LECTURE 23   The Genetic Basis of Cancer

I.  Instruction

    What is Cancer?

            A diverse class of diseases marked by abnormal cell proliferation.

    A.  Characteristics of Cancer cells.

        1.  Unlimited cell division

                i.e.  Hela cells...

        2.  Cancer characteristics are passed to progeny

Cancer-family syndromes:  Family members seem to inherit a nonspecific predisposition toward tumors of various types.

        3.  Cancer cells can metastasize

Tumor:  a mass of abnormal cells within an otherwise normal tissue.

Benign tumor:  The abnormal cells remain at the original site.

Malignant tumor:  Tumor cells not only continue to proliferate, but also spread beyond their original site and invade nearby tissues by a process called metastasis.

Metastasis:  The spread of cancer cells beyond their original site through blood or lymph vessels and start new centers of uncontrolled cell growth wherever they go, bring about unusual numbers of chromosomes cease to function in any constructive way, and they also lose their attachments to neighboring cells.

        B.  Forms of Cancer

1.  Sarcomas:  solid tumors of muscles, bone, and cartilage that arise from the embryological mesoderm.; they represent 1.9% of all cancers.

2.  Leukemias:  are diseases of the bone marrow that cause excessive production of leukocytes (white blood cells),  which originate in the bone marrow; they represent 3.4% of all cancers.

3.  Lymphomas:  are diseases of the lymph nodes and spleen that cause excessive production of lymphocytes, which originate in the lymph nodes and spleen; representing 5.4% of all cancers.

4.  Carcinoma:  tumors arising from epithelial tissue, such as glands, breast, skin, and linings of the urogenital, digestive, and respiratory systems, representing 89.3% of all cancers.

II.  Cancer Genes

 A.  Cancer cells have escaped from cell-cycle controls.

 B.  Tumor Suppresser Genes

Proteins encoded by these genes help prevent uncontrolled cell growth.  These genes are also called

        1.  BRCA 1 and BRCA 2  -------  Breast Cancer

Both genes are tumor suppresser genes, their wild-type alleles protect against breast cancer.  Mutations
in either gene increase the risk of developing cancer.  Mutant alleles are recessive.

        2.  p53:    tumor-suppressor gene, its protein product has a 53,000 dalton molecular weight

p53 uses three ways to prevent a cell from passing an mutations due to DNA damage to other healthy cells.

a:  Activate a gene, called p21 to halt the cell cycle, allow time for the cell to repair the DNA.

b:  Turn on genes directly involved in DNA repair.

c:  When DNA damage is irrepairable, p53 activates "suicide" genes, whose protein products cause death

      of the damaged cell by a process called "apoptosis" to protect other healthy cells.

    C.  Oncogenes

                Onco ~~~  "Tumor"  in Greek.

                Oncogenes:  Cancer causing genes.

Proto-oncogenes:  Normal cellular genes, code for proteins that stimulate normal cell growth and division.

        1.  Activation of proto-oncogenes:

            Proto-oncogenes can be induced in three different ways to become oncogenes.

a.  Translocation:  a proto-oncogenes can be activated if it is moved to a region with a strong promoter or enhance.

e.g.  Burkitt's lymphoma:  Proto-oncogene  c-mys is translocated from chromosome 8 to chromosome 14 near a fragile site (has tendency to break), which is contiguous with the immunoglobulin IgM constant gene.  This gene is very active in lymphocytes.  Hence, c-myc gene is now transcribed at a much higher rate than normal, resulting in cellular transformation, means transforming normal cell to cancerous cell.

b.  Gene amplification:  a proto-oncogene can be activated if it is amplified.

e.g.  c-ras and c-abl or genes on trisomic choromosomes are related to transformation.

c.  Point mutation:  a point mutation can cause a proto-oncogene to transform its host cell

e.g.  a  c-ras proto-oncogene was converted to an oncogene, when one genetic code GGC (coding for glycine) was converted to GTC (coding for Valine).

2.  Examples:

a)  ras gene:  The product of the ras gene, ras protein is a G-protein that relays a growth signal from a growth-factor receptor on the plasma membrane to a cascade of protein kinases (recall my lecture on signal transduction?).  The cellular response at the end of the pathway is the synthesis of a protein that stimulate the cell cycle.
Many ras oncogenes have a point mutation that leads to a hyperactive version of the Ras protein, which
leads to excessive cell division------- cancerous cell.

b)  bcr/c-abl  (Philadelphia chromosome)  Chronic myelogenous leukemia  (CML)

A type of cancer caused by overproduction of certain white blood cells.  The leukemic cells of almost all
patients with this disease have a reciprocal translocation between chromosomes 9 and 22.  The breakpoint
in  chromosome 9 occurs within an intron of a proto-oncogene called c-abl;  the breakpoint in chromosome 22 occurs within an intron of the bcr gene.  After the translocation, parts of the two genes are adjacent to one another.  During transcription, the RNA producing machinery, run these two genes together, creating a long RNA that after splicing is translocated into a fused protein, which somehow releases the normal controls on cell division, leading to overproduction of certain white blood cells----- leukemia.

