WHAT IS CANCER? Cancer is the uncontrolled division of cells. WHAT CAUSES CANCER? The accumulation of multiple mutations transform a normal cell into a cancer cell. The average cancer cell contains between six and eight different mutations. These mutations affect genes that control the cell cycle genes that control cell death genes that allow the cell to obtain nutrients and migrate through out the body. Cancer is more prevalent as you age because more time has passed for mutations to accumulate. The Effect of Age on all Cancer Rates in Males and Females
HOW ARE CANCER CELLS DIFFERENT FROM NORMAL CELLS? 1. They ignore signals that regulate the cell cycle. 2. They can divide forever. 3. They ignore apoptosis signals. 4. They are capable of angiogenesis. 5. They are capable of metastasis. CANCER CELLS IGNORE THE SIGNALS THAT REGULATE THE CELL CYCLE The cell cycle is controlled by the products of two classes of genes, proto-oncogenes and tumor suppressor genes. Normally the expression of these genes is balanced. 1. Proto-oncogenes encode proteins that promote cell division (These proteins act like the gas pedal on a car. They say "go".) 2. Tumor-suppressor genes encode proteins that inhibit cell division (These proteins act like the brakes on a car. They say "stop".) In cancer cells, the proto-oncogene(s) and tumor suppressor gene(s) are mutated. This is like the gas pedal in the car being stuck in the down position and the brakes of the car not functioning. The cell divides when it shouldn't.
CANCER CELLS DO NOT UNDERGO APOPTOSIS WHAT IS APOPTOSIS? As you read this, millions of your cells are dying to ensure your survival. The health of multicellular organisms depends not only on the ability of cells to grow and divide, but also self-destruct when they are no longer needed or become damaged. This programmed cell death is known as apoptosis. http://www.bio.miami.edu/~cmallery/255/255hist/mcb1.19.apoptosis.jpg
WHAT HAPPENS DURING APOPTOSIS? 1. Intracellular material is degraded. 2. The cell breaks into fragments surrounded by membrane. 3. The membrane is "tagged" with a "destroy me" signal that attracts macrophages which engulf the fragments and complete the destruction. http://219.221.200.61/ywwy/zbsw(e)/edetail13.htm WHY DO CELLS UNDERGO APOPTOSIS? 1. The cell has been damaged beyond repair. 2. The cell has outlived its usefulness. EX: Shut down of cytotoxic T-cells during the
immune response occurs by apoptosis Recall that during the immune response, Helper T-cells stimulate the proliferation of B-cells and T-cells allowing for the production of antibodies and cytotoxic T- cells. The cytotoxic T-cells destroy infected body cells. When all traces of the pathogen have been removed from the body, suppressor T-cells shut the cellmediated and humoral responses off. However, millions of cytotoxic T-cells are still circulating looking for infected body cells. The body removes these cells by programmed apoptosis and subsequent by ingestion by macrophages thus leaving only memory B and T-cells behind from the encounter. 3. The cell has become senescent (shows deterioration associated with aging). 4. The death of the cell is necessary for the organism to reach its final form during embryonic development. EX: Formation of digits in humans By the fourth week of human embryonic development, limb buds appear as outpockets from the body wall. By six-weeks, the terminal (end) portion of the limb buds flatten to form handplates and footplates (figure A). Fortyeight days after fertilization, select cells within the interdigital spaces of the hand and footplates undergo apoptosis allowing the digits to separate (figure B). Digit
separation is complete by fifty-six days after fertilization (figure C). Langman's Medical Embryology 7th Edition T.W Sandler 1995 If the cells in the interdigital space fail to undergo apoptosis, the fetus will be born with webbed hands and/or webbed feet. The medical term for this condition is syndactyly. There are many degrees of syndactlyl ranging
from complete (no digit separation), to incomplete (partial digit separation). Sometimes there is only a thin layer of skin remaining in the interdigital space. http://newborns.stanford.edu/images/syndactylydaclark.jpg Syndactyly occurs in 2-3 of every 10,000 live births. It can be associated with genetic disorders or may occur sporatically without any other conditions. Cancer not do die. They are immortal.
CANCER CELLS DIVIDE INDEFINITELY Normal cells are allowed between 50 and 80 divisions (passes through the cell cycle) before they stop dividing. This is called the Hayflick limit. The Hayflick limit exists because of a phenomena known as telomere shortening during cell division. WHAT ARE TELOMERES? whsc.emory.edu Telomeres are a sequence of repetitive bases at the ends of linear chromosomes that prevent adjacent chromosomes from attaching to each other. They are crucial to maintaining chromosome stability. The sequence of bases on the telomere varies from one species to the next. The sequence on human telomeres is show below. It is usually repeated about 2000 times on each chromosome end.
