Program - Society of Toxicology

Society of Toxicology 2011
Program Description (Continued)
Abstract #
Wednesday Morning, March 9
9:00 AM to 11:45 AM
Room 150
Symposium Session: Mechanisms of Inflammation in Skin
Carcinogenesis
Chairperson(s): Lauren Mordasky Markell, Penn State University,
University Park, PA, and Michael Borland, Penn State University,
University Park, PA.
Sponsor:
Dermal Toxicology Specialty Section
Endorsed by:
Carcinogenesis Specialty Section
Molecular Biology Specialty Section
The World Health Organization finds that 30% of all human cancers are
cancer of the skin, and one in five Americans will develop skin cancer in
their lifetime. Furthermore, increased cancer mortality has been linked to
a history of non-melanoma skin cancer. The majority of skin cancers arise
from chemical contact or exposure to ultraviolet radiation, but a complete
understanding of the mechanisms involved in cancer development remain
elusive. Chronic irritation and inflammation have also been observed at sites
of tumorigenesis; this, coupled with the fact that tumors routinely present
with deregulated proliferative signaling pathways, suggests inflammatory
signaling may significantly contribute to skin carcinogenesis. Understanding
how inflammation alters tumor development and progression could identify
novel preventative and therapeutic strategies to treat or reduce skin cancer.
Our divergent panel of experts will discuss the mechanisms by which the
inflammatory micro-environment alters skin tumor formation and progression,
the importance of epidermal homeostasis, the differential roles of
key inflammatory cells that contribute to the tumor phenotype, how mouse
models can be applied to human relevance, and how this research impacts
risk assessment and regulation. Because inflammation has been implicated
in other cancers, investigators can apply, exploit, and build upon the
discussed strategies and mechanisms for other cancer models. For those
investigators interested in the integrative and multi-disciplinary nature of
cancer biology, this discussion and collaboration will lay the groundwork
to help understand the novel mechanisms of skin carcinogenesis. In conclusion,
exploration of this topic will enable U.S. to identify potential targets
that can be related to the cause of cancer ultimately striving to decrease the
incidence and mortality of this very common worldwide cancer.
#1780 9:00 MECHANISMS OF INFLAMMATION IN
SKIN CARCINOGENESIS. ​L. Mordasky Markell
and M. G. Borland. Center for Molecular Toxicology
and Carcinogenesis, Penn State University,
University Park, PA.
9:00 INTRODUCTION. ​Lauren Mordasky Markell
#1781 9:05 A SERIES OF AUTOCRINE AND
PARACRINE FEEDBACK LOOPS IN
INFLAMMATION PATHWAYS ARE
REQUIRED FOR TUMOR FORMATION
IN SKIN CARCINOGENESIS. ​S. H. Yuspa.
National Cancer Institute, National Institutes of
Health, Bethesda, MD. Sponsor: L. Markell.
#1782 9:35 IKKα FUNCTION IN SKIN INFLAMMATION
AND TURMORIGENESIS. ​Y. Hu. NCI,
Frederick, MD. Sponsor: L. Markell.
#1783 10:05 MODELING THE INFLAMMATORY TO
IMMUNOSUPPRESSIVE SWITCH DURING
PREMALIGNANT PROGRESSION. ​A. Glick
and A. Gunderson. Veterinary and Biomedical
Sciences, Penn State University, University Park, PA.
Sponsor: L. Mordasky Markell.
Abstract #
#1784 10:35 DOES SEX MATTER IN THE
DEVELOPMENT OF NON-MELANOMA
SKIN CANCER? ​T. Oberyszyn 1 , N. J. Sullivan 1 ,
K. L. Tober 1 , M. A. Bill 2 , J. A. Riggenbach 1 , J. S.
Schick 1 and G. B. Lesinski 2 . 1 Pathology, The Ohio
State University, Columbus, OH and 2 Internal
Medicine, The Ohio State University, Columbus,
OH. Sponsor: L. Mordasky Markell.
#1785 11:05 BIOMARKERS AS INDICATORS
OF PHOTOTOXICITY: DO THEY
HAVE A ROLE AS PREDICTORS OF
PHOTOCARCINOGENESIS? ​D. B. Learn 1 , P.
D. Forbes 2 , C. P. Sambuco 1 , A. M. Hoberman 1 and S.
R. Eldridge 3 . 1 Charles River Laboratories Preclinical
Services, Horsham, PA, 2 Toxarus, Inc., Malvern, PA
and 3 Charles River-Pathology Associates, Frederick,
MD.
11:35 PANEL DISCUSSION/Q&A.
Wednesday Morning, March 9
9:00 AM to 11:45 AM
Room 143
Symposium Session: New Insights into the Nrf2-Keap1
Pathway and Its Impact on Human Disease
Chairperson(s): Thomas Kensler, Johns Hopkins Bloomberg School of
Public Health, Baltimore, MD, and Donna Zhang, University of Arizona,
Tucson, AZ.
Sponsor:
Mechanisms Specialty Section
Endorsed by:
Carcinogenesis Specialty Section
Metals Specialty Section
Molecular Biology Specialty Section
Damage mediated by reactive electrophilic intermediates can have a
profound effect on many cellular functions, and has been implicated in
cancer, inflammation, neurodegenerative diseases, cardiovascular diseases,
and aging. Eukaryotic cells have evolved anti-oxidant defense mechanisms
to neutralize reactive oxygen species (ROS) and maintain cellular redox
homeostasis. Eukaryotic cells also express cofactors and enzymes for trapping
reactive electrophiles. A key adaptive response system for protection
against ROS and electrophilic intermediates is mediated by the transcription
factor Nrf2, through the antioxidant responsive element (ARE) sequences
in the promoter regions of dozens of cytoprotective genes. Basal levels of
Nrf2 remain relatively low, due to its negative regulation by Keap1, which
targets Nrf2 for ubiquitination and degradation. However, upon activation,
cysteine residues of Keap1 are modified, leading to conformational
changes that impair ubiquitination of Nrf2, thus allowing Nrf2 to translocate
into the nucleus to activate the expression of its downstream genes. The
activation of the Nrf2 pathway is not only important in protecting cells
against the deleterious effects caused by carcinogens and environmental
toxicants, but, also, Nrf2 protects against drug-induced organ toxicity and
damage. Unfortunately, the dark-side of Nrf2 has been revealed indicating
that constitutive activation of Nrf2, due to mutations in either Nrf2 or
Keap1, creates an environment conducive to cancer cell growth and thus,
contributes to chemoresistance. Our knowledge on the Nrf2 pathway has
progressed rapidly, and new important insights into its complex regulation
have emerged. Thus it is important to highlight the novel mechanisms that
activate the Nrf2 pathway, cross-talk between Nrf2 with other essential cell
signaling pathways to maintain cellular homeostasis, the protective role of
Nrf2 in human diseases, and paradoxically its role as a hostage in cancer.
In conclusion, we will explore the essential role of Nrf2 in disease and in a
variety of biological processes that regulate the response to environmental
exposures.
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