Obesity, Energy Balance and Cancer: Mechanistic Insights from Transdisciplinary Studies Stephen D. Hursting, PhD, MPH Professor and Chair Department of Nutritional Sciences University of Texas at Austin and Professor, Department of Molecular Carcinogenesis University of Texas MD Anderson Cancer Center
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Obesity, Energy Balance and Cancer: Mechanistic … · Obesity, Energy Balance and Cancer: Mechanistic Insights from Transdisciplinary Studies Stephen D. Hursting, PhD, MPH Professor
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Obesity, Energy Balance and Cancer:
Mechanistic Insights from
Transdisciplinary Studies
Stephen D. Hursting, PhD, MPH
Professor and Chair
Department of Nutritional Sciences
University of Texas at Austin
and
Professor, Department of Molecular Carcinogenesis
University of Texas MD Anderson Cancer Center
Today’s Presentation
• Lessons from mice: molecular targets and
strategies for breaking obesity- cancer links
- Growth factors and their signals - Adipokines and their signals - Inflammatory signals
• Translation of mechanistic insights through
transdisciplinary, multilevel research
Will Warfarin Still be in Use
a Year from Now?
LOOMING QUESTION:
How to Decrease Cancer Risk in the
~700 Million Adults Worldwide Currently Obese?
Need a mechanistic approach to identify targets and
strategies to break obesity-cancer links
Cancer: A Complex Foe Obesity impacts the essential aberrations of cancer
∞
Inflammation
Genomic
instability
Tissue
invasion
and
metastasis
Limitless replicative
potential
Sustained
angiogenesis
Evading
growth
suppression,
apoptosis
and immune
surveillance
Dysregulated
growth signals and
cellular energetics
Adapted from: Hanahan & Weinberg,
Cell (2000) and Cell (2011)
?
Modeling Energy Balance and Human Cancer in Mice by Altering Key Genes and Pathways
Insert fig. 19.4
Hursting, et al., Mutation Res, 2005
CR (30%)
Overweight
DIO
Growth Factor Levels and MMTV-Wnt-1 Mammary
Tumor Growth in Lean, Overweight and Obese Mice
IGF-1 Insulin Leptin: Tumor Volume
(ng/ml) (pg/ml) Adiponectin (mm3)
390 380 0.2 120
526 398 0.6 510
718 596 1.8 1485
(29% body fat)
(35% body fat)
(47% body fat)
n=12 mice/group
Nunez, et al., Nutrition and Cancer, 2007 Dr. Nomeli Nunez
Transplanted Wnt-1 Tumor Growth in AZIP/F-1
(Fatless) Mice Versus Wild-Type Mice
AZIP/F1
Wild-type
Hursting et al., Cancer Res, 2007
Genetic Reduction of Systemic IGF-1 ~75% of IGF-1 in serum is produced by liver
Ecuadorians with Laron
Syndrome have very low
IGF-1 and inflammatory
cytokines, increased
longevity, and virtually no
cancer or diabetes.
NY Times 2/16/11.
Serum IGF-1
WT LID
200
100
0
IGF
-1, ng/m
l
Energy Balance Effects on Transplanted Mammary Tumor
Growth in Liver IGF-1 Deficient (LID) Mice
0
20
40
60
80
100
120
140
160
180
1 8 15 22 29 36 43 50 57 64 71
Tu
mo
r V
ol
(mm
3)
LID
Wild-Type
Dr. Nikki Ford
!
Diet Effects on Final
Tumor Volume in LID Mice
Obese Control
CR
Days after tumor cell injection
Ford, et al. Endocrine-Related Cancer, 2013
IGF-1 Infusion or mTOR Activation Impacts Transplanted MMTV-
Wnt-1 Mammary Tumor Growth in Calorie Restricted Mice
Nogueira et al. Endocrine-Related Cancer, 2012
Leticia Nogueira !
Dietary Energy
Balance Modulation of
Akt/mTOR Signaling (normal and tumor tissue)
Akt
mTOR
p70S6K 4E-BP1
S6 ribosomal
GSK-3
Cyclin D
Translation Proliferation
PI3K
RTK CR
DIO
Skin
Liver
Prostate
Colon
Pancreas
Mammary
Hursting, et al., Cancer Res, 2007
Moore, et al., Cancer Prev Res, 2008;
Olivo-Marston, et al., Mol Carcinogenesis 2009
Lashinger, et al, Cancer Prev Res, 2011
Blando, et al., Cancer Prev Res, 2011
Nogueira, et al, Endocr Rel Cancer, 2012
deAngel, et al., Mol Carcinogenesis, 2013
Lashinger, et al., Cancer Prev Res, 2013
LID
A-Zip
Insulin
IGF-1
RAD001 (Afinitor®) Inhibits mTOR and Wnt-1 Mammary Tumor
Growth in Lean, Control and Obese Mice
DeAngel, et al. Mol Carcinogenesis, 2013
Rebecca DeAngel
Cancer: A Complex Foe Obesity, CR impact the essential aberrations of cancer
∞
Inflammation
Genomic
instability
Tissue
invasion
and
metastasis
Limitless replicative
potential
Sustained
angiogenesis
Evading
growth
suppression,
apoptosis
and immune
surveillance
Dysregulated
growth signals and
cellular energetics
✔
?
?
✔
✔
✔
Does Obesity Promote Invasion, Metastases, EMT? Enrich Breast Cancer Stem Cells?
Dunlap, et al. Cancer Prevention Research 2012; 5:932-42