Download - Inflammation, Atherosclerosis, Neurodegeneration and Cancer · 60% of deaths world-wideoverview of inflammatory markers Chronic inflammation and atherosclerosis C-reactive protein

CPTA Annual Conference 2013 9/20/2013

Brad Stockert, PT, PhD 1

Brad Stockert, PT, PhD

Professor of Physical Therapy

California State University, Sacramento

Inflammation, Atherosclerosis,

Neurodegeneration and Cancer� OBJECTIVES

Upon completion of this course, you will be able to:

1. provide a current definition of chronic inflammation.

2. describe the evidence that chronic inflammation plays a role in the development & propagation of atherosclerosis, some neurodegenerative disorders and some forms of cancer.

3. explain the impact of anti-inflammatory medications on chronic inflammation.

4. discuss the impact of obesity and physical activity on chronic inflammation.

Inflammation, Atherosclerosis,

Neurodegeneration and Cancer� Acute and chronic inflammation

� overview of inflammatory markers

� Chronic inflammation and atherosclerosis

� C-reactive protein and atherosclerosis

� Chronic inflammation and neurodegenerative disorders

� Multiple sclerosis

� Parkinson disease

� Alzheimer disease

� Chronic inflammation and cancer risk

� overall, breast and colorectal cancer risk

The problem

� Chronic Noncommunicable Diseases (CNDs)

� 60% of deaths world-wide

� cardiovascular disease

� breast & colorectal cancer

� chronic lung diseases

� neurodegenerative disorders

� insulin disorders

The problem

� Chronic Noncommunicable Diseases (CNDs)

� chronic low-grade inflammation

� significant role in pathological processes

� obesity

� physical inactivity

� behavioral/lifestyle disorders

Acute Inflammation

� characteristic response

� multiple chemical mediators released

� “cytokines”

� low molecular weight glycoproteins

� interferons

� used to fight viral infections

� interleukins

� modulate inflammatory processes



Acute Inflammation


� multiple chemical mediators released

� sources of interleukins (ILs) during acute inflammation

� mast cells

� macrophages

� lymphocytes

Acute Inflammation


� sequential appearance of interleukins

� tumor necrosis factor-alpha

� interleukin-1 beta

� interleukin-6

� interleukin-1 receptor antagonist

� soluble tumor necrosis factor-alpha receptor

Acute Inflammation


� sequential appearance of interleukins

� tumor necrosis factor-alpha (TNF-α)

� interleukin-1 beta (IL-1β)

� secreted early in inflammatory process

� pro-inflammatory cytokines

Acute Inflammation


� sequential appearance of cytokines

� interleukin-1 receptor antagonist (IL-1ra)

� soluble tumor necrosis factor-alpha receptor (sTNF-R)

� secreted later in inflammatory process

� anti-inflammatory cytokines

� resolution/repair

Acute Inflammation



� interleukin-6 (IL-6)

� secreted after TNF-α & IL-1β

� secreted before IL-1ra & sTNF-R

Changes in Interleukins with Sepsis

TNF-α

IL-1

IL-6

sTNF-R

IL-1ra

pro-inflammatory anti-inflammatory



Acute Inflammation



� interleukin-6 (IL-6)

� stimulates liver production & secretion

� “acute-phase response” proteins in blood

Acute Inflammation



� “acute-phase response” proteins in blood

� sensitive markers of inflammation

� erythrocyte sedimentation rate (ESR)

� C-reactive protein (CRP)

� CRP strongly associated with CNDs

Chronic Inflammation

� characterization in absence of acute inflammation

� persistent 2-3 fold increase in pro-inflammatory cytokines

� TNF-α

� IL-6

� persistent 2-3 fold increase in inflammatory markers

� CRP

� ESR


� characterization in absence of acute inflammation

� 2-3 fold increase in pro-inflammatory cytokines & markers

� advanced age (>50 y.o.)

