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Lecture 12

Lecture 12 cancer.pdf

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Maurice Ringuette

Lecture 12 November 8, 20135:40 PM Can see that the major impact cancer has on individuals. Also on society. We all are impacted by cancer. We are going to see the theme that The molecules that are defected with cancer are the molecules that we talked in past lecture. We are talking about defects in the molecular machinery that concerns the see slide. Important to understand the cell biology principles to combat cancer and other diseases BIO230 Page 1 This diagram highlights the molecular machinery pathways in cancer. When you look across, there are many molecules that we discussed. Cadherin's, integrin's, control of cell growth, control of cell death and many of these aspects we discussed. When humans develop they start from one cell and end up with hundred thousand billion cells. Of those billion cells in our body there are many cells experiencing a mutation every day. So there are insults , changes in our DNA everyday. Normally these mutations, most of them will be repaired. By the DNA repair machinery which is constantly scanning the genome and 10 Cells in human body checking for errors. If there is a problem with repairing that DNA the then the body cant repair the aberrant cells. Then the --> p53 is activated and the cells are killed. There are two layers of protection, correction at the molecular level and destruction of the cell that protects us from mutations. The problem arises is if that one of these cells, if it gains a mutation that allows it to survive and divide it will grow a tumor. If there is one dangerous mutation that doesn’t allow for apoptosis ,This is a dangerous mutation, Cancer origins from one single cell. Clonal in origin from one cell. BIO230 Page 2 One example that gives evidence for the origin of cancer is shown here. The basic idea is that we can distinguish 2 cell types in this tissue sample. That’s because These cells are from the females and they have 2 X chromosomes and one of these X chromosomes is inactivated for dosage compensation. Males have an X and Y, and so one X is inactivated in females. There is one X and less active Y in males. This inactivation is random so when you look across the tissue one X chromosome is inactivated in the pink cell and one X is inactivated in the grey cells. You can see the random organization here. So all of these tissue around the outside if the diagram will be normal tissue with random inactivation and in the center this is a tumor. In the center, there is a tumor. The tumor cells are indicated in pink because a probe for one X chromosomes shows that all of these cells have the same X chromosomes inactivated. This is one piece of data that indicates that cancer is a group of cells derived from a single cell because they all have one X inactivation. If it was derived from a group of cells, then there would be one mixture of chromosome inactivation in another one like the surrounding tissue here. This provides that the evidence that the mutation occurred on one cell and it started and divided forming the tumor there dangerous thing about cancer is that they have uncontrollable growth. So you can monitor the tumor cell doublings and then monitor the diameter of the tumor and notice the exponential growth You start off from a single cell an after 30 doublings you can see the tumor on the x ray. And after 35-34 the tumor is palatable that means touchable and can be surgically removed at that point. And then after 40 doublings then the tumor becomes deadly. If you look at the size its 100 mm across. The you have a 10cm wide diameter. It's like a baseball and this is what kills, you have abnormal cell growing within a normal organ and now you end up with 10cm in diameter inactive group of cells which disrupts the rest of the organ function. That’s detrimental to the overall body. This is what ends up killing cancer patients. Exponential growth BIO230 Page 3 Can we categorize cancer cells by tissue type? Definition if a tumor is an uncontrolled growing mass of abnormal cells. (neoplasm) Epithelia are the tissues that coat our skin and organs. They are called carcinoma and the cells in-between the epithelia are found in the Uncontrolled growing of mass of abnormal cells connective tissue. Can be either Muscle cells, neuro cells, blood cells. Etc. They can be broken into two types. These are sarcomas. Blood cell cancers are leukemia. This relates to the single cell that started to divide. We can also describe different stages of cancer development. There are stages as the cancer become more dangerous. This is a begin tumor: Epithelial derived tumor. Around the outside we have the Ecm of the basal side of the tissue and have a growing mass of