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: 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

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 nodesAbdominal wall

Nerves

Vessels

Via lymphaticsPer continuitatem

Therapy

Surgical resection the only curative treatment

Likelihood of cure is greater when disease isdetected at early stage

Early detection and screening is of pivotalimportance

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 itscomplications

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 5–10 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 5070% at age 70

Mutations in the APC pathway cause increased proliferation

MMR defects give rise to TGF-beta RII mutations, which preventcell cycle inhibitor (p15) and protease inhibitor (PAI-1) expression

Cyclooxygenase (COX)

cell membrane lipids

arachidonic acid (aa)

prostaglandins

Phospholipase A2

COX-1

-2

aspirinibuprofenindomethacin

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 treatmenthave 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 pressuregenetic instability results in survival of cellsbetter adapted to lack of oxygen

Evolution of highly aggressive tumor cells

“Sign up to receive an e-mail message reminding you to have your colon screened at www.wewantthebestforyou.com”

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