Human Telomere Sequence 5'...TTAGGG TTAGGG TTAGGG TTAGGG TTAGGG TTAGGG..3' 3'...AATCCC AATCCC AATCCC AATCCC AATCCC AATCCC..5' WHAT HAPPENS TO THE TELOMERES DURING DNA REPLICATION? During each round of DNA replication, a section of the telomere base sequence is shaved off. This means that each time the cell passes through the cell cycle, the telomeres are shorter than the cycle before. WHY DOES THIS HAPPEN? As you recall, one limitation of DNA polymerase is it can only work in the 5 to 3 direction. As the daughter strands are synthesized from the parent strand template, one strand is synthesized continuously and the other strand is synthesized in fragments. These fragments are called okazaki fragments. As the DNA polymerase reaches the end of the chromosome, there is not enough DNA template to synthesize the final okazaki fragments. Thus, the 5 end of each newly synthesized strand is cut short. About 100 base pairs are shaved off with each round of replication thus shortening the telomere. See diagram below.
Cancerous cells keep dividing long past the Hayflick limit. This is because of a mutation to the gene that codes for telomerase. Telomerase allows a sequence of bases on the telomere of a chromosome to be replenished. nia.nih.gov
CANCER CELLS ARE CAPABLE OF ANGIOGENESIS Angiogenesis is the ability of cells to promote the growth of blood vessels. Normal body cells do not express the gene that allows for angiogenesis. Angiogenesis ensures that cancer cells (which have extremely high metabolic rates) have a constant supply of glucose and oxygen to generate ATP. It will eventually aid in the metastasis of the cancer to other parts of the body. www.omegagenesis.com
CANCER CELLS ARE CAPABLE OF METASTASIS Normal body cells (with few exceptions) are anchored in place. Metastasis is the ability of cancer cells to migrate to other parts of the body. Cancer cell Moving down a Pore in Lab http://wills4223.blogspot.com/2005_09_01_archive.html CANCER GENES Cancer results when mutations to each of the following types of genes accumulate in the same cell. 1. Proto-oncogenes: these genes produce proteins that tell cells to divide. In normal cells these genes are expressed until the Hayflick limit is reached after which
they are shut off. In cancer cells, the gene is always expressed. 2. Tumor Suppressor Genes: these genes produce proteins that inhibit cell division. In normal cells, these genes are shut off until the cell reaches the Hayflick limit after which they are expressed to inhibit further cell division. In cancer cells, the gene is never expressed. 3. Telomerase gene: this gene produces an enzyme that replaces the lost telomeric sequences. In normal cells (except stem cells) the gene is not expressed. In cancer cells the gene is expressed. 4. Angiogenesis gene: this gene produces a protein that stimulates the growth of blood vessels. In normal cells the gene is not expressed. In cancer cells it is expressed. 5. Metastasis gene: this gene produces a protein that allows the cell to migrate to other areas of the body. In normal cells the gene is not expressed. In cancer cells it is expressed. WHAT FACTORS MUTATE DNA? 1. UV radiation UV radiation disrupts the nitrogen base pairs and causes nitrogen bases on the same side of the DNA ladder to bond with each other. Adjacent thymines (yellow bars) are most often affected. The bonding of two adjacent
thymines on the same strand of the double helix is called a thymine dimer. http://earthobservatory.nasa.gov/features/uvb/images/d na_mutation.gif 2. Toxic chemicals (carcinogens) Carcinogens causes any number of alterations to the DNA double helix. 3. Viruses Some viruses carry onocogenes in their chromosomes. (An oncogene is a mutated version of a proto-oncogene which causes the gas petal for cell division to get stuck in the down position.) Viruses can also promote cancer when they insert themselves into human
chromosomes. They may disrupt the genes that control the cell cycle. 4. Errors during DNA replication During replication, about one in every 10,000 bases pairs is replicated incorrectly by DNA polymerase. DETECTION AND DIAGNOSIS OF CANCER Detection Most cancers are detected by imaging. This includes MRI, X-ray (mammograms), ultrasound or CT scans, all of which produce an image of the cancerous mass. Diagnosis The traditional method involves obtaining a sample of the tumor cells and examination of these cells by a pathologist. Click here to presentation on the pathology of cancer cells. Click on pathology and view entire series of slide. Listen to the audio clips. The cancer is given a grade based on the appearance of individual cells. Low grade cancers have the best prognosis. The cells are still organized and
differentiated. They retain some features of normal cell and are still responding to some cell cycle control signals. High grade cancers have a poor prognosis. These cells have lost their differentiation and organization. They have lost all resemblance to normal cells because they have accumulated more mutations. They are more likely to metastasize. www.psc.edu New technology allows cancer cells to be identified and staged by studying their gene expression. Cancer cells express genes that are not normally expressed or fail to express genes that are normally expressed. They may over or under express particular genes as well. Isolating the mrna transcripts from a tumor cell allow scientists to measure which genes are active.
Ex: Below are examples of mrna transcripts isolated from a cancer cell compared to a Normal Cell Normal Cell mrna transcripts Protooncogene mrna Tumorsuppressor mrna Glucose Metabolism mrna's Cancer Cell mrna transcripts Oncogene mrna Telomerase mrna Glucose Metabolism mrna's (overexpressed) Angiogenesis mrna Metastasis mrna