abnormal cells. This is not crossed the ECM to pass into a nother body complartments. We call this as being tumor, growing mass that is self-contained as a single tumor. Haven't left the ECM. Not as dangerous. As long as they are not causing disruptive to functions. Malignant tumors are dangerous: The cancer cells are dividing which derived from one of the normal cells that gained the mutation to form the group of cells. The cancer cells start dividing forming a group of cells and In malignant cases some break from the ECM barrier and start to go to the surrounding tissues. This is an aggressive tumor that is broken free and invade the surrounding tissue. This is relatively local. This will go to the surrounding connecting tissue and the cancer cells are moving into the connective tissue underneat the epithlum in this case. Now the next level of concern is when the tumor becomes metastasis. This is when the cancer starts to inavde other tissues and then form metastasis secondary tumors. BIO230 Page 4 This is when the tumor becomes epistasis. Starts to invade the other tissues through blood cell. Step 1: start will normal epithelium. Basal lamina specialized Ecm below the epithelium cells. STEP 2: one cell starts to grow uncontrollably after gaining a mutation becomes e benign tumor. Step3: it break through the ECM. The cells gain more individual properties and become migratory. Migrate away from initial site. They act like WBS crawling through the ECM. Crawl through the connective tissue , ecm, binds to blood vessels and pass through the epithelium that is coating that blood vesseil and pass into the blood. This environment in the blood is not hospitable for the blood cells. So most of them will die. One in a 1000 will survive. Those that did survive will pass through the blood stream and can find a region where the blood vessels become narrow and now these cells can leave the blood vessels and then they can populate a tissue outside the vessel at a second site in the body and this single cell and start growing again and start a second tumor. So we have the primary tumor which is present and then secondary tumor somewhere else. All of these sites are growing and disrupt multiple organ systems ebcause of the grewoing size of all the tumors. These are cellular changes of cancer development. Now let's consider the molecular changes in cancer cells The first change in a cancer cell is changes in DNA. There is a single cell that has changes in DNA, In this example there is a dramatic change in the DNA This is a karyotype where the chromosomes of a cell samples is spread out on a cover slip and we can analyze their organization. We can analyze their chromosomes. These are labelled with specific dyes that can distinguish one chromosmes from the other. So we can distinguish a set of chromosomes from dyes and we can color code the results from dyes. What goes wrong in the cancer tissue, now we have T in this cancerous tissue, single cells where we have 4 copies of chromseoms one, multiple copies of chromeoms 2 and some look like they are fragmented. Look at the othere example. In addtion to having a copy the chromeosme , some ieces of chromsoems have transcloated to other chromeosmes as well. Green and purple conencted. This tissue is in a cancerous cell that has progressed faraway. Because in the intital event may only be a comuple of mutations. These cancer cells start to lose control of themselves. Gain more mutations and they don’t follow the checkpoints and so progeny of the cencer celldivisions end up with extra chromomes. And these problems will build and build and cancer cells will ebcome more and more abnormal and dangerous. Cancr cell that has progressed far away. BIO230 Page 5 The intial change in the cell is a Change in DNA. What causes the mutations leading to cancer. What genes are mutated and how did they prmote cancer progression? When you think about what is causing cancer mutations is chemical mutagens: Mutations can also be cause d by radiations, and viruses. They can change the DNA in the cell and if its changedin a wrong way it can cause cancer. Chemical mutagen: how does it lead to the change in DNA. This structure looks This chemical is called afflotoxin: this is found in mouldy peanuts. If you ingest this afflotoxin in our body can be acted upon by this similar to a nucleotide. enzyme which convert it into this derivative called afflotoxin epoxide and afflotoxin epoxide can bind to gunaine in the DNA. There is a gunaine and there is an abnormal molecule attached to the G. When you look at the moelcule what does it look like? It looks like, compared to guanine, similar to a nucleotide. What's going to happen is as you know G will base pair with C but because G is bound to this molecule it will no longer bind to C. so a C now will not be added by base