obesity and cancer - upmc › sites › default › files › session 3-a 1 cruz... · projected...
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Obesity and Cancer
Zobeida Cruz-Monserrate Ph.D.
PancreasFest
July 2019
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What are some environmental factors that increase the risk of developing cancer?
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https://www.wcrf.org/sites/default/files/Pancreatic-cancer-report.pdf
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https://www.wcrf.org/sites/default/files/Pancreatic-cancer-report.pdf
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https://www.wcrf.org/sites/default/files/Pancreatic-cancer-report.pdf
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Absolute risk in for a rare disease
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Absolute risk in for a rare disease
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What is the relative risk of obesity that influence pancreatic cancer?
N Engl J Med 2014; 371:1039-1049
Obesity
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What is the relative risk of obesity that influence pancreatic cancer?
N Engl J Med 2014; 371:1039-1049
Obesity
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Becker, A.E, et. al., World J Gastroenterology, 2014
Obesity
Diabetes
Alcohol
Smoking
Obesity is a Modifiable PDAC Risk Factor
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Becker, A.E, et. al., World J Gastroenterology, 2014
Obesity
Diabetes
Alcohol
Smoking
Obesity is a Modifiable PDAC Risk Factor
Can we prevent?
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Projected Increase in Pancreatic Cancer Deaths by 2030 Thought to Correlate with Obesity Trends
Studies Forecast a 30-50%
Increase in Obesity
Prevalence
Cancer Incidence in the United States
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Projected Increase in Pancreatic Cancer Deaths by 2030 Thought to Correlate with Obesity Trends
Studies Forecast a 30-50%
Increase in Obesity
Prevalence
Cancer Incidence in the United States
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Projected Increase in Pancreatic Cancer Deaths by 2030 Thought to Correlate with Obesity Trends
Studies Forecast a 30-50%
Increase in Obesity
Prevalence
Obesity Trend in the United StatesCancer Incidence in the United States
Actual and predicted prevalence of
obesity (BMI ≥ 30)
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12/11/2013
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Obesity is a Worldwide Epidemic in Adults and Children
Wang, Y.C. et. al., The Lancet, 2011
Pro
port
ion
overw
eig
ht
(%)
Year
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Obesity Trends Increasing in the United States
http://stateofobesity.org/adult-obesity/
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Obesity Trends Increasing in the United States
http://stateofobesity.org/adult-obesity/
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Obesity Trends Increasing in the United States
http://stateofobesity.org/adult-obesity/
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15 Types of Cancer have being directly linked to being overweight or obese.
https://seer.cancer.gov/csr/1975_2015/
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Obesity is a Risk Factor for Many Cancers
Eugenia E. Calle* and Rudolf Kaaks 2004:4:579-591
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Obesity is Associated with Increased Healthcare Utilization in Hospitalized Patients with Pancreatic Cancer
60,140
Hospitalizations
54,985 (91.43%)
Normal Weight
3,740 (6.22%) Obese
1,415 (2.35%) Morbidly obese
Patient group:
Inclusion criteria:
A secondary diagnosis of pancreatic cancer
(ICD-9 codes: 157.0, 157.1, 157.2, 157.3, 157.4, 157.8, 157.9)
Exclusion criteria:
Age less than 18 years
Admission in the month of December
Exposure of interest:
- Obesity: 278.00, 278.01,V853, V85.30-V85.39,V85.4, V854.1-V854.5.
- Subgroup analysis: Morbid obesity: V85.4, V854.1-V854.5, 278.01
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Normal Weight vs Obese Pancreatic Cancer-Related Hospitalizations
26
Normal weight Obese P-valueAdjusted mean difference
*
Mortality rate 7.7% (7.2-8.3) 7.5% (5.8-9.6) 0.78781.00 (0.75-1.34) P=0.98
Adjusted odds
Mean length of
stay
5.6 days (5.5-
5.74)6.8 days (6.4-7.3) < 0.01
1.19 days (0.72-1.66)
P<0.01
Mean
hospitalization
charges
$48,337 ($46,300-
$50,373)
$61,056
($55,411-
$66,700)
< 0.01$13,432 ($7,848-$19,016)
P<0.01
Mean
hospitalization
costs
$12,489 ($12,091-
$12,889)
$15,652
($14,386-
$16,919)
< 0.01$3,311 ($2,022 - $4,599)
P<0.01
Palliative care
consult for
metastatic
pancreatic
cancer
19.3% (18.2%-
20.4%)
20.8% (17.2%-
24.9%)0.44 0.89 (0.72-1.11) P=0.32
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Obese vs Morbidly Obese Pancreatic Cancer-Related Hospitalizations
27
Obese Morbidly Obese P-valueAdjusted mean difference
*
Mortality rate 7.7% (7.2-8.2) 8.8 % (6.0-12.8) 0.48671.16 (0.75-1.79) P=0.496
Adjusted odds
Mean length of
stay5.6 days (5.8-5.7) 7.4 days (6.6-8.2) < 0.01 1.79 (1.02-2.57) P<0.01
Mean
hospitalization
charges
$48,672 ($46,660-
$50,684)
$67,726 ($57,824
- $77,627)< 0.01
$20,528 ($10,735-$30,321)
P<0.01
Mean
hospitalization
costs
$12,599 ($12,200-
$12,997)
$16,215
($14,470-
$17,961)
< 0.01$3,986 ($2,197 - $5,774)
P<0.01
Palliative care
consult for
metastatic
pancreatic cancer
19.3% (18.2%-
20.4%)
25.3% (19.1%-
32.8%)P =0.0575 1.11 (0.82-1.52) P=0.49
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How to measure obesity?
