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Thompson opac2013
1. Cancer
Prevention
Laboratory
Henry J. Thompson
Cancer Prevention Laboratory
Colorado State University
Fort Collins, CO
henry.thompson@colostate.edu
http//:www.cpl.colostate.edu
Energy metabolism within organisms and cells
and cancer processes
2. • Review evidence regarding energy restriction in
animal models
• Review evidence for relevance of energy pathways
in in vitro systems
• Discuss the cellular and molecular mechanisms
linking energy balance and flux and cancer
• Be sure to consider how animal model findings are or
not relevant to human cancer
• Highlight challenges and opportunities for future
research
What this presentation has been
requested to address
3. Above is the image at: thenewermetaphysicals.blogspot.com/2007/10/mo...
Simplicity as
compressed complexity,
complexity as unwoven
simplicity.
“Genius of the AND”
rather than the
“Tyranny of the OR”
Jim Collins (Built to
Last)
4. This presentation is less about
giving you answers and more
about stimulating thinking and
discussion in order to create the
opportunity for epiphanies
“Education is not about the filling of a pail; it is about
the lighting of a fire” Yates
• How does energy restriction relate to the “human condition?
• How does energy restriction affect carcinogenesis in animal
models?
• What is energy restriction and how does the organism and
cell “sense” its energy status (balance vs flux)?
• What links energy status to cancer: host systemic and cell
autonomous affecters?
PAUSE
5. • How does energy restriction relate to the
“human condition”?
• How does energy restriction affect carcinogenesis in animal
models?
• What is energy restriction and how does the organism and cell
“sense” its energy status (balance vs flux)?
• What links energy status to cancer: host systemic and cell
autonomous affecters?
CALORIC RESTRICTION
6.
7. 1000.0
1100.0
1200.0
1300.0
1400.0
1500.0
1600.0
1700.0
1800.0
1900.0
2000.0
17.5 18.3 19.1 19.9 20.7 21.6 22.4 23.2 24.1 24.9 25.7 26.6 27.4 28.2 29.1 29.9 30.7 31.6 32.4 33.2 34.1 34.9 35.7 36.6 37.4 38.2 39.1 39.9 40.7 41.5
105 110 115 120 125 130 135 140 145 150 155 160 165 170 175 180 185 190 195 200 205 210 215 220 225 230 235 240 245 250
kcal
BMI & Body Weight (lbs.)
Maintenance Energy Requirements: 5'5" Female
Age 25 Age 45 Age 65
Healthy
Weight
Under
Weight Overweight Obese
Morbidly
Obese
What does energy (calorie) restriction mean to you?
Energy stress—energy balance stress—energy availability stress
(quantitative and qualitative dimensions)
9. Limitation in Pre-Clinical Science
• Few (any?) reports of obesity reduction in
an autocthonous model for cancer
• Lewis Chodosh- inducible residual disease model
• Our lab “new” autochthonous model
• Transplant models
• Not many
• Hursting lab
• Cell based models: What’s the question being modeled?
• Sabatini- Nutrostat experiments: consequences of
[glucose]: AACR 2013 (high/low glucose-energy charge
and 3 cell fates)
• AVANTAGGIATI: Glucose availability regulates
accumulation of mutant p53 protein: Cell Cycle 2012
10. • What is energy restriction and how does it relate
to the “human condition?
• How does energy restriction affect
carcinogenesis in animal models?
• How does the organism and cell “sense” its
energy status (balance vs flux)?
• What links energy status to cancer: host systemic
and cell autonomous affecters?
13. Increasing
Age
BodyWeight
Increasing
Ad Libitum
10%ER
20%ER
40%ER
Pre-Clinical Model for Positive Energy Balance:
What is the effect of different planes of energy nutrition?
0
10
20
30
40
50
60
70
80
90
100
ACIncidence(%)
27 28 29 30 31 32 33 34 35 FI
Days Post Carcinogen
Control 10%ER 20%ER 40%ER
Zhu et al, Carcinogenesis 1997. 1999
0
1
2
3
4
5
6
Number/Rat
Control 90RF 80RF 60RF
Group
IDP DCIS AC
0
50
100
150
200
250
300
350
400
450
mm3
Control 90%RF 80%RF 60%RF
Group
14. 50.0
70.0
90.0
110.0
130.0
150.0
170.0
190.0
210.0
230.0
250.0
5 11 18 25 32 39 46
DR DS
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
4.5
24 27 32 35 39 42 46 49 53 59 63
AVE.#OFCANCERSPERANIMAL
DPC
DR DS
0.0%
10.0%
20.0%
30.0%
40.0%
50.0%
60.0%
70.0%
80.0%
90.0%
100.0%
24 27 32 35 39 42 46 49 53 59 63
%CANCERINCIDENCE
DPC
DR DS
(Cecchini et al Cancer Prev Res; 5(4);
583–92, 2012). In that publication from
the National Surgical Adjuvant Breast
and Bowel Project (NSABP), BMI >30
was significantly associated with
increased risk of invasive breast cancer
in high-risk premenopausal women
(HR= 1.70).
16. • What is energy restriction and how does it relate to the “human
condition?
• How does energy restriction affect carcinogenesis in animal
models?
• What is energy restriction and how does
the organism and cell “sense” its energy
status (balance vs flux)?
• What links energy status to cancer: host systemic and cell
autonomous affecters?
20. Energetics Paradigm
(How cells respond to continuous energy stress)
AMPK
Sirtuins
AMPK
AMP
Glycogen
NAD+/
NADH
Free
Fatty acids
ATP
cGuanylyl-
Cyclase
Energy
Status
PPARsE messengers
E sensors
Insulin/IGF-1
Glucocorticoids
Leptin/Adiponectin
21. Energy Availability (Net)
Stress
What time scale is important relative to cancer?
• Second, minute, hour, day week, month?
• As a systems biologist, how should you view energy availability?
Energy expenditure
• Physical activity
• SDA
• Futile cycling
• Thermogeneis
Energy intake
• Food
• Fluid
Energy Reserves
• Glycogen
• Fat
25. Time to reformulate?
What insights will advance the field?
• How do cells solve the problem of getting what they
need to proliferate in the energy restricted state?
• What is that cell’s fate when the problem cannot be
solved in a particular snapshot in time?
– Energy balance
– Availability of energy substrates/reducing equivalents
– The metabolic flexibility of the “target cell” defines
whether it is energy restriction Sensitive or Insensitive
• Sensitive: lacks ability to make adaptive changes in core
metabolism to accommodate its current replicative potential
• Insensitive: flexibility is not compromised: cell uses alterative
pathways to satisfy its requirements for proliferation
– Intervention development: ability to impose constraints
on metabolic flexibility in order to prevent or control the
fate of transformed cells)
26. • What is energy restriction and how does it relate to the
“human condition?
• How does energy restriction affect carcinogenesis in
animal models?
• How does the organism and cell “sense” its energy
status (balance vs flux)?
• What links energy status to
cancer: host systemic and cell
autonomous affecters?
27. Cellular Mechanisms (Failed size homeostasis)
• Cell Proliferation
– Jiang et al Cancer Res.
2003
• Apoptosis
– Thompson et al.
Cancer Res. 2004
• Vascularization
– Thompson et al.
Cancer Res. 2004
0
5
10
15
20
25
30
35
ProliferationIndex(%)
UI IDP DCIS AC
Lesion
Control10%ER20%ER40%ER
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
ApoptosisIndex(%)
UI IDP DCIS AC
Lesion
Lesion
28. 4EBP1Thr37/46 p70S6K
Raptor
Growth factors, nutrient and energy sensing network
PRAS40
IGF-1
PI3K-I IRS-1AKT
S473
AMPK
T172
Adiponectin,
Leptin
mTORC1
Ser2448LKB1
S428
Ser792 Thr246
Thr389
G1
S
G2
M
Cyclin D1 Apoptosis
Bax Bcl-2
p27
GADD153
FoxO3A
Thr32
ATP↑/AMP ↓
FoxO1
Thr24
IGF1R
TSC2
TSC1
Integrates IC, EC
Nutrient/Energy
Cues
Mediates Stress
Response
What’s missing: The HIPPO Pathway
• Controls cell/organ size and polarity
• Deregulated during carcinogenesis
• No studies of energy restriction
30. Summary: What can help us advance the field?
• Relevance of in vitro experiments or animal studies or human subject
protocols (inclusion/exclusion criteria) : depends on the question being
asked. No model is ideal, but is it inform our understanding of the
question?
• There are in reality a lot of gaps in the preclinical literature on energetics
and cancer: addressing which gaps will advance the field?
• Broaden the focus: energy balance suggests constancy but we learn
more if we realize that constancy is a measurement “artifact”. Energetic
systems are dynamic, constantly in flux, differentiated by adaptability
(flexibility) and heterogeneity of response .
• Perhaps what is most important for human health is hormetic energy
regulation: the level of energy stress that places the organism at an
adaptive advantage.
31. Our Team
Zongjian Zhu
Weiqin Jiang
Audrey Barnett
Nick Fernandez*
Joy Hester
Weiqin Jiang
John McGinley
Elizabeth Neil
Andre Powell*
Jennifer Price
Denise Rush
Jennifer Sells
Matthew Thompson
Jay Waterman*
Pamela Wolfe
Zongjian Zhu
Jarrod Zacher*
Jack Sneddin
John McGinley
Liz Neil
