Inflammation and Lung Cancer Risk Download

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Inflammation and Lung Cancer Risk
Qiuyin Cai
Vanderbilt Epidemiology Center
Vanderbilt University
Outline
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Inflammation and Cancer
Inflammation and Lung Cancer
Biomarkers
Arachidonic Acid Pathway
Inflammation
• Inflammation: A protective tissue response to injury or
destruction of tissues, which serves to destroy, dilute, or
wall off both the injurious agent and the injured tissues.
Inflammation is now recognized as a type of nonspecific
immune response.
• The classical signs of acute inflammation are pain, heat,
redness, swelling, and loss of function.
• Chronic inflammation prolonged and persistent
inflammation marked chiefly by new connective tissue
formation; it may be a continuation of an acute form or a
prolonged low-grade form.
Inflammation
Coussens & Werb: Nature. 420: 860-867, 2002
Inflammation Pathways
Inflammation and Cancer
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In 1863, Rudolf Virchow noted leucocytes in neoplastic tissues
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Non-infectious Agents
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Asbestosis, silicosis: Lung cancer
Bronchitis: Lung cancer
Cystitis, bladder inflammation: Bladder cancer
IBD, Crohn’s disease, chronic ulcerative colitis: Colorectal cancer
Chronic pancreatitis: Pancreatic cancer
Reflux esophagitis/Barrett’s esophagus: esophageal cancer
Skin inflammation: Melanoma
Prostatitis: Prostate cancer
Pelvic inflammatory disease/tissue remodeling: Ovarian cancer
Infectious agents
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Lymphoreticular infiltrate reflected the origin of cancer at sites of chronic inflammation
Viral infection
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HPV: Cervical cancer
HBV, HCV: Liver cancer
EBV: Lymphoma
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H Pylori: Stomach cancer
TB: Lung cancer
Bacteria
Contributes to about 15-20% of cancer world-wide.
Chronic Inflammation
• Many types of cancer, including lung cancer,
are heavily infiltrated by different types of
inflammatory cells, particularly the tumorassociated macrophages.
• These cells have ability to express a large
variety of cytokines and growth factors
• Some of these cytokines and growth factors
are known to function as regulators of tumor
growth, metastasis, and angiogenesis.
Inflammation and cancer
de Visser et al: Nat Rev Cancer. 6: 24-37, 2006.
Lung Cancer Risk Factors
• Cigarette Smoking
• Environmental Tobacco Smoke (ETS)
• Chronic lung diseases
• COPD
• Chronic bronchitis
• Tuberculosis
• Environmental exposures
• Asbestos
• Radon, Radiation
• Air pollution (indoor & outdoor)
• All these cause inflammation in the lungs
Chronic Inflammation
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A typical component in most lung disorders and lung
infections is inflammation and activation of inflammatory cells
with consequent free radical generation.
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Sustained cell proliferation in an inflammatory environment
with abundant reactive free radicals and pro-malignant growth
factors greatly potentiate and promote the development and
progression of cancers.
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The inflammatory process itself may provide the prerequisite
environment for the development of malignancy.
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In addition to infection by biological or physical agents,
inflammation can be initiated by carcinogen-induced tissue
injury.
Chronic Inflammation and Lung Cancer Risk:
Possible Mechanisms
Smoking, ETS
Chronic lung diseases
Chronic infection (bacteria, virus)
Environmental pollutants
Oxidative
DNA Damage
Nitric oxide
Pro-inflammatory
Cytokines
Inflammation
ROS/RNS
Production
Oxidative
Stress
Oncogene
Tumor suppressor gene
VEGF
Arachidonic
Acid
PGES
COX-2
Angiogenesis
PGE2
Cell growth
PGH2
PGIS
PGI2
Inhibition
Lung
Cancer
Chronic Inflammation and Lung Cancer Risk:
Possible Mechanisms
Hofseth and Ying: BBA. 1765: 74-84, 2006.