� obesity

� smoking

� atherosclerosis

� insulin-related disorders

Endocrinology of Adipose Tissue

� Adipose tissue secretes

� hormones

� leptin & adiponectin

� regulation of body weight, insulin sensitivity and

fuel oxidation


� Adipose tissue secretes

� hormones

� leptin & adiponectin

� “adipokines”

� cytokines (interleukins) from adipose tissue

� TNF-α

� IL-6

� CRP




� Adipose tissue secretes: TNF-α

� adipose tissue is main source without acute inflammation

� level proportional to obesity

� level decreases with weight loss

� level proportional to insulin resistance

� TNF-α impairs insulin receptors


� Adipose tissue secretes: IL-6

� 30% of IL-6 in nonobese individuals at rest

� level of IL-6 elevated with obesity

� adipose tissue is main source of IL-6 with obesity

� proportional to degree of obesity

� visceral fat > subcutaneous fat


� Adipose tissue secretes: IL-6

� 30% of IL-6 in nonobese individuals at rest

� level of IL-6 elevated with obesity

� main source of IL-6 with obesity

� visceral fat > subcutaneous fat

� level of IL-6 is proportional to insulin resistance

� impairs insulin receptors

� increases resting level of CRP

Endocrinology of Adipose Tissue� Adipose tissue secretes: CRP

� liver tissue is main source without acute inflammation

� nonobese individuals

� adipose tissue is main source without acute inflammation� obese individuals

� CRP level sensitive to changes in weight & training� CRP decreases with loss of weight

� CRP decreases with chronic training

Endocrinology of Adipose Tissue� Adipose tissue secretes: CRP

� indicator of pro-inflammatory state

� strong predictor of future problems


� vascular diseases: atherosclerosis & dementia

� amplifies impact of other pro-inflammatory cytokines

� suppresses fibrinolysis

� enhances thrombus formation


� Obese individuals

� obesity is strongly associated with chronic inflammation

� elevated level of pro-inflammatory mediators & markers

� TNF-α

� IL-6

� CRP

� increased incidence vascular & insulin-related disorders




� Obese individuals

� increase risk of developing

� vascular disorders

� atherosclerosis (MI, CVA, some dementias)

� dyslipidemia

� hypertension

� erectile dysfunction


� insulin resistance

� type II diabetes

Endocrinology of Muscle� Muscle tissue

� largest body tissue in nonobese

� secretes hormones & interleukins when active

� “myokines”

� interleukins from active muscle tissue

� IL-6

� IL-1ra

� sTNF-R

Endocrinology of Muscle

� Acute exercise without injury

� myokines secreted: IL-6

� secreted from Type I & II fibers

� amount secreted proportional to:

� duration & intensity of exercise

� IL-6 may increase 100-fold with intense exercise



� myokines secreted: IL-6

� secreted from Type I & II fibers

� amount secreted proportional to:

� duration & intensity of exercise

� suppresses TNF-α production

� stimulates glucose uptake



� myokines secreted: IL-1ra and sTNF-R

� inhibit signal transduction

� IL-ra blocks the IL-1 receptor

� sTNF-R competes with TNF-α receptor

� block inflammatory impact of IL-1β & TNF-α



� no pro-inflammatory cytokines released

� IL-1 and TNF-α are not secreted

� systemic levels of IL-1 & TNF-α are not changed

� IL-1ra and sTNF-R secreted from active muscle

� inhibit signal transduction

� action of IL-1 and TNF-α is blocked/impaired



Changes in Interleukins with Sepsis

TNF-α

IL-1

IL-6

sTNF-R

IL-1ra

pro-inflammatory anti-inflammatory

Changes in Interleukins with Exercise

IL-6

sTNF-R

IL-1ra

anti-inflammatory

Endocrinology of Muscle� Acute exercise and endotoxin

� Petersen AMW; J Appl Physiol 2005; 98:1154-1162.

