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The Learning Library
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Biology of CancerThe Cell Cycle I could spend a very long time going over this process, but I wanted to give a simplified overview of the signaling that drives a cell through the growth cycle before we get into oncology and look at all the things that can go wrong. Most cells will spend the bulk of their time in the G0 phase. This means they are mature and carrying out their daily functions. Its only when they are given growth signals do they enter the cell cycle and replicate. The cell cycle is highly controlled and regulated. There is a massive amount of regulation on controlling cell division. This is to prevent uncontrolled growth which leads to cancer. There are genes that promote growth and we call them proto oncogenes. They are capable of driving cancer, but they won't when they are normal and healthy. There are genes that block cell growth without the proper signals to advance the cell through the cell cycle. We call these tumor suppressor genes. These can be lost by mutations that renders them ineffective. The signal for the cell to enter the cell cycle comes in the form of growth factors. There are a ton of them like Epidermal Growth Factor, Vascular Endothelial Growth Factor and many more. These growth factors all have the same role but for different tissues. It all starts when the growth factor binds to its receptor on the cell. It will initiate a signaling cascade of the growth pathways inside the cell. They are the MAPK and mTOR pathway that mainly drive cell growth. I have a complete Thread on both these pathways in my cell signaling threads. They have 2 roles in delivering the growth signal to the cells. The first is simply to tell the cell to grow. The other is to remove the brakes by inhibiting the tumor suppressor genes that prevent cell growth. One such interaction is the AKT kinase will deactivate GSK3beta which blocks cyclin D which gets the cell moving into G1 phase of cell growth. The cell will advance through its cycle regulated by checkpoints. The first is to ensure the cell has all the resources to divide. This includes checking the DNA for any damage. The DNA Damage Repair (DDR) pathways are always active. They will block the cell cycle when they find damage. It will arrest until the damage is repaired and then proceed. If its too badly damaged, the cell will undergo programmed cell death. As long as the DNA is fine, the cell cycle will proceed. There are multiple checkpoints in the cell cycle that verify the DNA is good before, during and after it is copied. Cyclin D starts off the cell cycle and gets it started. It hands off the process to Cyclin E which checks the DNA and starts DNA synthesis. Cyclin E will eventually hand it off to Cyclin A which carries it through the synthesis of the DNA and verifies the DNA again after it is copied. Finally it is handed off to the Mitosis phase were Cyclin B carries it the rest of the way to the cell splitting. Each cyclin uses at least 1 cyclin dependent kinase which will perform many functions while activating the genes necessary for the next step in the cycle. Unless there is damage, the DDR pathways will be always there and always on. As soon as any damage is detected, the process stops and a repair is attempted before progress resumes. Mutations anywhere in these pathways can promote the growth of cancer. A gain of function mutation in a proto oncogene in the growth pathways can lead to increase and uncontrolled cell growth. When it comes to tumor suppressors, it takes a loss of both alleles for it to make an impact. 1 good gene can still function and hold back the cell cycle. Mutations in the cell checkpoints can allow cells to advance through the cycle when it shouldn't. That could allow a mutation to be carried through and lead to additional mutations to drive more cancer genesis. Loss in the DDR pathways can lead to genomic instability which can lead to translocations and massive amounts of mutations. This is when a tumor cell really starts to mutate. Introduction to Oncology The definition of cancer is uncontrolled growth. It is a genetically driven disease. It begins with the accumulation of genetic mutations in a cell over time. One mutation alone will not lead to cancer. Some people are born with enough mutated genes to give them cancer at birth. Some people are born with genes that give them a predisposition toward cancer, but that does not mean they will certainly get it. They are a higher risk. It takes a series of mutations over time to accumulate all the traits of cancer in one cell. There are two major factors that contribute to the formation of cancer with genetics and environment. Its about genetics of what we are born with and epigenetics what we accumulate over time from exposure. We can inherit specific genes that give us a predisposition toward a specific type of cancer. That does not mean we will get that cancer, but it can significantly increase the odds. The environment plays a major role in causing cell mutations. The biggest factor in cancer development are acquired mutations over time caused by chemicals or pollutants. We call these factors carcinogens. Some types of carcinogen in cancer are UV light from the sun or chemicals from cigarette smoking. Even the Oxidative stress caused by our own immune systems can cause mutations. Immune surveillance toward cancer is the job of the immune system. The immune system is designed to find and kill any mutated cells, and it does so all the time without us ever knowing it. The formation of a tumor begins when all the genetic variables come together for a mutated cell to escape the immune defenses and grow uncontrolled. The Types and Incidence of Cancer A tumor gets named based on the tissue