Biology 115, Lecture 22: Cancer

Spring, 1999 T. Irving; revised April 2000 A.Howard

Goals of this section:

Students should be able to:

• State and explain 5 characteristics of cancer cells
• Describe the development of cancer in terms of three stages
• Discuss three factors that contribute to the development of cancer
• Name two types of genes whose mutation is necessary to the development of cancer
• Tell how cancers are classified
• Give examples of routine screening tests, tumor marker tests, and proposed oncogene tests to diagnose cancer
• Describe 3 standard ways in which cancer is currently being treated
• List ways to prevent cancer from developing

Characteristics of cancer cells

• Cancer cells lack differentiation
• Cancer cells are immortal i.e. no limit to number of times can divide
• Do not exhibit contact inhibition
• Reduced need for growth factors (hormones) to grow
• When cancer occurs, it seems to be the result of a number of changes within a single cell
• Changes probably occur over a period of time

Benign and malignant tumors

• Changes in properties at the cellular level which are associated with cancer fit into two groups
  1. the cell multiplies continuously and/or at a higher than normal rate
  2. daughter cells move a round the body (metastasis) to begin new tumors.
• Cells with just change 1 can form a "benign" or non-cancerous tumor.
• These are frequently encapsulated and do not invade other tissues
• Cell with change 1 followed by change 2 is cancerous, a tumor will grow, metastasize and eventually kill the host.
• These cells are called malignant

Oncogenes/proto-oncogenes

• Proto-oncogenes are a group of possibly ~100 genes which can be involved in the onset of cancer
• Proto-oncogenes are genes that normally perform essential functions for the body
• Proto-oncogenes encode various functions:
• Some function by "turning on" other genes
• Some function in controlling cell growth and development
• often in response to certain hormones
• Some function to inhibit growth of cancer cells ("tumor suppressor genes")
• Others have as yet unknown functions
• Proto-oncogenes may change from essential genes to dangerous, harmful genes which contribute to the onset of cancer
• They are now said to be oncogenes ("cancer genes")

Processes that changes proto-oncogenes to oncogenes may include:

• Simple mutations
  proteins with altered structure and function
• Simple mutations nearby but not within gene sequence
  protein not altered, but may be synthesize too much, too little or at the wrong time
  • i.e. messes up regulation
  • Insertion of a retrovirus DNA copy nearby may mess up regulation
  • Variation: Gene picked up by a retrovirus & is picked up by retroviral RNA
  • Insertion of DNA copy of modified retrovirus into DNA of host cell can lead to altered protein regulation
• Amplification
  • Can happen if a gene is reproduced abnormally so that it is no longer 2 copies per cell but now many copies per cell
  • Too much protein will be made (lung cancer)
• Chromosomal irregularities:
  • Parts of a chromosome containing all or part of an oncogenes may break off and attach to a different chromosome.
  • Cause too much protein to be made and /or a protein with altered structure and function
  • Loss of part of a chromosome will result in loss of production of proteins
  • Alterations of gene activity without actually altering the gene
  • Any changes that may effect one gene may apply to more than one proto-oncogene within one cell

Carcinogens

• Many carcinogens have already been described.
• Organic chemicals in environment, food components, radiation
• All act as mutagens i.e. change proto-oncogenes to oncogenes
• Some substances act as promoters e.g. estrogen in endometrial cancer, dietary fat in colon cancer and possibly breast cancer.

Viruses

• Oncogenes may be supplied by infection with DNA viruses e.g. hepatitis B (liver), Human papilloma virus (cervix), Epstein-Barr virus in Burkitt's lymphoma and nasopharyngeal cancers
• Retrovirus HTLV causes adult T-cell leukemia in humans
• Proteins affected include those which are involved in cell growth, turning on other genes etc.
• Resulting changes in structure, quantities or time of appearance of gene products may result in profound changes in properties of cells

How do changes in proto-oncogenes to oncogenes occur?

Mutations, amplification etc. ultimately are caused by

1. damage to DNA by radiation or chemical mutagens
2. infection by cancer causing viruses
3. chemicals which alter gene activity without damaging DNA
4. alterations in proto-oncogenes can be inherited from parents.
   • Heredity seems to play a role in some breast, lung, and colon cancers.
   • Some childhood cancers due to inheritance of a dominant gene

Cancer causing agent	DNA damage to proto-oncogene	Alterations at the protein level	Effects on cell
radiation	chromosome breaks/deletions	Too much protein
Inheritance			uncontrolled rapid growth
Chemical mutagens	increased gene number mutations	Altered protein: Too little (or no) protein	Metastasis
Certain viruses	Insertion of viral DNA into host DNA; host DNA pickup by virus & reinsert host DNA	Protein synthesized inappropriate time
Tumor promoters (certain chemicals)	None	Normal protein synthesis too much, too little, wrong time

Lung Cancer

1. Chemical mutagens from cigarette smoke
2. Cause amplification of human proto-oncogene c-myc (up to 70-fold)
3. Results in over-expression of c-myc protein up to 50-fold normal
4. Since c-myc normally "turns-on" other genes, cause "turning-on" of wrong genes or right genes at wrong time
5. Contributes to lung cancer

Transformation requires more than one gene alteration

• For a normal cell to become completely cancerous ("transformed")
• believed to need alterations in about 5 proto-oncogenes
• Includes activation of 3-4 genes like c-myc which act in a positive way to cause cancer
• And an inactivation of 2-3 genes which normally act to suppress cancer-like growth
• Since each cell has 2 copies of each suppressor gene
• need two "hits" one per copy to knock out suppressor genes function completely
• You only need one of two positive-acting genes to get an effect
• This means that you would need probably ~10 individual gene alterations to make a cell change all the way from normal to cancerous

