Colorectal Cancer (CRC)

1) Epidemiology, Risk Factors

2) Symptoms, Stages, Therapy

3) Molecular Biology & Pathology

4) Screening
EPIDEMIOLOGY
one of the most common cancers in the world

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

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


2001: 130,000 new cases of CRC
56,500 deaths caused by CRC
Typical sites of incidence and sympoms of colon cancer
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))
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
Development of CRC
consumption of red meat

animal and saturated fat

refined carbohydrates

alcohol
increased risk
Dietary factors implicated in
colorectal carcinogenesis
dietary fiber

vegetables

fruits

antioxidant vitamins

calcium

folate (B Vitamin)
decreased risk
Dietary factors implicated in
colorectal carcinogenesis
Symptoms associated with CRC
weight loss

loss of appetite

night sweats

fever
rectal bleeding

change in bowel habits

obstruction

abdominal pain & mass

iron-deficiency anemia
TNM system

Primary tumor (T)

Regional lymph nodes (N)

Distant metastasis (M)

Staging of CRC
Staging of CRC
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%
Dukes staging system
Sites of metastasis
Liver

Lung

Brain

Bones
Via blood
Lymph nodes
Abdominal wall

Nerves

Vessels
Via lymphatics
Per continuitatem
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
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

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
Types of Screening
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
510 years

Current Screening Guidelines
Changes resulting in colon cancer
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
Mutations in the APC pathway cause increased proliferation
MMR defects give rise to TGF-beta RII mutations, which prevent
cell cycle inhibitor (p15) and protease inhibitor (PAI-1) expression
Cyclooxygenase (COX)
cell membrane lipids
arachidonic acid (aa)
prostaglandins
Phospholipase A
2

COX
-1
-2
aspirin
ibuprofen
indomethacin
COX and CRC
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
Microenvironment
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
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
CRC is a leading cause of death

Early stages are detectable

Screening can prevent CRC
Katie Couric: http://www.nccra.com/about/videos.htm
Summary