 In this video I'll cover the following objective, contrast the characteristics of normal cells with cancer cells, describe factors that control cell division, and the role they play in the development of cancer, the proto-oncogenes and tumor suppressor genes. When a tissue starts to grow and become abnormally enlarged, we call that a tumor, a benign tumor is not cancer, it's an abnormal growth, and it may produce a noticeable mass, but that tissue has not expanded beyond its normal boundaries and started to invade other tissues. The example we see here is a lipoma, a lipoma is a tumor consisting of adipose tissue, typically this forms just under the skin growing in the hypodermis or subcutaneous layer of adipose tissue, normally found just under the skin, but for some reason the cells start to divide and grow faster within that region forming a mass. This lipoma and most other benign tumors are not a serious risk to our health, although a benign tumor might disrupt the functions of an organ by pushing on an organ creating abnormal pressure, a surgical procedure to remove the benign tumor is usually all that would be required to alleviate any symptoms resulting from this abnormal growth. If a benign tumor is completely removed, it often will not regrow. In contrast, a malignant tumor is a cancerous tumor, a mass of tissue growth where the cells start to invade adjacent tissues and expand beyond their normal boundaries. So while a benign tumor would have a capsule of connective tissue helping to keep it contained within its boundaries, a malignant tumor would start to invade and move beyond that capsule. The example of a malignant tumor shown here in the pictures is a melanoma. A melanoma is a cancer resulting from uncontrolled division of melanocytes. Melanocytes are cells found in the epidermis of our skin in the deep layer of the epidermis, and melanocytes normally produce the brown pigment melanin, which gives color to our skin to help protect us from the damaging effects of UV light. One of those damaging effects of UV light is to create mutations and mutations in our skin cells can increase that risk of uncontrolled cell division producing a cancer like this melanoma. So while melanocytes normally give the coloration to our skin, including producing things like freckles and moles, the abnormal shape and pattern coloration and also the irregular borders of this darkened region on the skin are some of the cues that indicate that this is not a typical mole but is actually something to be more concerned about, something you would want to visit the doctor and have them take a sample of. And when they do take a biopsy, a tissue sample from a tumor, they will look at it under the microscope as what we have in the images on the bottom here. On the bottom left, the image of a biopsy from a lipoma shows that it contains normal connective tissue, primarily adipose connective tissue, as well as some dense irregular connective tissue. And those are tissues that would be normally found in the deep layers of the skin. That on the right here, we see the biopsy of a melanoma where we can see an enlarged region that contains some of the concentration of the pigment melanin and it's an enlarged rounded mass that is pushed down past the epidermis into the dermis and so the tumor is invading adjacent tissues and if a piece of that tumor breaks off and then spreads to another area of the body, it could travel through the bloodstream for example to reach a different organ, that's what we call a metastatic tumor. So when a tumor metastasizes, a piece of that tumor will break off and then grow in another organ. So while cancer is uncontrolled cell division that produces a malignant tumor, normally the cell cycle is regulated by cell cycle checkpoints. At these checkpoints, there are specific points in time through the cell cycle where the cell can stop and double check to make sure that there aren't any mutations in the DNA that the cell will be able to divide and produce two healthy daughter cells and not become a dysfunctional cell or a cancerous cell. Cyclins are proteins that normally accumulate during specific phases of the cell cycle so here in the graph we can see that cyclin D accumulates through G1 and S phase and then is degraded later as we enter G2 and mitosis and you can see that cyclin E accumulates at the end of G1 and then is degraded during S phase. Cyclin A accumulates at the end of S phase and into the G2 phase and then cyclin A will be degraded as we enter into mitosis whereas cyclin B will accumulate at the end of G2 and be degraded as well during mitosis. These cyclin proteins can then regulate other proteins including enzymes called CDKs or cyclin dependent kinases that will help to regulate the progression of the cell cycle. If there is a problem and for example there's a mutation in the DNA that was produced during DNA synthesis then cyclins would be broken down and so we wouldn't accumulate enough cyclin A to advance into the G2 phase if there was an error during DNA replication. The cyclin A level would remain low until that DNA could be repaired or it's possible that the cell would instead enter into a programmed cell death to prevent the mutation from being passed on to daughter cells. So the cyclin proteins bind to cyclin dependent kinases CDKs and then the CDK proteins