Lung Cancer Biomarkers
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Stage I and II lung cancer rarely causes symptoms
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Most lung cancer patients have advanced disease at diagnosis
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Early detection could potentially decrease lung cancer mortality
by diagnosing the disease at an earlier and potentially more
curable stage
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Biomarkers under evaluation:
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Circulating DNA markers
Serum proteomic profiles
Gene methylation/mutations
Conventional sputum cytology
Identifying biomarkers, especially using non-invasive methods,
that may be useful in the detection of early malignant or even
pre-malignant lesions are needed.
Biomarkers of Inflammation
• Prostaglandin
• C-reactive protein (CRP)
• Cytokines:
• IL-1, IL-6, TNF-α and receptors
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Fibrinogen
Leukocyte count
Adhesion molecules: VCAM-1
Amyloid A
Arachidonic Acid Pathway
Winterhalder et al: Ann Oncol. 15: 185-196, 2004
Prostaglandin E2
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The inflammation effects of PGH2 are largely mediated through PGE2.
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PGE2 increases cell proliferation, migration, angiogenesis, and
immunosupression and decreases apoptosis.
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Overproduction of PGE2 and prostaglandin E synthase (PTGES) has been
implicated in the pathogenesis of NSCLC.
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Suppression of the PGE2 receptor has been shown to inhibit the growth
of lung carcinoma cell lines, and PGE2 augments the activation of the
Ras signaling pathway in lung adenocarcinoma cells.
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Hidalgo et al (2002): case-control study (65 cases and 36 controls):
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Plasma PGE2 levels in NSCLC patients were elevated compared to normal
controls.
This study was limited by a small sample size and the use of post-diagnostic
blood PGE2 levels as a marker.
Urinary Prostaglandin E2 Metabolite (PGE-M)
• The most accurate index of
endogenous prostaglandins
production in humans is the
measurement of excreted
urinary metabolites.
• PGE-M could be measured
using a liquid chromatography
/tandem mass spectrometric
method.
• The measurement of urinary
PGE-M provides the most
accurate approach to assess
the endogenous production of
PGE2 in humans.
Murphey et al: Anal Biochem. 334:266-275, 2004
Urinary PGE-M in Normal Subjects
PGE-M (ng/mg Cr)
Ibuprofen
Rofecoxib
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6
5
P<0.001
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P<0.01
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3
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Pre-Ibuprofen
Post-Ibuprofen
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Pre-Rofecoxib
Post-Rofecoxib
Fig 2: PGE-M in normal subjects post non-selective (ibuprofen) & selective COX-2 inhibition (rofecoxib)
A significant component of PGE2 production is COX-2 derived.
Murphey et al: Anal Biochem. 334:266-275, 2004
Urinary PGE-M in NSCLC
A significant proportion of the excessive production of PGE2 in humans with NSCLC is COX-2 derived.
Murphey et al: Anal Biochem. 334:266-275, 2004
Shanghai Women’s Health Study (SWHS)
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Population-based prospective cohort study (PI: Wei Zheng)
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Long-term epidemiological investigations of cancer and other
chronic diseases
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Recruitment period: 3/1997-5/2000
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Approximately 75,000 women
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Biological samples:
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Blood: 76%
Urine: 88%
DNA: 88%
Urinary PGE-M
SWHS: Colorectal Cancer
Cai et al: J Clin Oncol. 24: 5010-5016, 2006
Urinary PGE-M
SWHS: Colorectal Cancer
Table 3. Association of Baseline Urinary PGE-M Levels and Subsequent Risk of Colorectal Cancer
PGE-M (by quartiles)
Q1
Q2
Q3
Q4
P*
for trend
All colorectal cancer (150 pairs)
Number of cases/controls
14/37
28/38
47/37
61/38
RR (95% CI)
1.0 (reference)
2.5 (1.1-5.8)
4.5 (1.9-10.9)
5.6 (2.4-13.5)
Number of cases/controls
7/21
15/22
29/20
37/25
RR (95% CI)
1.0 (reference)
2.1 (0.7-6.5)
4.8 (1.6-14.8)
4.9 (1.7-14.7)
Number of cases/controls
7/16
13/16
18/17
24/13
RR (95% CI)
1.0 (reference)
3.1 (0.8-11.6)
4.1 (1.0-17.3)
7.2 (1.7-30.7)
< 0.001
Colon cancer (88 pairs)
0.009
Rectal cancer (62 pairs)
0.048
*Conditional logistic regression models were used to derive P-values for linear trends by modeling
the log-transformed urinary PGE-M levels as continuous variable.