� endotoxin (Escherichia coli)

� physically inactive subjects injected with endotoxin

� 2-3 fold increase in TNF-α after endotoxin

Endocrinology of Muscle� Acute exercise and endotoxin

� endotoxin (Escherichia coli)

� physically inactive subjects injected with endotoxin

� 2-3 fold increase in TNF-α after endotoxin

� physically active subjects injected with endotoxin

� after riding stationary exercycle 2.5 hours

� no increase in TNF-α following endotoxin� exercise suppressed rise in TNF-α



� additional myokines secreted:

� Interleukin-8 (IL-8)

� neutrophil chemotaxis during acute inflammation

� stimulates local angiogenesis following exercise

� substantial local increase in concentration of IL-8

� acts in paracrine manner to stimulate local angiogenesis



� additional myokines secreted:

� Interleukin-15 (IL-15)

� local concentration increases with strength training

� local anabolic impact on muscle

� increase in synthesis of muscle proteins

� decrease in degradation of muscle proteins

� reduction in adipose tissue mass



Interleukin - 6

� absence of acute inflammation

� nonobese individuals

� ~30% from adipose tissue

� obese individuals

� majority from adipose tissue

� level proportional to degree of obesity

Interleukin - 6


� IL-6 known to cause:

� production of acute phase response proteins (CRP)

� liver

� adipose tissue

� increased level of CRP

� increased risk of behavioral/lifestyle disorders

Interleukin - 6


� IL-6 high resting level

� equivalent to traditional risk factors for heart disease

� hypertension

� hypercholesterolemia


� smoking

Interleukin - 6


� IL-6 high resting level

� equivalent to traditional risk factors for heart disease

� IL-6 is strongly associated with physical inactivity

� IL-6 decreases with chronic training

� IL-6 increases with physical inactivity

Interleukin - 6� Thompson, J Appl Physiol 2010;108:769-779.

� IL-6 measured at baseline & after 12 & 24 weeks of training

� moderate intensity aerobic exercise program

� IL-6 decreased after 12 & 24 weeks of training

� decrease in IL-6 inversely related to starting point

� those with the highest IL-6 at start had largest decrease

� IL-6 returned to baseline after 2 weeks of detraining

Interleukin - 6


� IL-6 resting level

� decreases with chronic endurance training

� increase in IL-6 receptor number

� decrease in IL-6 resting level

� increase in IL-6 sensitivity

� decrease in risk of behavioral/lifestyle disorders



Interleukin - 6


� IL-6 resting level

� independent risk factor for future

� cardiovascular disorders

� MI

� CVA

� dementia


C-Reactive Protein (CRP)

� CRP levels at rest

� inversely related to level of aerobic fitness

� children and adults (obese & nonobese)

� powerful predictor of future cardiovascular disorders

� myocardial infarction

� cerebrovascular accident

� hypertension

� diabetes



� marginally correlated with LDL cholesterol

� LDL and CRP both highly correlated with future problems

� identify different pathological processes or groups at risk

� ~1/2 of MIs occur in people with normal LDL cholesterol



� statin therapy

� Lipitor, simvastatin

� lowers LDL cholesterol level

� reduces CRP level

� reduction in chronic inflammation

� reduces risk more than reduction in LDL cholesterol

� reduction in chronic inflammation



� statin therapy

� aspirin therapy

� given to reduce platelet adhesion

� reduces risk of thromboembolism (MI, CVA)


� reduces chronic inflammation & risk of behavioral/lifestyle disorders

� acts synergistically with statins to reduce level of chronic inflammation

C-Reactive Protein (CRP)� CRP levels at rest

� statin therapy

� aspirin therapy

� physical activity


� independent of weight loss

� independent of statin &/or aspirin therapy

� aerobic and resistive exercises both work




� Chronic inflammation is associated with


� obesity

� elevation in pro-inflammatory mediators/markers

� TNF-α

� IL-6

� CRP


� Chronic inflammation is decreased with

� physical activity

� decrease in obesity

� anti-inflammatory medications

� each reduces level of pro-inflammatory mediators

� TNF-α

� IL-6

� CRP

Chronic Inflammation� Chronic inflammation is associated with

� behavioral/lifestyle diseases

� vascular diseases

� atherosclerosis

� MI

� CVA

� dementia






� insulin resistance

� type II DM

� metabolic syndrome





� cancers:

� breast

� colorectal



� vascular disorders


� cancers

� neurodegenerative disorders:

� Alzheimer Disease

� Multiple Sclerosis




� Reduction in risk of behavioral/lifestyle disorders

� changes in behavior/lifestyle

� use of anti-inflammatory medications

� most anti-inflammatory medications have increased risk of

� GI distress

� ulcers

� adverse drug reaction

� interaction with other medications




Inflammation & Atherosclerosis

� Previously held view of atherosclerosis

� cholesterol storage disease

� passive deposition of lipids into arterial walls

� continuing deposition of lipids encrusts arterial walls

� progressing stenosis provokes occlusive thrombic event


� Current view of atherosclerosis

� active process

� arterial walls are dynamic structures

� altered cellular behavior

� changes mediated by molecular signals

� cytokines



� Why doesn’t it get better over time instead of worse???

� primordial role for inflammation

� inflammation links risk factors with lesion formation

� inflammation transduces risk factors to changes in

biology and cell function



� ~50% of CV deaths occur in people without hyperlipidemia

� plaque rupture is poorly correlated with degree of stenosis

� ~50% of infarctions occur in arteries with <50% occlusion





� C-Reactive Protein (CRP)

� produced during acute inflammation

� level increases 1000-fold with acute infection

� level remarkably stable over time without infection

� measure of systemic inflammation

� strong predictor of future MI & CVA

Inflammation & Atherosclerosis� CRP predicts risk beyond traditional risk factors

� CRP <1 mg/l = low risk

� CRP 1-3 mg/l = moderate risk

� CRP >3 mg/l = high risk

� highest vs. lowest tertile of CRP

� 2-fold increased risk CV event with elevated CRP

� risk elevated regardless of cholesterol level

� TC, LDL-C & HDL-C

Inflammation & Atherosclerosis� Physician Health Study (1997)

� Ridker PM, N Eng J Med 1997;336:973-979.

� apparently health males followed for 8 years

� CRP higher among those that suffered MI or CVA

� CRP highest quartile vs. lowest quartile

� 3-fold increased risk of MI

� 2-fold increased risk of CVA

� independent of lipid & nonlipid risk factors

Inflammation & Atherosclerosis� Women’s Health Initiative

� Pradhan AD; JAMA 2002;288:980-987.

� prospective, case controlled study

� 75,000 females in US initially enrolled

� 304 developed heart disease

� 304 case-matched controls (age, smoking, ethnicity)

� CRP significantly elevated in those with heart disease

� 2-fold increased risk of heart disease

Inflammation & Atherosclerosis� Women’s Health Study

� Ridker PM; Lancet 2001; 358:946-947.

� 28,263 postmenopausal women

� monitored prospectively

� CRP & LDL-C significant predictors of CV risk

� CRP higher prognostic value

� high CRP & high LDL-C 8-fold increase risk

� CRP & LDL-C minimally correlated

� appear to identify separate pathological groups at risk

Inflammation & Atherosclerosis� Coronary angioplasty outcomes

� Buffon A; J Am Coll Cardiology 1999; 34:1512-1521.

� CRP measured before PTCA procedure

� assessed early & late outcomes

� restenosis

� complications



Inflammation & Atherosclerosis� Coronary Angioplasty outcomes

� Buffon A; J Am Coll Cardiol 1999; 34:1512-1521.

� CRP measured before PTCA procedure

� acute problems occurred

� 22% of patients with high CRP

� none in patients with normal CRP

� one year follow-up

� 63% with high CRP had restenosis

� 27% with normal CRP had restenosis

Inflammation & Atherosclerosis� Statin therapy

� lowers LDL-C

� inhibits cholesterol synthesis in liver

� powerful vascular anti-inflammatory agent

� lowers CRP

� impact greatest in people with highest CRP

� reduces CRP rapidly and for extended period

� change in LDL-C and CRP are not correlated


� Ridker PM; N Eng J Med 2001; 344:1959-1965.