Cancer develops in three clinical stages:
Initiation, Promotion, Progression

• 1 gene change? ~10 gene changes?
• No outward signs metastasis & cancer
  • It generally takes a long time of continuous exposure to mutagens/tumor promoters e.g. 20-30 years of cigarette smoking to produce a cancerous cell
  • Presumably you could arrest the progression form normal to cancerous at some stage short of cancer by removing the source of the mutagen/promoter
  • Its clear that one can increase chance of avoiding lung cancer by quitting before he or she is diagnosed as having cancer

Oncogenes and Metastasis

• Cancer cells produced by the body come from the body so will not be recognized as foreign in the same way as an invading virus
• Cancer cells do, however, produce surface molecules (antigens) which do allow the body's immune system to recognize them as foreign and so subject to destruction by killer T-cells
• Recall that antigens are presented to the immune system attached to Major Histocompatibility Complex (MHC) proteins on cell surfaces
• MHC devoid of foreign antigens is the "self" signal for a cell wrt its own immune system
• Two types MHC's, class I and class II
• Only class I involved in killer cell interactions
• Allow "docking" of killer cells which recognize and bind particular MHC-antigen combinations

Two types class I Major Histocompatibility Complex proteins: H-2K and H-2D

• Most cells have various amount H-2K and H-2D on their surfaces
• The higher the ratio of H-2D/H-2K for a cancer cell
  1. the less the immune response is to such cells by killer T-cells
  2. the more metastatic i.e. dangerous the cancer cell
• In metastasis, cells from original ("primary") tumor:
  leave the tumor ----> penetrate blood vessel walls
  ---->circulate in the bloodstream ------>escape through blood vessel walls
  -----> start "secondary" tumors in new locations
• Ones with a high H-2D/H-2K ratio are relatively invisible to killer T-cells during their time in the bloodstream so will be highly metastatic
• Ones with a low ratio will be picked off by killer cells so are less metastatic

Immune system and cancer

• In general, people with compromised immune systems will be more susceptible to cancer
• People with AIDS often get Karposi's sarcoma (a cancer of the blood vessels)
• Transplant patients on immunosuppressant drugs are more apt to develop lymphomas
• Immune system weakens as we age, perhaps explaining part of increased incidence of cancer with age

Types of cancers

• Carcinomas are cancers of epithelial cells, skin, breast, liver, pancreas, intestine, lung, prostate, thyroid
• Sarcomas are cancers of muscle and fibrous connective tissues
• Leukemias are cancers of the blood
• Lymphomas are tumors of lymph tissue

Diagnosis of cancer

• C - Change in bowel or bladder habits
• A - A sore that doesn't heal
• U - Unusual bleeding or discharge
• T - Thickening in tissue e.g. breast
• I - Indigestion or difficulty in swallowing
• O - Obvious change in a wart or mole
• N -Nagging cough or hoarseness

Any of these symptoms should be cause for concern, but by the time noticeable symptoms are detected it may be too late for effective treatment

Screening

• Need easy to do, inexpensive, fairly accurate methods
• Only Pap smear (cervical cancer) qualifies at present
• Breast and testicular self-examination
• Mammography
• Digital rectal examination, colonoscopy, stool blood tests
• Tumor Marker tests
  • Blood tests can sometimes detect tumor antigens/antibodies
  • Often used to detect relapses
  • Not generally accurate enough yet for screening
• Oncogene tests
  • the ras oncogene can be detected in stools samples
  • Unfortunately not all oncogenes can be detected
  • May soon be possible to screen for breast cancer oncogenes

Confirming Presence of cancer

• Biopsies
• CAT scans
• MRI imaging
• Ultrasound
• Autoradiography

Treatment of Cancer

Standard Techniques:

• Surgery:
  remove primary tumor
• Chemotherapy:
  Damage DNA or mess up DNA synthesis in rapidly dividing cells
• Radiation treatment:
  Damage DNA in rapidly dividing cells

Emerging and limited applicability treatments

• Bone marrow transplants (leukemias)
• Antihormone therapy (e.g.block estrogen receptors)
• Monoclonal antibodies (combine radioisotope or specific chemotherapeutic drug)
• Antimetastatic drugs
• "Cancer vaccines"
  • Use a single tumor antigen or a mixture of tumor antigens to inject into cancer patients
  • Hope is that the large influx of antigens or presentation of them in a certain way will boost immune response to cancer cells
  • Cancer cells will carry same antigens as those in the vaccine

Towards more specific anti-cancer drugs

As more is known about genesis of specific cancers, we can start thinking of ways to specifically counteract effects of specific alterations in specific oncogenes that are known to result in that particular cancer

Avoiding Cancer

• Don't smoke
• Don't sunbathe (or least use an effective sunscreen!)
• Avoid alcohol
• Avoid radiation
• Be tested for cancer
• Protect yourself from occupational hazards
• Watch your diet

Dietary Guidelines for avoiding cancer

• Don't get obese
• Lower total fat intake
• Eat high fiber foods
• Increase consumption foods with vitamin A & C (antioxidants)
• Reduce consumption of salt-cured, smoked foods, nitrite-cured foods
• Eat cabbage family vegetables
• Moderate consumption of alcohol:
  Drinking AND smoking particularly bad news