in which it begins. The Carcinoma is found in the epithelial tissue that makes up the skin that lines both the outside and inside of the body. It is further divided into two subcategories of Adenocarcinoma and Squamous Cell Carcinoma. The Adenocarcinoma forms inside the tissue of the organs while the Squamous Cell Carcinoma forms in the skin that covers the organs. Most solid tumors will fall into the Carcinoma. Sarcoma accounts for about 10% of all cancers and begins in the connective tissue of the cartilage, tendons, bone, muscle and fat. Leukemia is the cancer of the blood and starts in the bone marrow. It can spread into the circulation and even evolve to become a Lymphoma. Leukemia is a cancer of White Blood Cells. It is broken down in myelocytic and lymphocytic forms. The myelocytic form is made up of the cell lines that come from granulocytes, mainly neutrophils, while the lymphocytic form is made up of cells from the T cell or B cell lines. Acute Leukemia develops rapidly while chronic develops over the long term. You will never see a child with a chronic leukemia. All the childhood leukemia are acute. Lymphoma is a cancer that originates in the lymph nodes of the lymph system. It's a solid tumor and gets named based on which cell lines it originates in and which parts of the lymph nodes where it begins. Lymphoma is broken down into two kinds of Hodgkin's Lymphoma accounting for 5% of lymphoma and Non Hodgkin Lymphoma (NHL) accounting for 95% of lymphoma. NHL is further broken down into many types. About 14 million new cancers are diagnosed around the world each year and about 8 million people die from cancer each year. Lung cancer makes up about 12% of all cancers and affects about 235,000 people in the US each year. About 85% of lung cancer falls into Non Small Cell Lung cancer (NSCLC). It makes up the largest subset with small cell lung cancer making up the rest. Many lung cancers are diagnosed when they are advanced as they are hard to detect early. Up to 80% off all lung cancers stem from smoking. There are a lot of environmental contributing factors for lung cancers, especially occupational for firefighters. Breast cancer makes up about 12% of all cancers and affects about 285,000 people in the US each year. Breast cancer is the second leading cause of cancer deaths in women. Annual screening has led to a significant reduction in deaths related to breast cancer. About 70% to 80% of breast cancers are ductal cancers. This cancer has a huge genetic component with the BRCA gene which dramatically drives up the risk of breast cancer. Age and genetics are the largest contributing factors to breast cancer. Prostate cancer makes up about 8% of all cancers and affects about 248,000 men in the US each year. It leads to about 27,000 deaths each year. It is the second lead cause of cancer death for men. It is another cancer where screening can catch it early and significantly improve outcome. The highest risk factor is age with 60% of cases in men over 65. There is a PSA test that can easily be used yearly as a screen. Colon cancer makes up 10% of all cancers and affects about 105,000 people in the US each year. This is one of those cancers that can be caught and treated early with testing. The survival rate is high when caught early. Still, around 50,000 people die every year from Colon Cancer. The top risks for Colon cancer are age, diet, lifestyle such as smoking, and other illnesses like Inflammatory Bowel Disease. Liver cancer makes up about 700,000 cases worldwide every year and 42,000 in the US. It is far more common outside the US. The death rate is extremely high in Liver cancer as it goes undetected often until it's too late. It is twice as common for men as women. Chronic viruses of the liver like Hepatitis are the leading cause of liver cancer. Drinking and cirrhosis is another major factor that contributes to liver cancer. Skin cancer is one of the largest cancers in America with Melanoma making up about 1% of skin cancers. Melanoma affects about 77,000 people in the US each year. This one is of particular interest as it has a high genetic component with the BRAF V600E mutations. The number one risk factor is sun exposure. The blood cancers of Multiple Myeloma, Leukemia and Lymphoma make up about 10% of cancers. All of these cancers stem from the White Blood cells with a huge percentage of them coming from B cells. Acute Lymphoblastic Leukemia is the number one cancer in children who are born with cancer. It is a proliferation cancer of the B or T cells. Tumor Staging You will often hear people talk about a stage of cancer. What we typically know about these stages is different from the newer TNM system for staging cancer. There are 4 stages of cancer. Stage 1 is when the tumor is still contained to the tissue and does not invade nearby tissues. Stage 2 is when the cancer has grown bigger but is still contained in the original tissue. Stage 3 is when the cancer has broken beyond the original organ and begun to invade other nearby tissue or even lymph nodes. Stage 4 is when the cancer is metastatic and spread to distant locations. The statistics show that 90% of cancer deaths happen once the tumor has become metastatic. The newer TNM uses different conditions and you might hear it more often. The T is the stage of the tumor growth from stage 1 to stage 4. This is just as we described above, but now we add some newer indicators. The N indicates if there are involvement of lymph nodes nearby or even distant. A zero means no involvement while 1 to 3 will indicate how much lymph node involvement has occurred. Then the M stands for metastasis and will be 0 if metastasis has not occurred or 1 if metastasis has occurred. This is not much different, but you will probably hear it at some point. |
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