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Lecture 19

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Biological Sciences
Dan Riggs

Lecture 19 cancer the biology of cancer In the first couple of weeks, we talked about DNA replication and how it is regulated. We also talked about DNA repair and the genes controlling DNA repair. We had 3 lectures on the cell cycle. For the next 2 lectures, we will talk about is what happens when the cell cycle gets out of control? This has to do with cancer. We will talk about how the cancer differs from other cells, or the cancer phenotypes. We will learn about the types of things that contribute to cancer, such as the environment and how molecular biology can be employed to guide future cancer treatments. When you were 2 years old, you were learning language. You had no idea you were going to die. When you became 4-5, you began to be more aware of mortality and that people die. Eventually, you learn about cancer and you know someone who has cancer or has died from cancer. What you will see today is that a large percentage of the population has this in their future but eventually, you can take charge of your health and your destiny by doing a few simple things. Figure 16-2 shows cancer statistics of the USA. There are not a lot of difference between these statistics and what is going on in Canada. Along the bottom are different types of cancers. Along the y axis is the cancer cases per 100,000 people. Some are fairly high and some are fairly low. On the right side is the number of deaths per 100,000 people. What is the highest on the list? If you live long enough, males will get prostrate cancer but usually they don’t die from prostrate cancer because there are test for early detection and blood test and prostrate cancer comes late in life. Men and women can both die from breast cancer but the incidence of death is low because it is fairly treatable. Lung and colon cancer have a very high death rate. Why? For lung cancer, usually you need to remove the cancer but you need your lungs to breathe. This is one part of the answer. If you thing about where these tissues come from and what they do, you know that they are both epithelial tissue which means that they cover the interior of the lungs and the interior of the colon so they are exposed to your environment. Depending on what you breathe, if you smoke, etc these all affect your chances of getting lung cancer. For colon cancer, you are what you eat. If you eat a lot of saturated fats, those fats are metabolized to create intermediates. There are many chemical reactions that go on every day and these reactions can result in mutation which can result in cancer. Obviously you can have surgery to remove part of your colon or your stomach but of course you needn't that tissue to absorb food and conduct life. These things are treatable but they tend to be pretty severe cases. Differences between normal cells and cancerous cells. We will look at seven different things and in each case we will have what the normal cell looks like and what the cancerous cell exhibits. The first of the characteristics is suggested to be density dependent growth in the case of the normal cell and the density independent growth in the case of the cancer cell. This means that let's consider a class of cells which are normal cells and another of cancer cells which are cultured cells. When the normal cells begin to multiply, and there are a lot of cells in the environment, they began to slow down their cell cycle and sometimes even stop the cell cycle. In cancer cells, they don't seem care about that, they just keep cycling and cycling and not pay attention to the density of cells in the area. In association with this phenomenon, there is something called contact inhibition that normal cells exhibit. That is, if they divide and come in contact with some neighboring cells, they develop communication between the cells that tells them when it's beginning to get crowded and to slow things down. Cancer cells do not care for this and they continue to grow and divide uncontrollably. Normal cells in culture and in the body as part of the tissue, have something called anchorage dependent growth. They need to be touching other things in the extracellular matrix, another cell or something in order to give them the signal to grow and only when they do so do they carry out the cell cycle properly. In contrast, cancer cells display anchorage independent growth. This means that as the cancer cells divide, it can break away from the other neighbor that it was touching before and it can go to other places in the body in order to set up other secondary tumors. Figure 16 – 3 shows a culture of normal cells at the top. What you can see is a culture of normal cells at the top. When the cells contact their neighbors and the dish becomes very dense, the cell cycle arrests. They just sit there in a monolayer which can be seen from the side view. If you look at this growth property with cancer cells what you see is that they exhibit density independent growth and also contact inhibition. The cells pile up on top of one another to form tumor-like masses. This is the same thing that would happen if there was a mutation in the cancer cell developing in the colon or lungs and they would continue to divide and grow uncontrollably to make a tumor. The fourth one is that normal cells require growth factors in order for them to do their normal cell cycle controls. Cancer cells do not, In fact they often produce their own growth factors to further simulate their division. This is shown in figure 16 – 4. Along the bottom is time in culture in days and along the Y axis is the cell number. Normal cells in culture that are given lots of nutrients and particular types of growth factors, they would grow and divide normally. If you withhold those serum growth factors, then nothing happens. Over the course of the four day period they sit there and do nothing which is the blue dotted line. The solid blue line represents normal cells given growth factors and they start off with a division rate for a few days then the culture becomes full and the cell becomes in density dependent and contact inhibition state so they begin to slow down and stop. These cultures are called 3T3 cultures which means you transfer one third of the cells every three days which is not very important. Soon after the transfer they grow great for three days then you have to do it again. The cancer cells are represented by the two red lines. Whether they have or you’ve withheld growth factors from them, they grow at an exponential rate with no change in slope. These cells continue to pile up on top of one another and thus they toxify the medium as they produce waste products and they just keep growing forever and ever. Property five. In normal cells when something bad happens like a chromosomal rearrangement or some nondisjunction process that is going on which gives an abnormal number of chromosomes this is referred to as aneuploidy. Ploidy is diploid. Normal ploidy levels are the norm but when aneuploidy occurs as a result of mutation