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How to measure obesity?
Skinfold Thickness
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Skinfold Thickness Waist Circumference
How to measure obesity?
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How to measure obesity?
Skinfold Thickness Waist CircumferenceWaist : Hip Ratio
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How to measure obesity?
Skinfold Thickness Waist CircumferenceWaist : Hip Ratio
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Duct
Islet
Acini
IsletPDAC
What are the Molecular Mechanisms that Increase
the Risk of PDAC Development in Obese
Individuals?
Stroma is about
90% of tumor volume
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What are the Molecular Mechanisms that Increase the Risk of PDAC Development in Obese Individuals?
Obesity-Associated
Cancer In Mice
Obesity-Associated
Cancer In Humans
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What are the Molecular Mechanisms that Increase the Risk of PDAC Development in Obese Individuals?
Obesity-Associated
Cancer In Mice
Obesity-Associated
Cancer In Humans
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Adipose tissue depots in mice vs humans
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Adipose tissue depots in mice vs humans
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Obesity-Induced Changes in Adipose Tissue Microenvironment and Their Impact
on Cardiovascular Disease, Volume: 118, Issue: 11, Pages: 1786-1807, DOI:
(10.1161/CIRCRESAHA.115.306885)
Adipose tissue depots occur throughout the body
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Three types of adipocyte: brown, white and beige (brite)
39
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Three types of adipocyte: brown, white and beige (brite)
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“Crown-like” structures of immune cells defined adipose tissue inflammation
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Insulin Sensitivity and
Glucose homeostasis
Lipid Metabolism
Transport soluble
vitamins
Energy Storage
Vascular Homeostasis
Growth and
Development
Angiogenesis
Inflammation and
Immunity
White adipose tissue is essential for survival
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Adipose Derived
Stromal Cells
Mature Adipocytes
(fat cells)
Osteoblasts
(bone cells)Chondrocytes
(cartilage)
Monocytes
(white blood cells
and macrophages)Endothelial cells
(blood vessel lining)
Hepatocytes
(liver cells)Neuronal Cells
(brain cells)
Adipose Stromal Cells are Multipotent
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Fibroblast
Macrophage
Endothelial
Pre-adipocyte/ adipose stromal cell (ASC)
Mature adipocyte
Obesity
Obese
Stromal Vascular Fraction
(SVF)
Lean
What Factors from the Adipose Tissue Contribute
to the Development and Progression of PDAC?
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Fibroblast
Macrophage
Endothelial
Pre-adipocyte/ adipose stromal cell (ASC)
Mature adipocyte
Obesity
Stromal Vascular Fraction
(SVF)
Lipocalin-2 (LCN2)
Lean Obese
What Factors from the Adipose Tissue Contribute
to the Development and Progression of PDAC?
