20 research outputs found
Stress and Radiation-Induced Activation of Multiple Intracellular Signaling Pathways
Exposure of cells to a variety of stresses induces compensatory activations of multiple intracellular signaling pathways. These activations can play critical roles in controlling cell survival and repopulation effects in a stress-specific and cell type-dependent manner. Some stress-induced signaling pathways are those normally activated by mitogens such as the EGFR/RAS/PI3K-MAPK pathway. Other pathways activated by stresses such as ionizing radiation include those downstream of death receptors, including pro-caspases and the transcription factor NFKB. This review will attempt to describe some of the complex network of signals induced by ionizing radiation and other cellular stresses in animal cells, with particular attention to signaling by growth factor and death receptors. This includes radiation-induced signaling via the EGFR and IGFI-R to the PI3K, MAPK, JNK, and p38 pathways as well as FAS-R and TNF-R signaling to pro-caspases and NFKB. The roles of autocrine ligands in the responses of cells and bystander cells to radiation and cellular stresses will also be discussed. Based on the data currently available, it appears that radiation can simultaneously activate multiple signaling pathways in cells. Reactive oxygen and nitrogen species may play an important role in this process by inhibiting protein tyrosine phosphatase activity. The ability of radiation to activate signaling pathways may depend on the expression of growth factor receptors, autocrine factors, RAS mutation, and PTEN expression. In other words, just because pathway X is activated by radiation in one cell type does not mean that pathway X will be activated in a different cell type. Radiation-induced signaling through growth factor receptors such as the EGFR may provide radioprotective signals through multiple downstream pathways. In some cell types, enhanced basal signaling by proto-oncogenes such as RAS may provide a radioprotective signal. In many cell types, this may be through PI3K, in others potentially by NFKB or MAPK. Receptor signaling is often dependent on autocrine factors, and synthesis of autocrine factors will have an impact on the amount of radiation-induced pathway activity. For example, cells expressing TGFalpha and HB-EGF will generate protection primarily through EGFR. Heregulin and neuregulins will generate protective signals through ERBB4/ERBB3. The impact on radiation-induced signaling of other autocrine and paracrine ligands such as TGFbeta and interleukin 6 is likely to be as complicated as described above for the ERBB receptors.Fil: Dent, Paul. Virginia Commonwealth University; Estados UnidosFil: Yacoub, Adly. Virginia Commonwealth University; Estados UnidosFil: Contessa, Joseph. Virginia Commonwealth University; Estados UnidosFil: Caron, Ruben Walter. Virginia Commonwealth University; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Amorino, Geroge. Virginia Commonwealth University; Estados UnidosFil: Valerie, Kristoffer. Virginia Commonwealth University; Estados UnidosFil: Hagan, Michael P.. Virginia Commonwealth University; Estados UnidosFil: Grant, Steven. Virginia Commonwealth University; Estados UnidosFil: Schmidt Ullrich, Rupert. Virginia Commonwealth University; Estados Unido
Compensatory ErbB3/c-Src signaling enhances carcinoma cell survival to ionizing radiation
EGFR and ErbB2 are two members of the ErbB family of receptor Tyr Kinases identified as therapeutic targets for treating carcinomas. Breast carcinoma cells express different complements and variable proportions of ErbB receptor Tyr kinases, which activate unique and redundant signaling cascades that are essential for cell survival. Previously it was shown that a COOH-terminal truncation mutant of the EGFR (EGFR-CD533) blocks EGFR dependent signals and radiosensitizes breast carcinoma cells. In this study the effects of EGFR-CD533 and an analogous truncation mutant of ErbB2 (ErbB2-CD572) on ErbB receptor family dimerization and signaling are further investigated. Using adenoviral vectors in breast carcinoma cell lines with variable ErbB expression profiles, we demonstrate different effects for each deletion mutant. EGFR-CD533 blocks ligand stimulation of EGFR, ErbB2, and ErbB4, but is associated with a compensatory Tyr kinase activity resulting in phosphorylation of ErbB3. In contrast, ErbB2-CD572 produces a weaker, non-specific pattern of ErbB receptor family inhibition, based upon the ErbB expression pattern of the cell type. Investigation of the compensatory Tyr kinase activity associated with EGFR-CD533 expression identified an ErbB3/c-Src signaling pathway that regulates expression of anti-apoptotic Bcl family proteins. This signaling is active in the T47D cell line, which inherently over-express ErbB3, absent in MDA-MB231 cells, which have low ErbB3 expression levels, and is restored in a MDA-MB231 cell line engineered to over-express ErbB3. Furthermore we demonstrate that ErbB3/c-Src signaling is radio-protective, and that its elimination through pharmacologic inhibition of c-Src enhances radiation-induced apoptosis. In summary, these studies identify a novel ErbB3/c-Src survival signal and point to ErbB3 expression levels as an important variable in therapeutic targeting of ErbB receptors in breast carcinoma cells.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44234/1/10549_2005_Article_9023.pd
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IMRT for Carcinomas of the Oropharynx and Oral Cavity
The major potential advantages of IMRT have been addressed in a number of preliminary clinical investigations/trials which have generated encouraging results that salivary gland sparing can be achieved with improvements in xerostomia without risking increased failure rates. Dose escalation trials, although documenting the potential of IMRT as a tool for dose escalation, require refinement and intense physician involvement but have produced encouraging loco-regional tumor control rates. Finally, the ability of generating plans with outstanding dose conformality in the radiotherapeutic management of HNSCCs of the OP/(OC) has been clearly established
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Monte Carlo–based dosimetry of head-and-neck patients treated with SIB-IMRT
Purpose: To evaluate the accuracy of previously reported superposition/convolution (SC) dosimetric results by comparing with Monte Carlo (MC) dose calculations for head-and-neck intensity-modulated radiation therapy (IMRT) patients treated with the simultaneous integrated boost technique.
Methods and Materials: Thirty-one plans from 24 patients previously treated on a phase I/II head-and-neck squamous cell carcinoma simultaneous integrated boost IMRT protocol were used. Clinical dose distributions, computed with an SC algorithm, were recomputed using an EGS4-based MC algorithm. Phantom-based dosimetry quantified the fluence prediction accuracy of each algorithm. Dose–volume indices were used to compare patient dose distributions.
Results and Discussion: The MC algorithm predicts flat-phantom measurements better than the SC algorithm. Average patient dose indices agreed within 2.5% of the local dose for targets; 5.0% for parotids; and 1.9% for cord and brainstem. However, only 1 of 31 plans agreed within 3% for all indices; 4 of 31 agreed within 5%. In terms of the prescription dose, 4 of 31 plans agreed within 3% for all indices, whereas 28 of 31 agreed within 5%.
Conclusions: Average SC-computed doses agreed with MC results in the patient geometry; however deviations >5% were common. The fluence modulation prediction is likely the major source of the dose discrepancy. The observed dose deviations can impact dose escalation protocols, because they would result in shifting patients to higher dose levels