paring to the newly synthesized DNA strand and therefore will have an deletion Backbone. of the C. This is an example of how to have a moelcule that looks like a DNA base pair. The key thing here is it is not the intiial moelcule that is the problem but the body enzymes in the body modifes it into a form that covalently Exmaple on how to get a molecule that changes DNA leading to the deletion of C. looks like a DNA base pair BIO230 Page 6 How to figure out which molecules are safe and what are not. All sorts of government labs, when new products comes to the market that are going to be exposed to humans, agencies are going to run the compound through this test. The products are run through this tests and found if it can mutate DNA. All that is asked is if it can mutate DNA. If it can mutate DNA then you don’t want to ingest it because DNA mutations leads to cancer. The assay here is to ask if the chemicals are leading to mutations in DNA makes use of bacteria. The actual DNA we are assesing is bacterial DNA. Reverted the mutation The actual DNA they are accessing is bacterial DNA, and this bacteria is Back to normal. That’s why you special in this test. We are checking salmonella, but this salmonella has The ames test. See the one path a mutation in its enzyme for producing histidine. On its own the bacteria if you plate it on media that doesn't have histidine on it, takes the bacteria --> put on media, it will not grow. Because there are no mutagens added. However, you see that one colony of bacteria that has grown, and the only way it could have grown is because if there was a mutation in the salmonella that if you reverted the broken enzyme back to normal. Normally you think about mutations disrupting gene function. Now we look and ask if these mutations can repair the broken enzyme. Now this particular salmonella cell will now be able to grow without histidine and make a colony. You may ask isnt that going to be extremely rare? Then these mutations can be happening all across the bacterial chromosomes. What are the chances that there mutations is affecting the histidine producing gene specifically? The chances are extremely low. Its like winning the lottery. This is why we use bacteria because in one culture you can have millions and millions of bacterial cells. So you can actually pick that 1/ million event because you have millions of bacteria. That’s why bacteria is critical in this test. If you take the test compound that you are worried about, plate them out it with salmonella, plate it and ask when you add the chemical does it lead to the greater bacterial growth of the cell colony. So that means more mutations occurred and brought the histidine mutation back to normal. Compared to background will there be a more reversin or more mutagenesis vs background. You can see that this is a compund problem. Why are we adding the homogenized live exrtact? We have a purified compounds, and pure sample of histinde dependnt salmoenlla now why are we adding this extract? Lets look at this with a exam question. Why is the liver extract added: 1. supplies the cells that are cancerous. Incorrect because there are no cancer cells in theassay at all. Its bacterial cells we are looking at. 2. supplies the cells that might be modified to become cancerous. Incorrect we are using bacteria cells. 3. provides chemicals that might cause mutations. - incorrect. It came from purified chemicals. 4 modifies chemicals the purification came from. This is the key thing. We saw with afflotixin , if you took that afflotixin and put itinto this assya there wont be any problem. Only after the afflotixi is modified by enzymes in the huamn body are they modified into the cancerous form. So by adding the liver extract we not only testing the chemicals, but also any forms of the purified cacner cells the body might make. BIO230 Page 7 There are 2 classes. Oncogene and tumor suppressor (TSG). Oncogenes : gain of function genes Normal forms are called proto-oncogenes. Ras and Myc are proteins that drives the cell cycle forward and premits cell proliferation. So tehre is a gain o ffucntion within these genes which causes more cell proliferation. This is a problem with cancer. Gain of function 2. TSG Cancer is arising from loss of function. P53 and Rb holds the cell cycle back. If we remove these players there is a greater chance of cell proliferation and they will die. Loss of function One thing that arises is that the tumor supressor genes are recessive. Oncogene is domainnt. W start with two copies of our chromosome, and with the overactivity mutations gain of function for the oncogene, all we need is just one copy to turn on and we don’t need the other copies to function. We need to increase the total level of cell cycle promoting signal.
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