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Factors Related to Obesity Affecting PDAC
Obesity
Pancreatic Fatty
Infiltration
Inflammation
Leptin
IGF-1
Arginase
Resistance to Chemotherapy
COX2
Lipocalin-2 (LCN2/NGAL)
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Factors Related to Obesity Affecting PDAC
Obesity
Pancreatic Fatty
Infiltration
Inflammation
Leptin
IGF-1
Arginase
Resistance to Chemotherapy
COX2
Lipocalin-2 (LCN2/NGAL)
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Factors Related to Obesity Affecting PDAC
Obesity
Pancreatic Fatty
Infiltration
Inflammation
Leptin
IGF-1
Arginase
Resistance to Chemotherapy
COX2
Lipocalin-2 (LCN2/NGAL)
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Factors Related to Obesity Affecting PDAC
Obesity
Pancreatic Fatty
Infiltration
Inflammation
Leptin
IGF-1
Arginase
Resistance to Chemotherapy
COX2
Lipocalin-2 (LCN2/NGAL)
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Factors Related to Obesity Affecting PDAC
Obesity
Pancreatic Fatty
Infiltration
Inflammation
Leptin
IGF-1
Arginase
Resistance to Chemotherapy
COX2
Lipocalin-2 (LCN2/NGAL)
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Factors Related to Obesity Affecting PDAC
Obesity
Pancreatic Fatty
Infiltration
Inflammation
Leptin
IGF-1
Arginase
Resistance to Chemotherapy
COX2
Lipocalin-2 (LCN2/NGAL)
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Factors Related to Obesity Affecting PDAC
Obesity
Pancreatic Fatty
Infiltration
Inflammation
Leptin
IGF-1
Arginase
Resistance to Chemotherapy
COX2
Lipocalin-2 (LCN2/NGAL)
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Factors Related to Obesity Affecting PDAC
Obesity
Pancreatic Fatty
Infiltration
Inflammation
Leptin
IGF-1
Arginase
Resistance to Chemotherapy
COX2
Lipocalin-2 (LCN2/NGAL)
![Page 54: Obesity and Cancer - UPMC › sites › default › files › Session 3-A 1 Cruz... · Projected Increase in Pancreatic Cancer Deaths by 2030 Thought to Correlate with Obesity Trends](https://reader033.vdocuments.us/reader033/viewer/2022060414/5f12bcc392042329984ebc55/html5/thumbnails/54.jpg)
Factors Related to Obesity Affecting PDAC
Obesity
Pancreatic Fatty
Infiltration
Inflammation
Leptin
IGF-1
Arginase
Resistance to Chemotherapy
COX2
Lipocalin-2 (LCN2/NGAL)
![Page 55: Obesity and Cancer - UPMC › sites › default › files › Session 3-A 1 Cruz... · Projected Increase in Pancreatic Cancer Deaths by 2030 Thought to Correlate with Obesity Trends](https://reader033.vdocuments.us/reader033/viewer/2022060414/5f12bcc392042329984ebc55/html5/thumbnails/55.jpg)
Obesity-Induced PDAC in Genetically Engineered Mouse Models (GEMM)
10% or a 60% fat diet Test Diet DIO 58Y2 and DIO 58Y1; Lab Supply
lard
12% or a 40% fat diet AIN-76A, HFCD Corn oil
Chow vs HFD Research Diets lard
10% or a 60% fat diet (D12450J and D12492; Research Diets) lard
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Obesity-Induced PDAC in Genetically Engineered Mouse Models (GEMM)
Acinar
mK-Ras
K-RasG12D
Endogenous
mutant K-Ras expression in acinar cells
LSL/BAC % kcal of each nutrient
Caloric
Breakdown Control Diet High Fat Diet
Protein 18.3 18.1
Fat 10.2 61.6
Carbohydrate 71.5 20.3
Isocaloric
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Obesity-Induced PDAC in Genetically Engineered Mouse Models (GEMM)
Acinar
mK-Ras
K-RasG12D
Endogenous
mutant K-Ras expression in acinar cells
LSL/BAC % kcal of each nutrient
Caloric
Breakdown Control Diet High Fat Diet
Protein 18.3 18.1
Fat 10.2 61.6
Carbohydrate 71.5 20.3
Isocaloric
Energy Protein Fat Fiber kcal chow and purified
Prote
in k
cals
Fat k
cals
Carb
ohydrate
kca
ls
Fiber
0
20
40
60
80 LabDiet 5053-chow
LabDiet 58Y2-low fat purified
LabDiet 58Y1-high fat purified
gra
ms/
1000
Kca
l
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0
10
20
30
40Week 1
Week 5
BAC LSL/BAC BAC LSL/BAC
Low Fat High Fat
p=0.0009
p<0.0001
To
tal B
od
y W
eig
ht
(Gra
ms)
Total Body Weight
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BA
CLS
L/B
AC
Control Diet High Fat Diet
0
10
20
30
40Week 1
Week 5
BAC LSL/BAC BAC LSL/BAC
Low Fat High Fat
p=0.0009
p<0.0001
To
tal B
od
y W
eig
ht
(Gra
ms)
Total Body Weight
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0 5 0 1 0 0 1 5 0 2 0 0 2 5 0 3 0 0
0
2 0
4 0
6 0
8 0
D a y s o n D ie t
To
tal
Bo
dy
We
igh
t (g
)
e la -C R E C D , n = 2 4
e la -C R E H F D , n = 2 1
**
** *
**
** *
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Control Diet High Fat Diet
