The biology of cancer

I.  Introduction

-  one in three people in the U.S. will develop cancer at some point in his/her life

• 1,200,000 people diagnosed in 1999
• other two likely to have experienced it indirectly

-  cancer kills one in four people in the U.S.

• 1,500 cancer deaths every day
• half million deaths/year

-  cancer death rate -- 3% drop from 1990 - 95

II.  The nature of cancer

-  a family of 100 different diseases -- named for organ in which it arises

-  common characteristic -- uncontrolled cell division

-  caused by tumors or abnormal growth of cells -- neoplasm

A.  benign tumors

• abnormal mass of tissue that usually remains at site where it forms
  • surrounded by CT capsule
  • cells do not invade surrounding tissue
  • cells grow slowly
  • cells normally differentiated
• does not threaten health -- easily removed surgically
  • unless they press on nearby tissues and interfere with their functioning

B.  malignant tumors

• tumors that invade surrounding tissues and spread to multiple locations throughout body
• cells on way to becoming cancerous different from normal cells -- dysplasia
  • structural changes
    • ragged edges, cytoskeleton shrinks
    • large nuclei -- increased amount of DNA
    • proteins in plasma membrane altered/lost 
    • cells form disorganized clump -- increased incidence of division
• tumor reaches critical mass -- one million cells (1-2 mm diameter)
  • cells in center can't get sufficient supplies or adequate waste removal
  • tumor begins to secrete factors that cause blood vessels to invade -- angiogenesis
  • critical transition point
    • cells have supply lines
    • cells have escape routes to enter blood, spread, and begin to grow in new location -- metastasize
• catch cancer before critical mass -- removed by surgery
• if metastasizing occurred -- chemotherapy, radiation
• original tumor rarely cause of death -- metastases responsible for 90% of deaths of people with cancer
• circulatory/lymphatic pathways often explain patterns of metastases
  • cancer cells leaving tumor often implant in next capillary bed they encounter
    • usually lungs
    • in case of colon cancer -- liver
• cancer cells kill by interfering with ability of body cells to function normally

III.  Etiology of cancer

• loss of restraints on cell division
• escape from programmed cell death

A.  Loss of restraints on cell division

-  first step in development of cancer

-  answer to why this happens lies in genes -- cancer a genetic disorder

1.  Genes regulating cell division -- proto-oncogenes and tumor-suppressor genes

• proto-oncogenes

-  normal genes that regulate cell growth and development; encode:

• growth factors
• cell adhesion
• signals for cell division

• tumor-suppressor genes; encode:

- proteins that turn off cell division

- thus combined activity of both allows control of cell division -- normal growth and development

a.  Mutation in proto-oncogene forms an oncogene

-  speeds up rate of cell division

- roles in pancreatic, colon, some forms of lung cancer, leukemia, most deadly forms of breast and ovarian cancer

b.  Mutation in tumor suppressor gene (TSG)

- promotes cancer by taking breaks off cell division

- p53 -- product of p53 regulates another gene that produces a protein that keeps cell in nondividing state

• p53 mutation -- gene product no longer expressed
• p53 mutation -- culprit in colon, breast, lung, brain, bladder cancer

c. Damage must occur in at least two genes before cancer occurs

-  colon cells must accumulate damage to one oncogene and three TSGs before becoming cancerous

-  explains why can inherit a predisposition to certain cancers -- inherit one of more mutations

-  explains why immune system screens and kills many cells that have become cancerous -- surface cell markers

2.  Limited lifespan

-  telomeres -  cells have another safeguard against unrestrained cell division -- a mechanism that limits how many times a cell can divide

-  telomeres -- pieces of DNA at tips of chromosomes

• protect chromosomes during division
• telomeres
• enzyme that makes telomeres -- telomerase
  • not present after embryonic development
  • each chromosome has fixed amount of telomeres

-  each time cell divides, a piece of telomere in each chromosome shaved off

• when telomeres gone, chromosome tip no longer protected
• signal for cell to stop dividing

-  cancer cell produce telomerase -- fountain of youth

B.  Escape from programmed cell death - apoptosis

-  when genes that regulate cell division become faulty

• backup system activated
• biochemical suicide signal

-  mutation --> faulty  DNA --> detected by p53 gene product --> prevents replication of DNA until repair --> if damaged beyond repair p53 triggers events that lead to apoptosis

• p53 -- guardian of genome

-  if cell cancerous and p53 faulty due to mutation:  apoptosis will not be triggered

-  hard to kill cancer cells by radiation, chemotherapy -- relying on p53 to detect damage and trigger cell death

IV.  Pathogenesis of cancer

-  ability to attract a blood supply

• tumor reaches critical mass
• site of potential therapy

-  breakdown of cell adhesion

• unlike other cells cancer cells can travel throughout body
• CAM (cell adhesion molecules)
  • allow cells to attach to substrate
  • cell need to attach to function
• cancer cells produce enzymes that destroy CAMs
• oncogenes produce protein that send message to nucleus that cell is properly anchored

V.  Causes of cancer

-  how do changes in genes that lead to cancer come about?

A.  Viruses

• insert their DNA/RNA into host cell chromosome
• some viral genes are oncogenes
• insert next to proto-oncogene

B. Chemical carcinogens

-  environmental agents that foster the development of cancer

1.  binds DNA and causes damage

• does not bind DNA randomly
• some carcinogens associated with mutations of specific genes

-  examples of carcinogens

• many found in tobacco smoke -- most lethal mix known
  • influences more than just lung
  • responsible for 30% of all cancer deaths in US
  • responsible for 60% of all cancer deaths outside US
• chemical in herbicides, pesticides

2.  contribute to development of cancer by stimulating cell division rather than by causing mutation

-  cancerous cell already formed, extra stimulus for division

• estrogen influences on breast cancer, uterine cancer
  • sustained levels of estrogen linked with breast cancer
• estrogen does not promote uterine/breast cancer when taken in combination with progesterone

3.  radiation -- damages DNA

• UV light from sun
• radon -- decays into solid particles
  • sticks on dust
  • inhaled -- direct radiation to lung cells
  • 2% of total cancer deaths