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Warren C. Ladiges, D.V.M, M.S.
Professor

Department of Comparative Medicine
School of Medicine
University of Washington
Seattle, WA

P: 685-3260
F: 685-3006
wladiges@uw.edu

Veterinary Training
Washington State University, School of Veterinary Medicine.

Military Service
Research Officer, United States Army Medical Research and Nutrition Laboratory, Fitzsimons Army Medical Center, Denver, CO

Residency
University of Washington, Seattle, WA, Laboratory Animal Medicine and Pathology. Diplomate, American College of Laboratory Animal Medicine.

Postdoctoral Fellowship
Fred Hutchinson Cancer Research Center, Seattle, WA

Faculty Appointments Administrative and Service Activities Research focus- Biology of aging and cancer

There are strong indications that modulation of mammalian aging can be successful. Our own studies of extended longevity in mice that express mitochondrial targeted catalase (mCAT) serve as an example (Figure 1).

The limitations of lifespan as an endpoint in these types of studies and the uncertain correlations of life span with health parameters have led biogerontologists to give increasing attention to conditions of improved “health span”, i.e., enhanced health and organ function during aging and protection from age-related diseases such as cancer. The highest risk factor for developing most types of cancer is advancing age. In this regard, we have documented an improved health span in mCAT mice by the demonstration of a decreased incidence of a range of cancers during aging (Figure 2) . A significant finding was decreased malignancy and tumor burden in tissues of epithelial origin suggesting that mitochondrial targeted catalase was suppressing progression but not necessarily initiation of age-related cancer. Metastases to distant organs are the unfortunate consequences of most late-stage human cancers and present intense treatment challenges in the elderly.

Recent evidence now suggests that metastasis may be driven by reactive oxygen species (ROS). When transgenic mice programmed to develop metastatic breast cancer were crossed with transgenic mice expressing mitochondrial targeted catalase, tumors were less invasive (Figure 3)

and there was a robust reduction of metastatic tumor burden in the lungs (Figure 4) suggesting that ROS may be driving metastatic tumor progression in this mouse model. The metastatic cells may be altering ROS signaling by constitutively activating mitogenic and metabolic pathways that further increase the levels of endogenous ROS. Rapid tumor growth results in hypoxia and glucose deprivation, which stimulates the production of chemo-attractants and the recruitment of ROS-producing macrophages. These polarized macrophages could be programmed for tumor support, since their deletion in a mouse model of metastatic breast cancer prevents the metastatic phenotype. Therefore, metastatic cancer is highly dependent on a friendly and actively supporting microenvironment for its invasive qualities.

A long term goal of the genetics of aging must be the translation of basic research findings to the development of pharmacologic interventions for improved human health. In the case of solid human tumors, it takes some 20 years from the time of exposure to a carcinogen to the clinical appearance of a tumor. Thus, therapies directed at the delay of tumor progression should be an important component of age-related research in cancer. It is generally apparent that in most cases where mitochondrial dysfunction contributes to disease, a major cause of damage is ROS produced by mitochondria, either directly or as a secondary disruption of other cellular metabolic pathways. This evidence supports the mitochondrial free radical theory of aging, and assumes that the accumulation of oxidation-induced damage of macromolecules, including DNA, is associated with aging. ROS are a natural byproduct of normal mitochondrial function. Mitochondrial metabolism leads to the formation of the superoxide radical, the first molecule in the pathway responsible for the production of ROS (Figure 5). ROS generation occurs as the result of chronic leakage of electrons during normal respiratory function or from bursts of intra-mitochondrial, cytoplasmic, or extracellular ROS production in response to stress or inflammation. Within the mitochondria, superoxide is converted to diffusible hydrogen peroxide and subsequently to the highly mutagenic and toxic hydroxyl radical. It follows that ROS contribute to the age-related development of cancer, although the cellular and carcinogenic mechanisms are not well understood. Based on this concept, we suggest that relevant strategies for treating metastatic cancer can arise by decreasing mitochondrial oxidative damage and altering ROS levels as the result of increased amounts of endogenous mitochondrial antioxidant enzymes, or by ectopic delivery of antioxidant enzymes or drugs to mitochondria. A focus on mitochondrially targeted antioxidants rather than conventional, untargeted antioxidants is warranted given the general failure of systemic antioxidants (e.g., vitamin E) to retard aging and age-related diseases including cancer.