D.  Multiple mutations  --- colon cancer

More than one somatic mutation is generally needed to produce all the changes characteristic of a full-fledged cancer cell.  Like most cancer, colorectal cancer develops gradually.  The development of a malignant tumor is paralleled by a gradual accumulation of mutations that activate oncogenes and knock out tumor suppresser genes.

III.  Telomeres and Cancer

Telomerase:  An enzyme prevents the erosion of the ends of the chromosomes.

In many malignant tumors, the gene for telomerase is activated, thus removing a natural limit on the number of times the cell can divide  ---- leads to uncontrolled division  --- growth   ---- tumor.

IV.  Defenses For Cancer

    A.  Chemotherapy and Radiation Therapy

Chemotherapy:  Use of anti-cancer drugs to treat cancerous cells.  Chemotherapy reaches all parts of the body, not just cancer cells.

Common side effects:  nausea & vomiting, hair loss, anemia, reduced ability of blood to clot, mouth sores, and increased likelihood of developing infections. Most side effects stop when treatment finishes.

Chemotherapy is not effective to prostate cancer, and most late advanced stage of cancer.

Radiation Therapy:  Effectively treats cancer by using high-energy rays to pinpoint and destroy cancerous cells in human body.

Site effects:  Red, itching and peeling skin in treatment area, fatigue, loss of appetite, and hair loss in the treatment area.  Most side effects stop when treatment finishes.

B.  Immunotherapy:

A therapeutic approach to treat disease by stimulating or enhancing the immune response against the disease.

1.  Interferons:  Proteins produced by the body with the specific purpose of regulating cell functions.

Interferons are produced in the laboratory in large quantities and are sometimes used in the treatment of certain cancers, and they can also be secreted by virus-infected cells to inhibit viral reproduction.

2.  Immunotoxins:

Immunotoxins are hybrid proteins consisting of an antibody and a toxin.  It is the classical "magic bullet" approach to treat cancer, first suggested by Dr. Paul Enrlich nearly a century ago.  Genetic recombinant immunotoxins can be used to treat patients with T-cell leukemia and lymphoma.  The antibody part of the immunotoxins locate the cancerous cell, and the toxin part of the immunotoxin kills the cancerous cell.

3.  Interleukin:  A hormone-like substance produced by the body (certain blood cells, specifically) that stimulates the growth of blood cells, which is important to the body's immune system.

C.  Gene Therapy

Gene therapy is an experimental medical intervention that involves modifying the genetic material of living cells to fight disease.

i.e.   1.  supply cells with healthy copies of missing or altered genes.

            treated disease:  cystic fibrosis and hemophilia

        2.  change how a cell functions by stimulating immune system cells to attack cancer cells or by
             introducing resistance to human immunodeficiency virus (HIV), the virus causes AIDS.

V.  Preventive Maintenance

A.  Do not smoke.

B.  Avoid excess exposure to the sun; always wear sun screen with an SPF of 30, even on overcast days.
Please answer the following questions:

                What is sun tan?

                What is sun burn?

                What is SPF 30?

C.  Avoid smoke-cured meats, which contains nitrates, a potent carcinogen.

D.  Eat plenty of fiber from veggie and fruit.

Because veggie and fruits contain many salicylic acid, which reduce inflammation, therefore reduce the risk of heart disease and bowel cancer.

----- "Journal of Clinical Pathology"  June 27, 2001, London (Reuters)

E.  Eat food containing vitamins A, C, and E, which protect against some kinds of cancer.  But, the use of high dose of antioxidants such as Vitamin C might also have a prooxidant effect.  Vitamin C can induce genotoxin formation, if generated in significant amount, these genotoxins can generate cancer-causing mutations.

-----  "Science", Volume 292, Page 2083.  June 15, 2001.

F.  Annual Mammograms.

VI.  A newly developed so called wonder drug to combat cancer:

 Stop the Madness: How IMC-C225 Halts the Spread of Cancer

1. Cells normally divide to produce more cells only as the body needs them. This process is controlled in part by "oncogenes"--genes that direct cell growth--and by tumor-suppressor genes, which are in charge of cell death. Some cancers occur when a defective oncogene, operating in the nucleus of a cell, sends out a flood of protein signals that cause the cell to embark on a course of rapid cell division. The resulting tumor cells proliferate--urged on by growth signals in the blood stream that attach to the surface of the cells. The tumor-suppressor genes that would normally stop this proliferation either can't keep up or
break down.

2. One of the most important cellular signals produced by the oncogene is called epidermal growth factor (EGF).  Normally in short supply, it is found in excess amounts in up to half of all types of malignant tumors. While the surface of a normal cell may have about 10,000 EGF receptors, cancer cells can have a million or more. EGF binds to its receptors on the surface of a cell and then triggers a cascade of enzymes inside that play an important role in keeping the tumor alive, well-nourished, and spreading.

3. IMC-C225 is an antibody developed in the lab that identifies and locks onto the receptors of a cancer cell before EGF can reach it, in essence gumming up the trigger. The result: Growth enzymes are not activated, and the cell eventually stops dividing.

Business Week/July 9, 2001