are kinases that can phosphorylate other proteins including other kinases and a variety of other enzymes but by regulating the function of other cell signaling proteins the CDKs can regulate transcription of genes and ultimately regulate the progression of the cell cycle. As the cell is progressing through the phases of the cell cycle it is the accumulation of cyclin proteins and the resulting activation of cyclin dependent kinases that enables the advancement of the cell from one phase into the next pushing the cell past the cell cycle checkpoints. For example at the end of G1 cyclin E accumulates activating CDK2 and this high activity of CDK2 phosphorylating its target proteins is what will push the cell into the S phase of the cell cycle to initiate DNA synthesis. Similarly the accumulation of cyclin A leading to activation of the cyclin dependent kinase CDK2 will be required in order to advance the cell cycle further through S phase and G2 phase to progress into the M phase of the cell cycle and then the accumulation of cyclin B and CDK1 will be required in order to proceed past the M checkpoint during mitosis before cytokinesis will produce two daughter cells. If there were any mutations that accumulated and if the cell was not healthy the cyclin proteins would not accumulate to high enough levels to activate CDKs and advance the cell cycle this will allow time for DNA repair to fix any mutations in the DNA however if the cell cannot be repaired it's also possible that the cell will instead enter a programmed cell death to prevent any daughter cells from inheriting mutations that would cause cancer or disrupt the functions of an organ. So the proteins that normally stimulate the cell cycle to promote growth and speed up the rate of cell division are known as proto-oncogenes the example that we see here is the epidermal growth factor signaling pathway. Epidermal growth factor is a protein that's released by cells in order to stimulate growth epidermal growth factor will bind to a receptor that's an integral membrane protein embedded in the plasma membrane the epidermal growth factor receptor when when it binds epidermal growth factor will become activated and then stimulate a cell signaling mechanism downstream leading to the activation of the kinase erk the extracellular signal regulated kinase which will then stimulate the transcription of the cyclin genes and the translation of the messenger RNA to produce the cyclin proteins and as the cyclin proteins accumulate they will activate the CDK enzymes and stimulate the cell cycle to speed up however an oncogene would be an abnormal version of a proto-oncogene if a proto-oncogene becomes mutated in a way that causes that protein to further speed up the cell cycle leading to an abnormal acceleration of the cell cycle then that proto-oncogene has mutated and become an oncogene the epidermal growth factor receptor is one example of a proto-oncogene that is known to become mutated forming an oncogene in contrast to proto-oncogenes which normally speed up the cell cycle tumor suppressor genes have a normal function of slowing down the cell cycle p53 is an example of a tumor suppressor gene in response to DNA damage or other abnormalities disruptions of the cells functions or low oxygen available availability known as hypoxia the p53 protein becomes activated by these stressful events and will slow down the cell cycle p53 will lead to a decreased expression of cyclin genes so there will be less accumulation of cyclin proteins and the cdk enzymes will become less active to slow down the cell cycle allowing some time for DNA repair or allowing time for the cell to deal with the stressful situation if DNA repair is successful then the cell cycle can start again and p53 will become inactivated enabling the cell to progress through the cell cycle divide and produce more daughter cells however if DNA repair isn't possible if the cell isn't able to recover from the stress p53 can also activate a programmed cell death mechanism so this is known as apoptosis apoptosis is a programmed cell death mechanism where the cell will break down in a relatively tidy fashion rather than just bursting open and spilling its contents into the environment the cell will break down into small packages that can be cleaned up by the immune system so p53 normally helps to prevent cancer by slowing down the cell cycle and allowing time for DNA repair however when the p53 gene becomes mutated that mutation could disrupt the function of p53 and if the p53 gene isn't working that would increase the risk of developing cancer as p53 isn't able to slow down the cell cycle and promote DNA repair more mutations can accumulate and some of those mutations could be in proto-oncogenes causing them to become oncogenes some of these mutations could be in other tumor suppressor genes and it could inactivate those leading to even further risk of accumulation of mutations so as multiple mutations accumulate leading to acceleration of the cell cycle this is the multiple hits of mutations that ultimately lead to the formation of cancer and so while one mutation in a really important tumor suppressor gene could drastically increase the risk of developing cancer typically multiple mutations are needed for a pre-cancerous tumor to progress to full-blown malignant cancerous tumor