5.3 months / 160 days
D a y s o n D ie t
Pe
rc
en
t s
urv
iva
l
0 6 0 1 2 0 1 8 0 2 4 0 3 0 0 3 6 0 4 2 0 4 8 0
0
2 0
4 0
6 0
8 0
1 0 0K R a s
(G 1 2 D )/e la -C R E C D ; n = 4 8
K R a s(G 1 2 D )
/e la -C R E H F D n = 3 2
*p = 0 .0 0 0 4
Median survival (Days)
269 CD vs 195.5 HFD
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Control Diet High Fat Diet
5.3 months / 160 days
D a y s o n D ie t
Pe
rc
en
t s
urv
iva
l
0 6 0 1 2 0 1 8 0 2 4 0 3 0 0 3 6 0 4 2 0 4 8 0
0
2 0
4 0
6 0
8 0
1 0 0K R a s
(G 1 2 D )/e la -C R E C D ; n = 4 8
K R a s(G 1 2 D )
/e la -C R E H F D n = 3 2
*p = 0 .0 0 0 4
Median survival (Days)
269 CD vs 195.5 HFD
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D a y s o n D ie t
Pe
rc
en
t s
urv
iva
l
0 6 0 1 2 0 1 8 0 2 4 0 3 0 0 3 6 0 4 2 0 4 8 0
0
2 0
4 0
6 0
8 0
1 0 0K R a s
(G 1 2 D )/e la -C R E C D ; n = 4 8
K R a s(G 1 2 D )
/e la -C R E H F D n = 3 2
*p = 0 .0 0 0 4
Median survival (Days)
269 CD vs 195.5 HFD
Pancreas Lung Metastasis
High Fat Diet
7 months / 210 days
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BA
CLS
L/B
AC
Control Diet High Fat Diet
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Factors Related to Obesity Affecting PDAC
Obesity
Pancreatic Fatty
Infiltration
Inflammation
Leptin
IGF-1
Arginase
Resistance to Chemotherapy
COX2
Lipocalin-2 (LCN2/NGAL)
![Page 66: Obesity and Cancer - UPMC › sites › default › files › Session 3-A 1 Cruz... · Projected Increase in Pancreatic Cancer Deaths by 2030 Thought to Correlate with Obesity Trends](https://reader033.vdocuments.us/reader033/viewer/2022060414/5f12bcc392042329984ebc55/html5/thumbnails/66.jpg)
66
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67
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68
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73
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Knowledge Gaps
How are factors secreted from adipose tissue affecting the tumor microenvironment of PDAC?
Are these factors affecting cancer cells only or other cells in the tumor microenvironment?
How is the adipose cellular microenvironment contributing to PDAC?
Are the characteristics of an obesity-associated PDAC the same as non-obese PDAC?
Best preclinical model that mimics human obesity-associated PDAC.
Identify specific patient populations Who are at greatest risk of developing obesity-related cancer Who will benefit most from weight loss or enhanced screening
Identify markers, metabolic intermediates or predictors of obesity-related cancer
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Paradoxical impact of obesity on cancer immunotherapy
“There is heightened immune dysfunction and tumor progression but also
greater anti-tumor efficacy and survival after checkpoint blockade
which directly targets some of the pathways activated in obesity.”
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Paradoxical impact of obesity on cancer immunotherapy
There is a statistically significant improvement in progression-free survival
and overall survival in obese patients
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Impact of obesity on exhaustion and PD-1 checkpoint blockade in patients with cancer
CD3+ infiltrates in the TME of human colorectal cancers
There are significantly fewer tumor-infiltrating cells in obese patients
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Paradoxical impact of obesity on cancer immunotherapy
“There is heightened immune dysfunction and tumor progression but also
greater anti-tumor efficacy and survival after checkpoint blockade
which directly targets some of the pathways activated in obesity.”
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Acknowledgments Collaborators
Darwin Conwell MD, MS
Phil Hart MD
Somashekar Krishna, MBBS, MPH
Luis Lara, MD
Terence Williams, MD, PhD
Anne Noonan, MD
Tom Mace Ph.D.
Mary Dillhoff MD
Martha Belury Ph.D.
Lei Cao Ph.D.
Willa Hsueh MD
Joshua Blakeslee Ph.D.
Sue Knoblaugh DVM, Diplomate ACVP
Funding Sources:
http://go.osu.edu/cruz-monserrate
https://sites.google.com/view/zcm-lab/home
POSTDOCTORAL POSITION
AVAILABLE!!!!
Cruz-Monserrate Laboratory
Samantha Hazelett, MS
Kelly Dubay
Julia Dellick
Valentina Pita, MS University Fellow
Sabrina Kaul, Pelotonia Undergraduate Fellow
Olivia Ueltschi, Pelotonia Undergraduate Fellow
Ila Lahooti
Corbin Pontious
Kristyn Gumpper
GHN Clinical Coordinators
1R01CA223204
ZCM-Lab Summer 2019
@ZCMLab
U01DK108327