or nondisjunction event etc., the cell has a failsafe mechanism to keep cancer from occurring. What it does is actually commit suicide. It initiates a process called apoptosis which is programmed cell death. This is some of the mechanisms by which cells kill themselves or kill other cells. When aneuploidy occurs, the cell puts in place this mechanism to get rid of it so it doesn't become cancerous. Cancer cells have escaped this somehow and are often seen as being aneuploidy. This is seen in figure 16 – 5 which is the karyotype of all the chromosomes in a particular tumor lines. In some way apoptosis fails. They have chromosome abnormalities and they have overridden that program to conduct suicide. As you might remember, normal cells have a relatively finite lifespan. As they age the levels of telomerase becomes lower and lower. When that happens, the cell enters a quiescent state; it divides a certain number of times and then it just sits there and eventually will die. In contrast to that, in cancer cells people observe that the telomerase activity is very high even though these cells divide many more times than what is normal and should have low-levels of telomerase, they tend to have higher levels. For the sixth point, normal cells tend to talk to one another. They establish gap junctions through which they can communicate in a variety of different ways to tell each other what is going on. One of the things they can say is if it's getting too crowded that they should shut down the cell cycle because density is getting too high and the increasing contact of neighboring cells and this slows the growth of the cell. In contrast to this, cancer cells don't care about the rest of the pack so they form fewer gap junctions than normal cells so their communication between neighbors is not important to them. Normal cells secrete a variety of factors. One of the things that they secrete are proteinases which are types of proteins that destroy other proteins. These are useful for if you have a cell in a matrix with other cells; it is often surrounded by an extracellular matrix so some of its growth and communication between cells is mediated by manipulating its external environment. Cancer cells have elevated levels of the secreted proteinases. They pump out these proteolytic enzymes because some of them want to break down the extracellular matrix to get away. This will loosen the tissues so when these cells that display anchorage independent growth, basically they can detach from the primary tumor, invade adjacent tissues, possible get into the blood stream or the lymphatic system, and be carried to distant sites in the body. This process is referred to as metastasis or the cells are said to metastasize. The normal cells whether in culture or in the body, go through a finite number of divisions and eventually go through cell death. They can be replaced by adjacent cells or in some cases such as in the blood, with stem cells that give rise to new blood cells. Eventually all cells are going to die. During the process where the cells are still active, something happens to them. There is chromosome rearrangement, or some nondisjunction event that gives rise to aneuploidy which initiates apoptosis or cell death. This is another way that cells can die. Before we come to that, in lecture 1or 2, we talked about meiosis and nondisjuction and a disease called down syndrome and trisomy 21. This is one of the situations where aneuploidy is taking place but it is one of the few that is actually tolerant. If you had the trisomy situation for chromosome 1 or 2 or 3 etc, there are only a couple of situations out of the 23 chromosomes in which this is tolerated (17, 21, and x chromosomes). Otherwise, the cell says this cannot be fixed so initiate cell death. Normal cells can obviously be mutated. Lots of things are going in the cell environment and over the course of a lifetime of an individual human, there are going to be specific and multiple mutations that occur. These mutations are going to affect the way the cells conduct their business. In particular the way the cell cycle is regulated. The cell cycle becomes deregulators and cancer cells are produced and become immortal meaning they don't obey the rules of shutting down the cell cycle rather they just grow and divide and in some cases invade other tissues and set up secondary tumors there and become abnormal. When this initially happens or when a cancer cell develops, it divides a number of times and creates a tumor, most cases the tumor is usually benign this is taken as a good thing but only in relative terms. If you learned that you have a benign tumor, you can in some measure be relieved but it still means that you have a tumor which is a mass which is unresponsive to normal growth controls but it lacks the ability at least so far to invade other tissues. It cannot to set up secondary tumors elsewhere. Quite often, these types of tumors can be removed surgically. Sometimes the tumors become malignant tumors. This means that they have metastasized. They are unresponsive to growth controls and they are capable of sending off individual cancer cells to get into the bloodstream and the lymphatic system and get carried all over the body, and begin to lodge somewhere and growing divide and result in secondary tumors. There are three major causes of cancer. The first one is chemicals and just called chemical carcinogenesis. If you read the label of any package you pick up at the store there are many big words and often those chemicals are used to extended the shelflife of food or processing etc. If you have an industrial job that is probably bad for you. If you pollute your own air with smoking for instance then you have other problems that will occur. The second cause is radiation. Nuclear power plant comes to mind when you think of radiation. Do not take a job at a nuclear power plant to expose yourself to nuclear radiation. What about the sun? As humans continue to degrade their environment and degrade the atmosphere, more harmful ultraviolet rays will come through causing some degree of sunburn and exposure to radiation. The third cause of cancer is through viruses. Some viruses can cause cancer. There are some types of genes called oncogenes that viruses can take from its previous host and put into you. Where you live is important to your exposure to cancer. For example, say you are Japanese and you’re male. You decide to move to Hawaii so you do a little digging into what happens in Hawaii and your grandfather died of a stomach cancer so you look at the statistics and the grandfather was Japanese seen in blue. The incidence for stomach cancer in Japanese males is very high but if you move to Hawaii which is the red line, which is the first generation of migrants from Japan to Hawaii, that incidence of stomach cancer goes down almost 50%. Now you tell this to your wife and she does some digging and finds that her chance of getting breast cancer in Japan is extraordinarily low but if she moves to Hawaii it goes up by 300%. For her daughte
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