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Inflammation and Lung Cancer Risk

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Title: Inflammation and Lung Cancer Risk


1
  • Inflammation and Lung Cancer Risk
  • Qiuyin Cai
  • Vanderbilt Epidemiology Center
  • Vanderbilt University

2
Outline
  • Inflammation and Cancer
  • Inflammation and Lung Cancer
  • Biomarkers
  • Arachidonic Acid Pathway

3
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.

4
Inflammation
Coussens Werb Nature. 420 860-867, 2002
5
Inflammation Pathways
6
Inflammation and Cancer
  • In 1863, Rudolf Virchow noted leucocytes in
    neoplastic tissues
  • Lymphoreticular infiltrate reflected the origin
    of cancer at sites of chronic inflammation
  • Non-infectious Agents
  • Asbestosis, silicosis Lung cancer
  • Bronchitis Lung cancer
  • Cystitis, bladder inflammation Bladder cancer
  • IBD, Crohns disease, chronic ulcerative colitis
    Colorectal cancer
  • Chronic pancreatitis Pancreatic cancer
  • Reflux esophagitis/Barretts esophagus
    esophageal cancer
  • Skin inflammation Melanoma
  • Prostatitis Prostate cancer
  • Pelvic inflammatory disease/tissue remodeling
    Ovarian cancer
  • Infectious agents
  • Viral infection
  • HPV Cervical cancer
  • HBV, HCV Liver cancer
  • EBV Lymphoma

7
Chronic Inflammation
  • Many types of cancer, including lung cancer, are
    heavily infiltrated by different types of
    inflammatory cells, particularly the
    tumor-associated 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.

8
Inflammation and cancer
de Visser et al Nat Rev Cancer. 6 24-37, 2006.
9
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

10
Chronic Inflammation
  • A typical component in most lung disorders and
    lung infections is inflammation and activation of
    inflammatory cells with consequent free radical
    generation.
  • 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.
  • The inflammatory process itself may provide the
    prerequisite environment for the development of
    malignancy.
  • In addition to infection by biological or
    physical agents, inflammation can be initiated by
    carcinogen-induced tissue injury.

11
Chronic Inflammation and Lung Cancer Risk
Possible Mechanisms
12
Chronic Inflammation and Lung Cancer Risk
Possible Mechanisms
Hofseth and Ying BBA. 1765 74-84, 2006.
13
Lung Cancer Biomarkers
  • Stage I and II lung cancer rarely causes symptoms
  • Most lung cancer patients have advanced disease
    at diagnosis
  • Early detection could potentially decrease lung
    cancer mortality by diagnosing the disease at an
    earlier and potentially more curable stage
  • Biomarkers under evaluation
  • 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.

14
Biomarkers of Inflammation
  • Prostaglandin
  • C-reactive protein (CRP)
  • Cytokines
  • IL-1, IL-6, TNF-a and receptors
  • Fibrinogen
  • Leukocyte count
  • Adhesion molecules VCAM-1
  • Amyloid A

15
Arachidonic Acid Pathway
Winterhalder et al Ann Oncol. 15 185-196, 2004
16
Prostaglandin E2
  • The inflammation effects of PGH2 are largely
    mediated through PGE2.
  • PGE2 increases cell proliferation, migration,
    angiogenesis, and immunosupression and decreases
    apoptosis.
  • Overproduction of PGE2 and prostaglandin E
    synthase (PTGES) has been implicated in the
    pathogenesis of NSCLC.
  • 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.
  • Hidalgo et al (2002) case-control study (65
    cases and 36 controls)
  • 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.

17
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. 334266-275, 2004
18
Urinary PGE-M in Normal Subjects
A significant component of PGE2 production is
COX-2 derived.
Murphey et al Anal Biochem. 334266-275, 2004
19
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. 334266-275, 2004
20
Shanghai Womens Health Study (SWHS)
  • Population-based prospective cohort study (PI
    Wei Zheng)
  • Long-term epidemiological investigations of
    cancer and other chronic diseases
  • Recruitment period 3/1997-5/2000
  • Approximately 75,000 women
  • Biological samples
  • Blood 76
  • Urine 88
  • DNA 88

21
Urinary PGE-M SWHS Colorectal Cancer
Cai et al J Clin Oncol. 24 5010-5016, 2006
22
Urinary PGE-M SWHS Colorectal Cancer
Cai et al J Clin Oncol. 24 5010-5016, 2006
23
Urinary PGE-M and Lung Cancer
Csiki et al Clin Cancer Res. 11 6634-6640, 2005
24
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
25
Prostacyclin (PGI2)
  • PGI2, another major PGH2 metabolite, may differ
    from other bioactive prostaglandins and may exert
    cancer inhibitory effects on the development of
    lung cancer.
  • Keith et al (2002) have shown that manipulation
    of PGI2 synthase (PTGIS) substantially reduces
    the occurrence of murine lung cancer.
  • The non-specific inhibitory effect of NSAIDs on
    COX-2 enzymes may act as a double-edged sword,
    decreasing both pro-inflammatory prostaglandins
    (e.g. PGE2) and anti-inflammatory PGI2.
  • This may explain some of the null associations
    found in epidemiological studies regarding NSAID
    use and lung cancer risk.

26
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)
  • 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.

27
Biomarkers of Inflammation
  • Prostaglandin
  • C-reactive protein (CRP)
  • Cytokines
  • IL-1, IL-6, TNF-a and receptors
  • Fibrinogen
  • Leukocyte count
  • Adhesion molecules VCAM-1
  • Amyloid A

28
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)

29
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.

30
CRP and Lung Cancer
  • NSCLC patients with elevated CRP concentrations
    had greater concentrations of IL-6, 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).

31
CRP and Lung Cancer
  • Two small nested case-control studies reported
    positive association of baseline CRP and lung
    cancer risk.
  • Ilyasova 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).
  • Trichopoulos et al, CEBP, 2006 Greek component
    of the EPIC study
  • 72 lung cancer patients and 144 controls OR
    1.31 (95 CI 1.11-1.53).
  • 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.

32
CRP and Lung Cancer
  • SWHS 77 cases and 158 controls

33
Pro-inflammatory Cytokines and Lung Cancer Risk
  • Ilyasova 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-a) 39 1.67 0.79-3.55
Log (CRP) 42 1.64 1.20-2.24
34
NSAID use and Lung Cancer
Skriver et al Int J Cancer. 117 873-876, 2005
35
Genetic Markers
  • Genetic polymorphisms of genes involved in
    prostaglandin synthases and PGE2 metabolism

36
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 2002-2005 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.

37
PTGIS Polymorphisms
38
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

39
Future Study
Vanderbilt Lung SPORE Lung Cancer Risk and
Inflammation Pathways Shanghai Womens Health
Study Southern Community Cohort Study
40
Acknowledgements
  • Vanderbilt University Medical Center
  • Wei Zheng
  • Bill Blot
  • Xiao Ou Shu
  • Gong Yang
  • Wanqing Wen
  • Hui Cai
  • Regina Courtney
  • Qing Wang
  • Wande Guo
  • Ji-Rong Long
  • Jason Morrow
  • Kimberly Campbell
  • Shanghai Cancer Institute
  • Yu-Tang Gao and his team
  • NCI
  • Wong-Ho Chow
  • Bu-Tian Ji
  • Nathaniel Rothman
  • Institute of Cancer Epidemiology, Danish Cancer
    Society
  • Jorgen H. Olsen and his team
  • International Epidemiology Institute
  • Bill Blot and his team
  • Jon P. Fryzek
  • Grant Supports
  • SWHS NCI
  • Vanderbilt Lung SPORE NCI
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