� high CRP & low LDL-C higher risk of CV event than

low CRP & high LDL-C

� people with low or normal LDL-C and high CRP may

benefit significantly from statin therapy


� decreases recurrent events after stent placement in

in patient with high CRP independent of LDL-C

� survivors of MI over 5 year follow-up

� CRP increased with standard treatment & placebo

� statin therapy decreased CRP regardless of LDL-C

� statin therapy associated with better clinical outcomes

in patient with initially higher CRP

� Walter DH; J Am Coll Cardiol; 2001; 37:839-846


� ~25% of current U.S and European adults have:

� high CRP

� low LDL-C

� not currently given statins for primary prevention

Inflammation & Atherosclerosis� Aspirin therapy

� reduces risk of first CV event by 44%� N Eng J Med 1989;321:129-135.

� several contradictory studies relating aspirin with CRP

� few controlled for initial CRP level

� low dosage of aspirin used� low dosage has anti-platelet activity

� low dosage is not anti-inflammatory



Inflammation & Atherosclerosis� Aspirin therapy

� reduces risk of first CV event by 44%

� several contradictory studies relating aspirin with CRP

� few controlled for initial CRP level

� low dosage of aspirin used

� impact greatest in person with high CRP

� largest impact on quartile with highest CRP level

� impact declines in direct proportion to CRP level

Inflammation & Atherosclerosis� Summary of findings

� Increased risk of cardiovascular event associated with:

� elevated LDL-cholesterol

� elevated CRP

� Decreased risk of cardiovascular event associated with:

� reduction in LDL-cholesterol

� statins

� reduction in CRP

� statins

� aspirin




Neurodegenerative Disorders� Glial cells have inflammatory properties

� glial cells can secrete:

� TNF-α

� IL-1β

� TNF-α and IL-1β elevated with

� Parkinson Disease

� Multiple Sclerosis

� Alzheimer Disease

� Huntington Disease

� ALS

Neurodegenerative Disorders� Glial-mediated inflammation

� beneficial acutely

� acute insults trigger compensatory neurogenesis

� chronic inflammation inhibits neurogenesis

� NSAIDs attenuate inflammation� restore neurogenesis

� Marchetti B; Trends in Pharmacol Sci 2005; 26:517-525.

� Monje ML; Science 2003; 302:1760-1765.

Neurodegenerative Disorders� Parkinson Disease

� majority of cases are idiopathic

� degenerative disorder of basal ganglia

� abnormal movement pattern

� loss of dopamine neurons in substantia nigra

� evidence of chronic inflammation

� microglia activity high in areas of degeneration

� elevated TNF-α

� elevated IL-1β



Neurodegenerative Disorders� Parkinson Disease

� majority of cases are idiopathic

� degenerative disorder of basal ganglia

� abnormal movement pattern

� loss of dopamine neurons in substantia nigra

� evidence of chronic inflammation

� chronic NSAID use decreases risk ~45%

� Cox-2 inhibitors reduce neuronal damage� demonstrated in animal models only

� Lucas S; Brit J Pharm 2006; 147:S232-S240.

Neurodegenerative Disorders� Multiple Sclerosis

� demyelinating CNS disorder

� T-cell mediated autoimmune disorder

� chronic glial cell activation

� elevated level of proinflammatory cytokines

� TNF-α and IL-1β

� spontaneous remyelination occurs

� process is not robust

� process is inhibited by inflammation


� detailed autopsy study

� 67 with MS and 28 without MS� Frischer JM; Brain 2009; 132:1175-1189.


� detailed autopsy study

� 67 with MS and 28 without MS

� pronounced inflammation found in

� acute and relapsing forms

� progressive forms

� all lesions

� all stages of disorder

� correlation between axonal injury & disability



� proinflammatory cytokines

� TNF-α and IL-1β elevated locally

� levels correlate with stage of disorder� Marchetti B; Trends in Pharmacol Sci 2005; 26:517-525.




