1. Obesity, Metabolism and Cancer:
Mechanistic Insights from
Preclinical 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

2. Today’s Presentation
• Lessons from mice (and humans): 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

3. Will Warfarin Still be in U
a Year from Now?
LOOMING QUESTION:
How to Decrease Cancer Risk in the
~600 Million Adults Worldwide Currently Obese?
Need a mechanistic approach to identify targets and
strategies to break obesity-cancer links

4. 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)
?

5. Modeling Energy Balance and Human Cancer in
Mice by Altering Key Genes and Pathways
Insert fig. 19.4
Hursting, et al., Mutation Res, 2005

6. 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 Vol
(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, 2007Dr. Nomeli Nunez

7. Transplanted Wnt-1 Tumor Growth in AZIP/F-1Transplanted Wnt-1 Tumor Growth in AZIP/F-1
(Fatless) Mice Versus Wild-Type Mice(Fatless) Mice Versus Wild-Type Mice
AZIP/F1
Wild-type
Hursting et al., Cancer Res, 2007

8. Genetic Reduction of Systemic IGF-1Genetic 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/ml

9. Transplanted Mammary Tumor GrowthTransplanted Mammary Tumor Growth
in Wild-Type and Liver IGF-1 Deficient (LID) Micein Wild-Type and Liver IGF-1 Deficient (LID) Mice
Wild-Type
Dr. Nikki Ford Ford, et al. Endocrine-Related Cancer, in
*
Serum IGF-1 Levels

10. Energy Balance Effects on Transplanted Mammary TumorEnergy Balance Effects on Transplanted Mammary Tumor
Growth Liver IGF-1 Deficient (LID) MiceGrowth Liver IGF-1 Deficient (LID) Mice
Wild-Type
Dr. Nikki Ford
Diet Effects in LID Mice
Obese Control CR
Days after tumor cell injection

11. Insert fig. 19.4
Grossman and Cleary, Biochimie, 2012
The Balance Between Leptin and Adiponectin
in the Control of Carcinogenesis

12. IGF-1 Infusion or mTOR Activation Impacts Transplanted MMTV-IGF-1 Infusion or mTOR Activation Impacts Transplanted MMTV-
Wnt-1 Mammary Tumor Growth in Calorie Restricted MiceWnt-1 Mammary Tumor Growth in Calorie Restricted Mice
Nogueira et al. Endocrine-Related Cancer, 2012
Leticia Nogueira!

13. Dietary Energy
Balance Modulation of
Akt/mTOR Signaling
(normal and tumor tissue)
Akt
mTOR
p70S6K4E-BP1
S6 ribosomal
GSK-3
Cyclin D
TranslationProliferation
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
LID
A-Zip

14. RAD001 (Afinitor®
) Inhibits mTOR and Wnt-1 Mammary Tumor
Growth in Lean, Control and Obese Mice
DeAngel, et al. Mol Carcinogenesis, 2013
Rebecca DeAngel

15. 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
✔
?
?

16. Control Obese
0
2000
4000
6000
8000 Vehicle
GemHCL
GemC18 NP
a
b
c
a
a
bTumorsize(mm3)
Before tumor cell injection
0 5 10 15
0
20
40
60
Control
Obese
Weeks on study
Bodyweight(g)
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ResearchPaper
Stearoyl gemcitabinenanoparticlesovercomeobesity-inducedcancercell
resistancetogemcitabineinamousepostmenopausal breastcancermodel
Volume 14, Issue 4 April 2013
Keywords: chemoresistance, nanoparticles, obesity, tumor
Authors: Rebecca E. De Angel, Jorge M. Blando, Matthew G. Hogan, Michael A. Sandoval, Dharmika S.P.
Lansakara-P., Sarah M. Dunlap, Stephen D. Hursting and Zhengrong Cui
View affiliations
Abstract:
Obesity is associated with increased breast tumor aggressiveness and decreased response
to multiple modalities of therapy in postmenopausal women. Delivering cancer
chemotherapeutic drugs using nanoparticles has evolved as a promising approach to
improve the efficacy of anticancer agents. However, the application of nanoparticles in
cancer chemotherapy in the context of obesity has not been studied before. The nucleoside
analog gemcitabine is widely used in solid tumor therapy. Previously, we developed a novel
stearoyl gemcitabine solid-lipid nanoparticle formulation (GemC18-NPs) and showed that
the GemC18-NPs are significantly more effective than gemcitabine in controlling tumor
growth in mouse models. In the present study, using ovariectomized diet-induced obese female C57BL/6 mice with orthotopically
transplanted MMTV-Wnt-1 mammary tumors as a model of postmenopausal obesity and breast cancer, we discovered that obesity
induces tumor cell resistance to gemcitabine. Furthermore, our GemC18-NPs can overcome the obesity-related resistance to
gemcitabine chemotherapy. These findings have important clinical implications for cancer chemotherapies involving gemcitabine or
other nucleoside analogs in the context of obesity.
Preview:
Cancer Biology and Therapy
Similar findings with pancreatic cancer
equilibrative nucleotide transporter 1,
ribonucleotide reductase M1