Cai et al: J Clin Oncol. 24: 5010-5016, 2006
Urinary PGE-M and Lung Cancer
Csiki et al: Clin Cancer Res. 11: 6634-6640, 2005
Correlation of Intratumoral PGE2 Levels and
Urinary PGE-M in NSCLC
Celecoxib inhibited intratumoral COX-2, reduced intratumoral PGE2 synthesis and resulted in a
concomitant decrease in urine PGE-M levels.
Csiki et al: Clin Cancer Res. 11: 6634-6640, 2005
Prostacyclin (PGI2)
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PGI2, another major PGH2 metabolite, may
differ from other bioactive prostaglandins
and may exert cancer inhibitory effects on
the development of lung cancer.
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Keith et al (2002) have shown that
manipulation of PGI2 synthase (PTGIS)
substantially reduces the occurrence of
murine lung cancer.
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The non-specific inhibitory effect of NSAIDs
on COX-2 enzymes may act as a doubleedged sword, decreasing both proinflammatory prostaglandins (e.g. PGE2)
and anti-inflammatory PGI2.
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This may explain some of the null
associations found in epidemiological
studies regarding NSAID use and lung
cancer risk.
Urinary Prostacyclin Metabolite (PGI-M)
• Because of the very short half-life of the active
species, PGI2 synthesis in biological tissues can only
be monitored by measuring PGI-M, the primary
breakdown product of PGI2.
SWHS: Lung Cancer (82 cases and 82 controls)
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Assayed by Cayman Chemical using EIA kit
Higher urinary PGI-M is associated with decreased lung cancer
risk.
Need to use a more accurate detecting method.
Biomarkers of Inflammation
• Prostaglandin
• C-reactive protein (CRP)
• Cytokines:
• IL-1, IL-6, TNF-α and receptors
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Fibrinogen
Leukocyte count
Adhesion molecules: VCAM-1
Amyloid A
C-reactive Protein (CRP)
• CRP is a nonspecific, but sensitive marker of systemic
inflammation.
• As a downstream biomarker, CRP provides functional
integration of overall upstream cytokine activation.
• Produced in liver at the stimulation of pro-inflammatory
cytokines:
• Interleukin-6 (IL-6)
• Interleukin-1 (IL-1)
• Tumor necrosis factor- (TNF-)
• CRP levels remain stable and measurable in serum
samples stored for decades.
• High within-person correlation in repeated measurements
(same r as for systolic blood pressure)
C-reactive Protein (CRP)
• CRP has been shown in numerous
epidemiological studies to be a robust and
independent predictor of future cardiovascular
events.
• CRP is accepted as a risk marker fro
cardiovascular disease.
• Erlinger et al (2004) reported that plasma CRP
concentrations were elevated among persons
who subsequently developed colon cancer,
suggesting that CRP may have etiological
significance.
CRP and Lung Cancer
• NSCLC patients with elevated CRP
concentrations had greater concentrations of IL6, a pro-inflammatory cytokine.
• Sin et al (2006): Plasma CRP has excellent
predictive powers in identifying participants with
bronchial dysplastic lesions whose lesions
progress to more advanced stages of dysplasia.
• The baseline CRP levels in these participants were
64% higher than those without progressive disease (p
= 0.027).
CRP and Lung Cancer
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Two small nested case-control studies reported positive
association of baseline CRP and lung cancer risk.
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Il’yasova et al, CEBP, 2005: Health Aging and Body Composition
study (ages 70-79 years):
• 42 lung cancer patients: HR = 1.64 (95% CI: 1.20-2.24).
• Additional adjustment for smoking reduced the HR estimates (HR: 1.54,
95% CI, 1.12-2.12).
