We are addressing the question of whether age-associated oncogenesis, and more specifically, tumor progression, is associated with mitochondrial (mt) ROS. We hypothesize that age-associated cancers are driven by increasing levels of mitochondrial-mediated ROS. Our preliminary data suggests that ROS is associated with tumor progression, and provides the rationale for three specific aims to better understand the mechanisms whereby protection of mitochondria reduces oncogenesis.
Aim 1 is designed to determine what cellular processes are involved in the mCAT suppression of metastatic tumor progression in the lungs of young and old mice, primary skin tumor progression in young and old mice. We will use primary skin tumor and pulmonary metastatic mammary tumor models in the presence and absence of mitochondrial-targeted catalase (mCAT) to analyze neoplastic progression and tumor metastasis. We will compare the host response and the protective effects of mCAT in young and old mice.
Aim 2 is designed to determine the contribution of specific cell types in the mCAT suppression of tumor progression. There is increasing evidence that the microenvironment plays a critical role in oncogeneis. Our preliminary results showing attenuation of tumor progression via expression of mCAT could be explained, in part, by mCAT expression within specific cell types within the microenvironment of the neoplastic cells. We will therefore assess the roles of mCAT expression in several different stromal cell types and compare their putative suppressive effects with epithelial cells (both neoplastic and non-neoplastic) that express mCAT. Specific mCAT expression will be driven by cell-specific Cre transgenesis.
Aim 3 is designed to evaluate the efficacy of mitochondrial antioxidant and protective drugs for intervention in tumor progression and metastasis. We will correlate the differences in modes of action of the drugs with differences in effects on tumor progression, cell proliferation and survival in order to better understand the mechanisms whereby protection of mitochondria reduces neoplasia and enhances an anti-aging phenotype. The experimental approach is designed to determine if specific mitochondrial targeted antioxidant mimetic are effective in suppressing tumor progression in young and old animals with cancer or in aged wild type mice that develop multiple tumor types.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG001751-30
Application #
8431786
Study Section
Special Emphasis Panel (ZAG1-ZIJ-6)
Project Start
Project End
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
30
Fiscal Year
2013
Total Cost
$282,333
Indirect Cost
$96,562
Name
University of Washington
Department
Type
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Campbell, Matthew D; Marcinek, David J (2016) Evaluation of in vivo mitochondrial bioenergetics in skeletal muscle using NMR and optical methods. Biochim Biophys Acta 1862:716-24
Loeb, Lawrence A (2016) Human Cancers Express a Mutator Phenotype: Hypothesis, Origin, and Consequences. Cancer Res 76:2057-9
Treuting, P M; Snyder, J M; Ikeno, Y et al. (2016) The Vital Role of Pathology in Improving Reproducibility and Translational Relevance of Aging Studies in Rodents. Vet Pathol 53:244-9
Liu, Sophia Z; Marcinek, David J (2016) Skeletal muscle bioenergetics in aging and heart failure. Heart Fail Rev :
Ahn, Eun Hyun; Lee, Seung Hyuk; Kim, Joon Yup et al. (2016) Decreased Mitochondrial Mutagenesis during Transformation of Human Breast Stem Cells into Tumorigenic Cells. Cancer Res 76:4569-78
Kruse, Shane E; Karunadharma, Pabalu P; Basisty, Nathan et al. (2016) Age modifies respiratory complex I and protein homeostasis in a muscle type-specific manner. Aging Cell 15:89-99
Chiao, Ying Ann; Kolwicz, Stephen C; Basisty, Nathan et al. (2016) Rapamycin transiently induces mitochondrial remodeling to reprogram energy metabolism in old hearts. Aging (Albany NY) 8:314-27
Ahn, Eun Hyun; Hirohata, Kensen; Kohrn, Brendan F et al. (2015) Detection of Ultra-Rare Mitochondrial Mutations in Breast Stem Cells by Duplex Sequencing. PLoS One 10:e0136216
Birk, Alexander V; Chao, Wesley M; Liu, Shaoyi et al. (2015) Disruption of cytochrome c heme coordination is responsible for mitochondrial injury during ischemia. Biochim Biophys Acta 1847:1075-84
Quarles, Ellen K; Dai, Dao-Fu; Tocchi, Autumn et al. (2015) Quality control systems in cardiac aging. Ageing Res Rev 23:101-15

Showing the most recent 10 out of 278 publications