� TNF-α and IL-1β elevated locally

� levels correlate with stage of disorder

� injection of TNF-α &/or IL-1β (rat model)

� extensive demyelination

� blocking TNF-α &/or IL-1β (rat model)

� decreases expression of disorder� Lucas S; Brit J Pharm; 2006;147:S232-S240.







� NSAIDs impact

� ameliorate & delay progression

� effectiveness related to “COX-2” inhibition

� Statins impact

� no evidence of effectiveness� Marchetti B; Trends in Pharmacol Sci 2005; 26:517-525.





� Cannabinoids impact

� anti-inflammatory properties� cannabidiol > THC

� Pletcher MJ. JAMA 2012; 307:173-181

� ameliorate progression & symptoms (rat model)� Walter L; Brit J Pharmacol 2004; 141:775-785.

Neurodegenerative Disorders� Alzheimer Disease

� severe cognitive dysfunction

� neurofibrillary tangles

� amyloid plaques contain

� activated microglia

� inflammatory mediators

� TNF-α and IL-1β are elevated


� original association with inflammation

� patients with Rheumatoid Arthritis

� patients with heart disease

� take high dose NSAIDs chronically

� reduced incidence of Alzheimer Disease



� clinical trials using NSAIDs

� no benefit in some studies

� design flaws?

� late initiation

� dosage used

� no change in inflammatory markers



� clinical trials using statins

� may be protective

� cross-sectional study of 3 hospital data-bases

� incidence of AD 60% lower in patients taking statins� Liao JK; Ann Rev Pharm Toxicol: 2005; 45:89-118.






� Rotterdam study with 6992 participants

� prospective clinical trial

� 9 year follow-up� Haag M; J Neurol Neurosurg Psychiatry 2009; 80:13-17.




� Rotterdam study with 6992 participants

� prospective clinical trial

� 9 year follow-up

� statin use associated with 60% decreased incidence

� non-statin cholesterol lowering medication

� no effect on incidence of AD



� physical activity as an intervention

1) longitudinal study of 5925 older females

� walking more associated with ~35% decreased risk

Yaffe K; JAMA 2001; 161:1703-1708.

2) longitudinal study of 349 adults >55 years of age

� higher levels of cardiorespiratory fitness associated with

less cognitive decline over 6 years

Barnes DE. Exc & Sport Sci Rev 2007;35:24-29.



� physical activity as an intervention

3) longitudinal study of 4615 adults

Laurin D. Arch Neurol; 2001:58:498-504.

� physical activity associated with:

42% decrease in level of cognitive decline

50% decrease in incidence of AD

37% decrease in incidence of any form of dementia




Cancer

� uncontrolled growth of cells

� multiple forms

� multiple causes

� multiple locations



Top 3 New Cancer Sites by Gender

� males:

� prostate (25%)

� lung/bronchus (15%)

� colorectal (10%)

� females:

� breast (27%)

� lung/bronchus (14%)

� colorectal (10%)

Cancer and Inflammation� Theodor Boveri (1862-1915)

� first postulated link between cancer & inflammation

� tumorigenesis promoted by chronic inflammation

� Several subsequent investigators & studies have shown� elevated CRP associated with increased cancer risk

� association shown with many forms of cancer

� lung, breast, rectum & prostate cancers

� association not found with infectious cancers

Cancer and Inflammation� Rotterdam study

� Siemes C. J Clinical Oncology 2006;24:5216-5222.

� 7,017 participants >55 years of age

� mean follow-up time = 10.2 years

� high levels of CRP [>3mg/L]

� compared risk vs. subject with low CRP [<1mg/L]

� associated with increased risk of incident cancer

� lung cancer association strongest

Cancer and Inflammation� Greek study

� Trichopoulos D. Cancer Epidemiol Biomarkers Prev 2006;15:381-384.

� prospective study with 28,572 volunteers at start

� 496 cancer cases

� 996 case-matched control cases

� matched for age, smoking, BMI and other attributes

Cancer and Inflammation� Greek study

� Trichopoulos D. Cancer Epidemiol Biomarkers Prev 2006;15:381-384.