Treatment of metastatic disease in humans has an alarmingly high rate of failure because effective targets still have not been identified. Generally, it is considered that cellular senescence can result in the suppression of tumor progression. In this regard, the tumor microenvironment may play a major role in determining whether tumor cells are allowed to progress. It may be that with aging changes in the microenvironment in response to an aggressive tumor are inadequate or maladaptive and allow metastasis. Less aggressive tumors may send different signals that trigger apoptosis and help to suppress tumor progression. There is now evidence to suggest that soluble factors released by the hypersecretory senescent cells that accumulate in the stroma of aging tissues can facilitate tumor progression. These non-tumor cells may be attractive targets for strategies to reverse ROS-mediated senescence using mitochondrial targeted antioxidants.

While awaiting definitive demonstration of the relationships between ROS and cancer development, a number of groups are assessing the biological impact of modulating ROS. Our group is focusing on delaying or preventing metastasis and metastatic progression since we have shown that transgenic mice expressing mCAT have decreased age-associated malignancies and metastatic tumor burden. Our approach is based on the concept that attenuation of ROS in non tumor cells of the microenvironment is an effective means of counteracting the pro-tumor support these cells are being programmed by cancer cells to provide. Several strategies could be considered. It is conceivable that with improved viral vector systems, catalase directed specifically for mitochondria could be inserted directly into relevant tissues. For example, if the distant site of metastasis is the lungs, delivery systems to the lungs could be tested. A second strategy would be the use of antioxidant mimetics, which are small molecules that have an affinity for mitochondria or are conjugated to a carrier that has an affinity for mitochondria. The real question is whether they act in an anti-oxidant or pro-oxidant manner, since the vitamin E analogue, alpha-tocopherol, has been shown to induce cancer cell death by a process involving mitochondrial-mediated ROS. However, the effect on non-tumor cells in the microenvironment is less well understood. It may be that mitochondrial-specific antioxidant mimetics have different effects in malignant tumor cells and non tumor cells, ie., pro-oxidant and anti-oxidant, respectively, so that the end result would be a complementation of activity to suppress and eliminate metastatic cells.

In conclusion, a central role for mitochondria in cancer and aging is an exciting synthesis of hypotheses and evidence, which connects these closely related phenomena. The prominent involvement of mitochondrial ROS suggests that these by-products of normal mitochondrial function are likely important players in a very wide range of cancer and age-related processes. Therefore, a better understanding of the precise functions of ROS in pathways such as senescence, apoptosis and macromolecular damage is paramount. Emerging mouse models of modulated ROS, small molecule, targeted antioxidants and surrogate models of various cancers provide a full armamentarium to pinpoint the beneficial and harmful actions of ROS. Understanding the larger picture of ROS metabolism, signaling and damage will provide opportunities for therapeutic interventions which are in critical need to address aging, age-related diseases and metastatic cancer.

Teaching

Students are taught on a one-on-one basis how to design and conduct a short (three months) research project that incorporates objectives of ongoing research efforts described in our Research Program (see above). A new course is being developed to be offered beginning in 2012 that will focus on the latest research findings on the relationship between diet, exercise and cancer in an interactive group discussion format.

Recent Publications and Presentations

2011

Pettan-Brewer C, Mangalindan R, Ladiges W. An orthotopic model of metastatic breast cancer in middle aged mice. Pathobiology of Aging and Age-related Diseases, 2011, Dec Epub.

Pettan-Brewer C, Morton J, Enns L, Kehrli KRM, Sidorova J, Goh J, Coil R, Hopkins H, and Ladiges WC. Tumor progression is delayed in mice expressing a truncated XRCC1 protein. Am J Cancer Research, in press.

Goh J, Pettan-Brewer C, Enns L, Fatemie S, and Ladiges W. Are exercise and mitochondrial antioxidants compatible in the treatment of invasive breast cancer? Bioenergetics, in press.

Goh J, Kirk EA, Lee SX, Ladiges WC. Exercise, physical activity and breast cancer: The role of tumor-associated macrophages. Annual Reviews in Exercise Immunology, in press.

Enns L and Ladiges W. Targeting PKA signaling to prevent metabolic syndrome and delay aging. In Medical Complications of Type 2 Diabetes. In-Tech Pub, Chap 17:303-320, 2011.

