Colorectal Cancer (CRC)
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Colorectal Cancer (CRC). Epidemiology, Risk Factors Symptoms, Stages, Therapy 3) Molecular Biology & Pathology Screening. EPIDEMIOLOGY. one of the most common cancers in the world US: 4 th most common cancer (after lung, prostate, and breast cancers)

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Colorectal Cancer (CRC)

Epidemiology, Risk Factors

Symptoms, Stages, Therapy

3) Molecular Biology & Pathology

Screening


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EPIDEMIOLOGY

one of the most common cancers in the world

US: 4th most common cancer (after lung, prostate, and breast cancers)

2nd most common cause of cancer death (after lung cancer)

2001: 130,000 new cases of CRC 56,500 deaths caused by CRC



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Risk factors for CRC

Age

Adenomas, Polyps

Sedentary lifestyle, Diet, Obesity

Family History of CRC

Inflammatory Bowel Disease (IBD)

Hereditary Syndromes

(familial adenomatous polyposis (FAP))


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Development of CRC

result of interplay between environmental and

genetic factors

Central environmental factors:

diet and lifestyle

35% of all cancers are attributable to diet

50%-75% of CRC in the US may be preventable

through dietary modifications


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Dietary factors implicated in

colorectal carcinogenesis

consumption of red meat

animal and saturated fat

refined carbohydrates

alcohol

increased risk


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Dietary factors implicated in

colorectal carcinogenesis

dietary fiber

vegetables

fruits

antioxidant vitamins

calcium

folate (B Vitamin)

decreased risk


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Symptoms associated with CRC

rectal bleeding

change in bowel habits

obstruction

abdominal pain & mass

iron-deficiency anemia

weight loss

loss of appetite

night sweats

fever


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Staging of CRC

TNM system

Primary tumor (T)

Regional lymph nodes (N)

Distant metastasis (M)


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Staging of CRC

Dukes staging system

A Mucosa 80%

B Into or through M. propria 50%

C1 Into M. propria, + LN ! 40%

C2 Through M. propria, + LN! 12%

D distant metastatic spread <5%


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Sites of metastasis

Via blood

Via lymphatics

Per continuitatem

Liver

Lung

Brain

Bones

Lymph nodes

Abdominal wall

Nerves

Vessels


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Therapy

Surgical resection the only curative treatment

Likelihood of cure is greater when disease is

detected at early stage

Early detection and screening is of pivotal

importance


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Screening

What is screening?

a public health service in which members

of a defined population are examined to

identify those individuals who would benefit

from treatment

to benefit:

to reduce the risk of a disease or its

complications


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Types of Screening

fecal occult blood test (FOBT)

chemical test for blood in a stool sample.

annual screening by FOBT reduces colorectal cancer deaths by 33%

Flexible sigmoidoscopy can detect about 65%–75% of polyps and 40%–65% of colorectal cancers.

rectum and sigmoid colon are visually inspected


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Current Screening Guidelines

regular screening for all adults aged 50 years or

older is recommended

FOBT every year

flexible sigmoidoscopy every 5 years

total colon examination by colonoscopy

every 10 years or by barium enema every

5–10 years



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Molecular Biology & Pathology

CRCs arise from a series of histopathological and

molecular changes that transform normal epithelial cells

Intermediate step is the adenomatous polyp

Adenoma-Carcinoma-Sequence (Vogelstein & Kinzler)

Polyps occur universally in FAP,

but FAP accounts for only 1% of CRCs

Adenomatous Polyps in general population:

33% at age 50

70% at age 70



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MMR defects give rise to TGF-beta RII mutations, which prevent

cell cycle inhibitor (p15) and protease inhibitor (PAI-1) expression


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-1 prevent

COX

-2

Cyclooxygenase (COX)

cell membrane lipids

Phospholipase A2

arachidonic acid (aa)

aspirin

ibuprofen

indomethacin

prostaglandins


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COX and CRC prevent

COX-2 not detectable in normal colon but in 90% of

CRCs and 40% of adenomas

Animal models: COX-inhibition results in 50%

reduction of carcinomas and >90% reduction of

adenomas

Epidemiological studies: patients regularly taking

aspirin showed 40-50% reduced risk of CRC

But: minimal effective dose and duration of treatment

have not yet been determined


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Microenvironment prevent

Control mechanisms of mitosis & apotosis lost

High metabolic rates, glycolysis (Warburg),

high lactic acid output

Result: hostile microenvironmental conditions

(Hypoxia, low pH, low glucose,

free oxygen radicals)


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Hypoxia prevent

Central factor for tumor growth and spread

Correlated to tumor hypoxia:

Therapy outcome & probablility of metastasis

Hypoxia exerts selective pressure

genetic instability results in survival of cells

better adapted to lack of oxygen

Evolution of highly aggressive tumor cells


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CRC and the Internet prevent

“Sign up to receive an e-mail

message reminding you to have

your colon screened at

www.wewantthebestforyou.com”


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Summary prevent

CRC is a leading cause of death

Early stages are detectable

Screening can prevent CRC

Katie Couric: http://www.nccra.com/about/videos.htm


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