� prospective study with 28,572 volunteers at start

� 496 cancer cases

� 996 case-matched control cases

� matched for age, smoking, BMI and other attributes

� CRP levels were higher in cases with cancer

� 4.1 mg/L for cancer cases

� 2.6 mg/L for control cases

� association strongest for lung cancer

Cancer and Inflammation� Impact of physical activity on overall cancer risk

� Thune I. Med Sci Sports Exc 2001;33:S530-S550.

� review of cohort & case-control studies

� occupational & recreational physical activities

� both provide protection against overall cancer risk

� graded dose-response manner

� regardless of gender

� confounding variables had little impact



Breast Cancer and Inflammation� Breast cancer

� excess body weight causes 20% cancer death in

women >50 years of age in the U.S.

� obesity is a risk factor for breast cancer

� obese females have increased incidence of:

-metastatic cancer at time of diagnosis

-poorer outcome


� excess body weight causes 20% cancer death in

women >50 years of age in the U.S.

� obesity is a risk factor for breast cancer

� weight loss is associated with decreased risk in

post menopausal females

� weight gain is associated with increased risk in

pre-menopausal females � Pichard D; Maturitas; 2008; 60: 19-30.


� females post menopause

� high estrogen levels promote breast cancer

� adipose tissue is primary source of estrogen

� adipose tissue is primary source of TNF-α

� TNF-α stimulates estrogen synthesis

� TNF-α stimulates angiogenesis

� TNF-α is proinflammatory

� obese females have elevated estrogen

� obese females have higher risk of breast cancer

Breast Cancer and Inflammation

� Breast cancer and anti-inflammatory medications

� aspirin inhibits cyclooxygenase activity

� aspirin lowers prostaglandin levels

� lowering prostaglandins reduces aromatase activity

� lower level of estrogen observed

� Bardia A. Breast Cancer Res Treat 2001;26:149-155.

� theoretically lower estrogen should translate to

a lower rate of breast cancer

Breast Cancer and Inflammation

� Breast cancer and anti-inflammatory medication

� large, prospective cohort design

� Bardia A. Breast Cancer Res Treat 2001;26:149-155.

� 26,580 post menopausal females

� linked to cancer registry

� self-reported use of aspirin and NSAIDs


Breast Cancer and Inflammation� Breast cancer and anti-inflammatory medications

� 1,581 incident breast cancers reported

� aspirin users:

-lower incidence of breast cancers vs. non users

-relative risk 0.8

-dose response relationship observed

-aspirin use >6 times/week had relative risk 0.7

-results did not vary by tumor receptor status

-independent of hormone-receptor signaling pathway




� 1,581 incident breast cancers reported� Bardia A. Breast Cancer Res Treat 2001;26:149-155.

� non-aspirin NSAID users:

-no association with reduction in cancer incidence

-no association regardless of tumor receptor status


� statins have anti-inflammatory properties

� theoretically could reduce the risk of breast cancer

� statins have other anti-cancer properties

� inhibit tumor growth

� induce apoptosis

� inhibit angiogenesis

� induce regression of tumor metastasis� Hindler K. The Oncologist 2006;11:306-315.




� response to statins varies

� response varies by tumor type

� breast, colorectal and prostate cancers reduced

� response varies by type of statin used

� lipophillic responses > hydrophillic responses� Hindler K. The Oncologist 2006;11:306-315.





� statins reduce the incidence of breast cancer

� 72% reduction in incidence

� found with all statins� Cauley JA. J Womens Health 2003;12:749-756.





� statins reduce the incidence of breast cancer

� statins reduce the incidence of prostate cancer

� 56% reduction in incidence

� found with all statins� Shannon J. Am J Epidemiol 2005;162:318-325.

Breast Cancer and Inflammation� Breast cancer and physical activity

� Thune I. Med Sci Sports Exc 2001;33:S530-S550.

