 177LuCl3, and killed at 3, 6, 24, 48, 168, and 24 hours after injection, respectively. Furthermore, the effect of time after onset of exposure was analysed using mice injected with 0.26, 2.4, and 8.2 MBq of 177LuCl3, and killed at 45, 90, and 140 days after injection. Global transcription patterns of irradiated kidney cortex and medulla were assessed and enriched biological processes were determined from the regulated gene sets using Gene Ontology terms. Results The average dose rates investigated were 1.6, 0.84, 0.23, 0.11 and 0.028 mGy/min, with an absorbed dose of 0.3 Gy. At 45, 90 and 140 days, the absorbed doses were estimated to 0.3, 3, and 10 Gy. In general, the number of differentially regulated transcripts increased with time after injection, and decreased with absorbed dose for both kidney cortex and medulla. Differentially regulated transcripts were predominantly involved in metabolic and stress response-related processes dependent on dose rate, as well as transcripts associated with metabolic and cellular integrity at later time points. Conclusion The observed transcriptional response in kidney tissue was diverse due to difference in absorbed dose, dose rate and time after exposure. Nevertheless, several transcripts were significantly regulated in all groups despite differences in exposure parameters, which may indicate potential biomarkers for exposure of kidney tissue.Nuclear Medicine and Biology 11/2014; 41(10). DOI:10.1016/j.nucmedbio.2014.07.010 · 2.41 Impact Factor
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- "Along with these issue goes the debate about radiation-induced MMP activation. Although radiation seems to generally activate MMPs [75,88–90], tumor cells not necessarily show pronounced invasion but the tumor stroma including ECM is remodeled dose-dependently   . Hence, future studies might elucidate the micro-and macroenvironmental interplay between integrins and MMPs with regard to tumor–stroma interactions and fibrotic normal tissue side effects. "
ABSTRACT: Interlocking gene mutations, epigenetic alterations and microenvironmental features perpetuate tumor development, growth, infiltration and spread. Consequently, intrinsic and acquired therapy resistance arises and presents one of the major goals to solve in oncologic research today. Among the myriad of microenvironmental factors impacting on cancer cell resistance, cell adhesion to the extracellular matrix (ECM) has recently been identified as key determinant. Despite the differentiation between cell adhesion-mediated drug resistance (CAMDR) and cell adhesion-mediated radioresistance (CAMRR), the underlying mechanisms share great overlap in integrin and focal adhesion hub signaling and differ further downstream in the complexity of signaling networks between tumor entities. Intriguingly, cell adhesion to ECM is per se also essential for cancer cells similar to their normal counterparts. However, based on the overexpression of focal adhesion hub signaling receptors and proteins and a distinct addiction to particular integrin receptors, targeting of focal adhesion proteins has been shown to potently sensitize cancer cells to different treatment regimes including radiotherapy, chemotherapy and novel molecular therapeutics. In this review, we will give insight into the role of integrins in carcinogenesis, tumor progression and metastasis. Additionally, literature and data about the function of focal adhesion molecules including integrins, integrin-associated proteins and growth factor receptors in tumor cell resistance to radio- and chemotherapy will be elucidated and discussed.Seminars in Cancer Biology 08/2014; 31. DOI:10.1016/j.semcancer.2014.07.009 · 9.33 Impact Factor