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Trichopoulos et al, CEBP, 2006: Greek component of the EPIC study:
• 72 lung cancer patients and 144 controls: OR = 1.31 (95% CI: 1.111.53).
• When excluding lung cancer patients in the first year of follow-up, the OR
was 1.63 (95% CI: 1.25-2.14).
These studies were limited by small sample size and lack of information
on acute inflammatory disease and medicine use.
These results support the hypothesis that inflammation is associated
with lung cancer.
CRP and Lung Cancer
SWHS: 77 cases and 158 controls
Table 5. Association of baseline hsCRP with lung cancer risk
hsCRP
# of Cases
# of Controls
OR (95% CI)
T1 (Low)
21
59
1.00 (reference)
T2
28
47
1.67 (0.85-3.32)
T3 (high)
28
52
1.51 (0.77-3.18)
Pro-inflammatory Cytokines and Lung Cancer Risk
• Il’yasova et al: CEBP, 2005.
Health Aging and Body Composition Study
Markers
N
HR
95% CI
Log (IL-6)
42
1.43
0.91-2.26
Log (TNF-α)
39
1.67
0.79-3.55
Log (CRP)
42
1.64
1.20-2.24
NSAID use and Lung Cancer
Skriver et al: Int J Cancer. 117: 873-876, 2005
Genetic Markers
• Genetic polymorphisms of genes involved in
prostaglandin synthases and PGE2 metabolism
PTGIS Polymorphisms
• Danish Diet, Cancer and Health Cohort:
• 432 incident cases of lung cancer
• 432 age and sex-matched controls
• This cohort was established in 1993, and subjects were
enrolled between December 1993 and May 1997 in
Copenhagen and Aarhus, Denmark.
• Population-based case-control study:
• 159 cases of primary lung cancer recruited between 20022005 in two lung cancer treatment centers in the county of
North Jutland, Denmark.
• 444 age and sex-matched controls were randomly selected
from the population of North Jutland County.
PTGIS Polymorphisms
Cases
N
%
Controls
N
%
OR
95% CI
rs5629
G/G
G/T
T/T
363
177
31
63.6
31.0
5.4
480
313
59
56.3
36.7
6.9
1.00
0.73
0.72
reference
0.55-0.96
0.42-1.25
rs5580
A/A
A/C
C/C
175
291
101
30.9
51.3
17.8
257
438
164
29.9
51.0
19.1
1.00
1.02
0.86
reference
0.76-1.38
0.59-1.27
Summary
• Inflammation plays an important role in
lung carcinogenesis
• Urinary PGE-M and PGI-M and blood
hsCRP may be useful biomarkers for
lung cancer
• Genetic variations in genes involved in
prostaglandin production may be
associated with lung cancer risk
Future Study
Vanderbilt Lung SPORE:
Lung Cancer Risk and Inflammation Pathways
Shanghai Women’s Health Study
Southern Community Cohort Study
Smoking, ETS
Chronic lung diseases
Chronic infection
Environmental pollutants
Arachidonic
Acid
PGI2
Inhibition
(PGI-M)
Cox-2
Nitric Oxide Pro-inflammatory
Cytokines
(hsCRP, CRP gene)
 Cell growth
 Apoptosis
PGH2
Inflammation
PTGIS
PTGES
PGE2
(PGE-M,
15-PGDH)
 Angiogenesis
 Invasiveness
 Immunosuppression
Lung
Cancer
Acknowledgements
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Vanderbilt University Medical
Center
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Wei Zheng
Bill Blot
Xiao Ou Shu
Gong Yang
Wanqing Wen
Hui Cai
Regina Courtney
Qing Wang
Wande Guo
Ji-Rong Long
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Jason Morrow
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Kimberly Campbell
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Shanghai Cancer Institute
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NCI
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Jorgen H. Olsen and his team
International Epidemiology
Institute
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Wong-Ho Chow
Bu-Tian Ji
Nathaniel Rothman
Institute of Cancer
Epidemiology, Danish Cancer
Society
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Yu-Tang Gao and his team
Bill Blot and his team
Jon P. Fryzek
Grant Supports
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SWHS: NCI
Vanderbilt Lung SPORE: NCI