Goh J, Enns L, Fatemie S, Hopkins H, Morton J, Pettan-Brewer C, Ladiges W. Mitochondrial targeted catalase suppresses invasive breast cancer in mice. BMC Cancer, 2011 May 23;11:191. PMID: 21605372 PMCID: PMC3123323

McNeill DR, Lin PC, Miller MG, Pistell PJ, de Souza-Pinto NC, Fishbein KW, Spencer RG, Liu Y, Pettan-Brewer C, Ladiges WC, Wilson DM 3rd. XRCC1 haploinsufficiency in mice has little effect on aging, but adversely modifies exposure-dependent susceptibility. Nucleic Acids Res. 2011 Oct;39(18):7992-8004. PMID: 21737425 PMCID: PMC3185405

Wiley, JC, Pettan-Brewer KC, Treuting PM, Ladiges WC. Increased cognition and decreased plaque formation in APP/Psen1 transgenic mice treated with phenylbutyric acid. Aging Cell, 2011 Jan 27 Epub ahead of print. PMID: 21272191

Pettan-Brewer KC, Morton J, Mangalindan RS, Ladiges W. Dietary modulation of the DNA repair gene XRCC1 in APC Min mice fed a high fat diet. Pathobiology of Aging and Age-related Diseases, 2011, June Epub.

Ladiges W. Pathobiology of Aging. A new look at an old problem. Pathobiology of Aging and Age-related Diseases, 2011, June Epub.

Ladiges W. Anti-oxidant directed polarization of macrophages in age-related cancer. Proceedings San Antonio Nathan Shock Aging Center Conference on Aging, 2011 Nov.

2010

Ladiges W , Wanagat J, Preston B, Loeb L, Rabinovitch P. A mitochondrial view of aging, reactive oxygen species and metastatic cancer. Aging Cell, 2010 Aug;9(4):462-5. PMID: 20456297

Lee HY, Choi CS, Birkenfeld AL, Alves TC, Jornayvaz FR, Jurczak MJ, Zhang D, Woo DK, Shadel GS, Ladiges W, Rabinovitch PS, Santos JH, Petersen KF, Samuel VT, Shulman GI. Targeted expression of catalase to mitochondria prevents age-associated reductions in mitochondrial function and insulin resistance. Cell Metab. 2010 Dec 1;12(6):668-74. PMID: 21109199 PMCID: PMC3013349

Enns LC, Bible KL, Emond MJ, Ladiges WC. Mice lacking the Cβ subunit of PKA are resistant to angiotensin II-induced cardiac hypertrophy and dysfunction. BMC Res Notes. 2010 Nov 16;3:307. PMID: 21080942 PMCID: PMC2993729

2009

Enns L, Morton J, Treuting P, Emond M, Wold N, McKnight GS, Rabinovitch P, Ladiges W. Disruption of protein kinase A in mice enhances healthy aging. PLoS One, 2009, Jun 18;4(6):e5963. PMID: 19536287 PMCID: PMC2693670.

Ladiges W, Van Remmen H, Strong R, Ikeno Y, Treuting P, Rabinovitch P, Richardson A. Lifespan extension in genetically modified mice. Aging Cell, 2009 Aug, 8(4):346-52. PMID: 19485964

Enns LC, Morton JF, Magalindan RS, McKnight GS, Schwartz MW, Kaberlein MR, Kennedy BK, Rabinovitch PS, Ladiges WC. Attenuation of age-related metabolic dysfunction in mice with a targeted disruption of the C beta subunit of protein kinase A. J Gerontol A Biol Sci, 2009, 64 (12):1221-1231. PMID: 19776218 PMCID: PMC2773816

2008

Enns LC, Wiley JC, Ladiges WC. Clinical relevance of transgenic mouse models for aging research. Crit Rev Eukaryot Gene Expr. 2008;18(1):81-91. PMID: 18197787

Moore G, Knoblaugh S, Gollahon K, Rabinovitch P, Ladiges W. Hyperinsulinemia and insulin resistance in Wrn null mice fed a diabetogenic diet. Mech Ageing Dev. 2008 Apr;129(4):201-6. PMID: 18295300 PMCID: PMC2706000.

Treuting PM, Linford NJ, Knoblaugh SE, Emond MJ, Morton JF, Martin GM, Rabinovitch PS, Ladiges WC. Reduction of age-associated pathology in old mice by overexpression of catalase in mitochondria. J Gerontol A Biol Sci 2008;63(8):813-22. PMID: 18772469


Department of Comparative Medicine
Magnuson Health Sciences Building
Room T-142, Box # 357190
Seattle, Washington 98195-7190
phone: (206) 543-8047
fax: (206) 685-3006

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