17. Mechanisms and Mediators of Adipose Tissue-Stimulated Angiogenesis
Y. Cao. Nature Reviews Drug Discovery, 2010
PAI-1 PAI-1

18. 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

19. (75% CD44+
/24-
/Aldefluor+
) (2% CD44+
/24-
/Aldefluor+
)
2012
Spe
sign
Cells
disa
Ce
(
and
ce
EMT migration, invasion
!

20. 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
✔
✔
✔
✔
✔
✔
?

21. Inflammation and Cancer
• Malignancies often arise from areas of
chronic infection and inflammation
• Chronic inflammatory conditions linked to
tumorigenesis include:
-Gastritis (H. Pylori) – Gastric Cancer
-Cystitis – Bladder Cancer
-Bronchitis – Lung Cancer
-Esophagitis – Esophageal Cancer
-Dermatitis – Skin Cancer
-Ulcerative colitis – Colon Cancer
-Inflammatory bowel disease – Colon Cancer
-Hepatitis (including NASH) – Liver Cancer
-Pancreatitis – Pancreatic Cancer (up to 55-fold increased risk)

22. Mechanisms Underlying the Obesity-Cancer Link: 2013?
Microenvironment (EMT,
CSCs)
Obesity and Cancer: Emerging Mechanistic Targets
S. Hursting and M. Hursting.
Arterioscler Thromb Vasc Biol, 2012

23. The Obesity-Cancer Link
IncreasedIncreased
InsR/IGF-1RInsR/IGF-1R
SignalingSignaling
IncreasedIncreased
Hormone/Hormone/
Growth FactorGrowth Factor
SignalingSignaling
Energy Balance, Metabolism and Cancer:
Transdisciplinary Research Approaches

24. Example 1. Diet and Exercise Pilot Trial in
Obese Postmenopausal Women
Proliferation
(Ki-67)
Mammographic
Breast Density
Serum
insulin, cytokines,
adipokines,
IGF1, IGFBP-3,
Response Biomarkers
mRNA
estrogen
response
genes,
cytokines
28 High Risk
Women:
BMI >30 kg/m2
No HRT
6-month
Intervention
RPFNA Repeat RPFNA

25. Diet/Exercise Intervention
• NHLBI low-calorie (1250 kcal/day) Step I
diet, achieved with 2 shelf-stable
prepackaged meals, 3 high protein
shakes, 5 fruits and vegetables/day
• Goal of 45 minutes exercise 5 days/week
(usually walking)
• In-person, group behavior modification
class weekly (including weigh-in and
submission of exercise and food diaries)

26. Proc Nutr Soc, 2012
2012

27. Example 2. Integrated Phase II Trial and
Animal Studies of Lovaza® (omega-3-acid
ethyl esters)
C. Fabian, MD Placebo
1 yr
Lovaza (4g/d)
High-Risk Women
Serum/Benign Breast Tissue Biomarkers
1. Response: Ki-67, cytomorphology
2. Mechanism: qRTPCR: ER-genes; miR’s;
Proteomics: mTOR, MAPK signaling;
Cytokines
Change in
Biomarkers
Lovaza (208 mg/kg diet)
Placebo
Cancer
Endpoint
3 mos
ER-
Mouse Models
S. Hursting, PhD, MPH
Komen Promise Grant; BCRF

29. Acknowledgements
University of Texas at Austin
John DiGiovanni, Michele Forman, Nomeli Nunez, Rong Cui
University of Texas-M.D. Anderson Cancer Center
Sue Fischer, Donna Kusewitt, JJ Shen, Powel Brown
Mt. Sinai Medical Center
Derek LeRoith, Shoshana Yakar
National Cancer Institute
Curt Harris, Chuck Vinson, Lyuba Varticovski
Kansas University Medical Center
Carol Fabian, Brian Petroff, Bruce Kimler
UNC-Chapel Hill
Chuck Perou
Weill-Cornell Cancer Center
Andrew Dannenberg
Funding: National Cancer Institute, National Institute of Environmental Health Sciences, American
Institute for Cancer Research, Breast Cancer Research Foundation, Susan G. Komen Foundation