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



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

Risk factors for CRC


Adenomas, Polyps

Sedentary lifestyle, Diet, Obesity

Family History of CRC

Inflammatory Bowel Disease (IBD)

Hereditary Syndromes

(familial adenomatous polyposis (FAP))

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

Dietary factors implicated in

colorectal carcinogenesis

consumption of red meat

animal and saturated fat

refined carbohydrates


increased risk

Dietary factors implicated in

colorectal carcinogenesis

dietary fiber



antioxidant vitamins


folate (B Vitamin)

decreased risk

Symptoms associated with CRC

rectal bleeding

change in bowel habits


abdominal pain & mass

iron-deficiency anemia

weight loss

loss of appetite

night sweats


Staging of CRC

TNM system

Primary tumor (T)

Regional lymph nodes (N)

Distant metastasis (M)

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%

Sites of metastasis

Via blood

Via lymphatics

Per continuitatem





Lymph nodes

Abdominal wall




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



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


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

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

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

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

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

-1 prevent



Cyclooxygenase (COX)

cell membrane lipids

Phospholipase A2

arachidonic acid (aa)





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


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

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)

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

CRC and the Internet prevent

“Sign up to receive an e-mail

message reminding you to have

your colon screened at”

Summary prevent

CRC is a leading cause of death

Early stages are detectable

Screening can prevent CRC

Katie Couric: