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Biochemistry 2280A
Chris Brandl

Cancer Youtube: M D Anderson answer the question: What is Cancer? Molecular Basis of Cancer Cancer is characterization by genetic and biochemical defects. Biochemistry and molecular biology provide avenues for cures. Cancer is: - the leading cause of death in North America - Strikes victims of all ages - More prevalent as the population ages. Types of tumours: Benign Tumours: are contained within the originating tissue Malignant Tumours: are able to invade surrounding tissues and are thus much more difficult to treat Benign tumor (left): It’s encapsulate and can be surgically removed. They do not move from their place of origin. Malignant tumor (right): these tumors are not contained, so they can move throughout the body. It can start a benign but it can secrete proteases that allow it to go through the basal lamina and get to a blood vessel go into the blood stream where it can penetrate through blood vessels and metasise in other tissues. A very difficult form of cancer to treat. It ends up spreading throughout the body. Cancer is a Genetic Disease Susceptibility to cancer can be inherited • retinoblastoma (a cancer of the eye)- if you have one of the recessive alleles you will get cancer within 2 years after birth. • xeroderma pigmentosa (a cancer of the skin) • some forms of breast cancer and intestinal cancer. Aprox 10% inherited. Some genes that result in cancer can be inherited. Some forms of cancer can be inherited. So we know cancer is a genetic disease because it can be inherited. Chemicals that damage DNA can result in cancer= carcinogens. Mutagens=things that cause DNA damage, can cause cancer because cancer is a genetic disease, and vice versa. Preventable causes of cancer: 1. Environmental agents • Agents that cause DNA damage Radiation (x-rays, UV), Carcinogens • Chemicals (carcinogens) that cause cells to divide: Tumor promoters- asbestos ** causes cells to divided and there is a greater chance that they will become cancerous. There’s a difference between a carcinogen and a mutagen. A mutagen is something that causes DNA damage, whereas a carcinogen is something that causes cancer. Most mutagens are carcinogens but not all, also there are some carcinogens that are not mutagens. Other carcinogens cause cells to divide more frequently. So in this case, these carcinogens do not cause DNA damage. The more cells we have around, the more chance one of them becomes damaged and leads to cancer. E.g. Tumor promoters- asbesto. 2. Viruses: Hepatitis (liver cancer) HPV (cervical cancer) There are other causes of cancer. Some viruses can cause cancer. What is the most preventable cause of cancer? SMOKING! 30% of all cancers can be attributed to smoking Males: Stomach- less pickled food therefore it has dropped dramatically. Lung- gone up Females: *** trends very similar to men. The difference can be explained by a smoking graph. Men started smoking sooner. Cigarette smoke contains 69 chemicals that are known to cause cancer: Tar - a mixture of dangerous chemicals Arsenic – Rat poisoning Benzene - an industrial solvent, refined from crude oil Cadmium - used in batteries Formaldehyde - used in mortuaries and paint manufacturing Polonium-210 - a highly radioactive element Chromium - used to manufacture dye, paints and alloys 1,3-Butadiene - used in rubber manufacturing Polycyclic aromatic hydrocarbons - a group of dangerous DNA-damaging chemicals Nitrosamines - another group of DNA-damaging chemicals Acrolein - formerly used as a chemical weapon The risk of cancer increases with age… why? In young people is not as prevalent because they haven’t accumulated many mutations yet. A single mutation is not sufficient to cause cancer in most cases. • Tumour progression involves successive rounds of mutation and selection for growth - perhaps as many as 10 rounds (figure 21-44) • At each round a descendent from a progenitor cell acquires another mutation that allows it to grow faster or in abnormal places • Cancer is not due to a single mutation but usually many mutation and it’s progressive. In most cases of cancer, it’s a series of mutations that causes the problem. Because of that, cancer tends to be more relevant in older people. The successive nature of cancer is shown in this figure. (Top) Starting with a normal cell/tissue growing mono-layer; because there’s contact inhibition- it grows abnormally as a clump, these cells do not proliferate outside of the mono-layer. One of the cells may pick up a single mutation allowing it to grow faster, and then it becomes a larger percentage of that pop of cells. At some point one of the cell from that group acquires another mutation, which may allow it to grow outside of that monolayer, so now contact inhibition is lost and it may be able to grow outside the monolayer. The third mutation may allow one of these cells to go through the basal lamina. Multiple steps after that can allow it to metastasize and move on. In the diagram they show 3 mutations leading to a tumor, but in reality it’s more than that. So most cancer originate from one initial mutation. It has been estimated that 20 ect. Mutations are responsible for cancer. It takes many years for a cell to become a cancer cell. Properties of Cancer Cells. • Do Not respond to signals that normally control cell division (for example, growth factors, hormones); that is, cancer cells do not need these signals to divide. • Are immortal - do not respond to the normal signals that trigger cell death • Are extremely genetically unstable - defective in repair pathways (more point mutations), major chromosome abnormalities. They have a lot of point mutations- they have copy number variation and some major chromosome abnormalities. Normal cells respond to external signals which tell them when to divide, differentiate or not, thus controls growth rate. Cancer cells do not respond to those normal signals. Normal cells have a finite lifespan, cancer cells will go on forever almost. This is one of the major mutations in CML (chronic myelogenous leukemia); there’s a translocation between chromosome 22 and 9, such that the end of 22 is now stuck on 9. Often there are major chromosomal rearrangements typical of cancer. • Metastatic cancer cells can escape to and multiply in abnormal places • Avoid replicative cell aging that is programmed by the normal shortening of telomeres that occurs when cells divide • Normal cells only grow in specific environments. Cancer cells can move grow elsewhere and proliferate. Cancer Causing Genes Two types of cancer causing genes; oncogenes (dominant) and tumor suppressors (recessive). Normal gene= proto-oncogene (A)Oncogene: we have 2 chromosomes, and then a gene change in an oncogene making it hyperactive leading to cancer. This is the dominant scenario. (B)Tumor suppressor: In this case it’s under-activity that’s the problem. In this case we have 2 functional alleles, so a single mutation does NOT cause a problem, but a mutation in the 2 alleles causes a problem. This is the recessive case.. If one of the two alleles gets inactivated- you are protected by the second allele. If the second gets damaged then that will lead to cancer. Some people are born with 1 mutation on one allele so it is easier for them to get the disease because they only need one more mutation These oncogenes are present in an aberrant form so - their level may be altered, we can have more of them - or their localization may have changed - or their sequence may have changed that their enzymatic activity. 1. Oncogenes: A mutant form of a normal gene whose presence causes cancer. Proto-oncogene
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