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))

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 increased risk

refined carbohydrates
alcohol

Dietary factors implicated in colorectal carcinogenesis

dietary fiber vegetables fruits

decreased risk
antioxidant vitamins calcium folate (B Vitamin)

Symptoms associated with CRC

weight loss

rectal bleeding change in bowel habits obstruction

loss of appetite
night sweats fever

abdominal pain & mass

iron-deficiency anemia

Staging of CRC

TNM system Primary tumor (T) Regional lymph nodes (N)

Distant metastasis (M)

Staging of CRC
Dukes staging system A B C1 C2 D Mucosa Into or through M. propria Into M. propria, + LN ! Through M. propria, + LN! distant metastatic spread 80% 50% 40% 12% <5%

Sites of metastasis
Via blood

Via lymphatics
Liver Lymph nodes Per continuitatem

Lung
Brain Bones

Abdominal wall
Nerves Vessels

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

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 510 years

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 Phospholipase A2 arachidonic acid (aa) COX -1 -2 aspirin ibuprofen indomethacin

prostaglandins

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

CRC and the Internet

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

Summary

CRC is a leading cause of death Early stages are detectable Screening can prevent CRC
Katie Couric: http://www.nccra.com/about/videos.htm