� review of 41 studies with 108,031 breast cancer cases


� both provide protection against breast cancer risk


� impact higher if activity was >4.5 MET

� impact higher with more MET-hours/week



Colon Cancer and Inflammation� Colorectal cancer and inflammation

� noninfectious chronic inflammation associated with:

increased incidence colorectal and lung cancer

� idiopathic inflammatory bowel disease

� colorectal cancer incidence increases over time

� ~25% colorectal cancer cases are familial

� most cases develop from adenomatous polyps

� 90% of colorectal cases in patients >50 years of age


� prospective case control study

� Gunter MJ. Cancer Res 2006;66:2483-2487.

� 29,133 Finnish male smokers

� 130 cases of colorectal cancer

� 260 case matched controls


� prospective case control study

� Gunter MJ. Cancer Res 2006;66:2483-2487.

� CRP 25% higher in subjects with colorectal cancer

� odds ratio was 2.9 in highest vs lowest CRP quartile

� “dose-response” relationship observed

� risk of colorectal cancer increased with higher CRP


� prospective cohort study

Il’yasova D. Cancer Epidemiol Biomarkers Prev 2005;14:2413-2418.

� 2438 male and female subjects 70-79 years of age

� 296 incident cancers

� 5.5 year follow-up


� inflammatory markers strongly associated with cancer death

� hazard ratio for cancer death with inflammatory markers

1.64 for elevated CRP

1.82 for elevated TNF-α

� elevated CRP & TNF-α strongly associated with

increased incidence of lung cancer deaths

� elevated CRP strongly associated with increased

incidence of colorectal and breast cancer deaths


� aspirin for prevention of colorectal cancer

� review of RCTs, case control studies and cohort studies� Dube C. Annals of Internal Medicine 2007;146:365-375.

� relative risk (RR) of colorectal cancer in aspirin users

� RCT – RR = 0.82

� case control studies – RR = 0.87

� cohort studies – RR = 0.72





� prospective study of 47,363 males � Chan AT. Gastroenterology 2008;134:21-28.





� prospective study of 47,363 males � Chan AT. Gastroenterology 2008;134:21-28.

� determined dose-response relationship

� 0.5 – 1.5 tablets/week – RR = 0.94

� 2.0 – 5.0 tablets/week – RR = 0.80

� 6.0 – 14.0 tablets/week – RR = 0.72

� >14.0 tables/week – RR = 0.30

� required 6-10 years of use to show effectiveness



� review of 5 RCTs (14,033 subjects)� Rothwell PM. Lancet 2010. (published online, October, 2010)

� primary and secondary prevention trials

� 30-1200 mg/day




� review of 5 RCTs (14,033 subjects)

� >75 mg/day resulted in decreased:

- cancer incidence

- cancer mortality

� benefit increased with duration of use

- required 5+ years of use



� 2 large cohort studies analyzed� Chan AT. New Eng J Med 2007;356:2131-2142.

� 82,911 females and 47,363 males

� 22 years of follow-up






� 423 (67%) had moderate to strong expression of COX-2

� 213 (33%) did not express COX-2

� COX-2 promotes inflammation & proliferation

over-expressed in many forms of cancers







� 423 (67%) had moderate to strong expression of COX-2

� 213 (33%) did not express COX-2

� 2 regular aspirin tablets/day vs COX-2 expression

� RR = 0.64 for tumors expressing COX-2

� RR = 0.96 for tumors not expressing COX-2


� statins for prevention of colorectal cancer

� 47% decrease in incidence of colorectal cancer� used statins >5 years

� all statins effective� Poynter JN. N Eng J Med 2005;352:2184-2192.

� Hindler K. The Oncologist 2006;11:306-315.

Colon Cancer and Inflammation� Impact of physical activity on colon cancer risk

� review of 48 studies 40,764 colon cancer cases� Thune I. Med Sci Sports Exc 2001;33:S530-S550.


� both provide protection against colon cancer risk


� impact higher if activity was >4.5 MET

� impact higher with more MET-hours/week

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