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Hallmarks of CancerHallmarks of Cancer In 2000, the first hallmarks of cancer were published. There are six behaviors all cancers will develop as they go from benign growth to metastatic growth. This was the first attempt to organize the complexity of cancer biology. Since then, we have added four more.  Cancer begins when a cell loses control over the functions that regulate cell growth. It begins with genetic instability, loss of mortality, uncontrolled growth and loss of growth inhibitors. These are the main genetic drivers of cancer. Then it proceeds to immune invasion by learning to escape immune detection and promoting an environment of tolerance. There are a few other hallmarks of cancer that transition into invasion, angiogenesis, and metastasis. We will look at all the Hallmarks of Cancer first. Then we will dig deeper into the genetic and immunologic drivers of cancer. Hallmark 1: Sustained Proliferative Signaling The first hallmark of cancer is sustained growth signaling. Under normal circumstances, the cells of the body do not replicate unless it is necessary. Some cells will normally replicate frequently and others will never replicate. Cancer begins when a cell begins to act on its own replicating without the necessary signaling. This can happen when a mutation occurs in one of the growth pathways. These are those proto-oncogenes that mutate to become oncogenes which drives cell proliferation. They are mutations in the growth pathway for growth signals like EFGR, VEGF, FGFR and PDGF and many more. These types of mutations will lead to an always on state for those growth factor receptors.  You can also see duplication events where a growth factor receptor gets copied many times. This leads to hyper activation of these receptors called amplification mutations. It can be mutations in the internal cellular growth pathways like RAS, RAF, MEK, ERK, PI3K and AKT. They govern cell growth survival and proliferation. It only takes one mutation of an oncogene to drive increased cell growth. These cells can be perfectly normal in every way except they are replicating at a faster rate. Hallmark 2: Evading Growth Suppressors The second hallmark of cancer is the loss of those genes that prevent cells from growing without the proper signals. They involve proteins that verify the DNA during the cell cycle checkpoints like p53, p21 and Rb.  They include the DNA Damage Repair (DDR) pathway proteins and enzymes that fix damage to the DNA. DNA damage repair pathways fix damage from stress like oxidation, radiation and chemicals. These tumor suppressor genes are broken down into gatekeeper genes and caretaker genes. The gatekeepers are those genes that act as the breaks to cell replication. They are there to prevent it from occurring unless the proper signals have been given. The caretaker genes are there to ensure the integrity and control DNA repair.  Hallmark 3: Resist Death Signals The third hallmark is the shifting of the balance between the signals that tell a cell to survive over those that tell it to die. This is common in all cells. You want a healthy cell to survive.  Only when something goes wrong, should it initiate programmed cell death (Apoptosis). In cancer, the pathways for the survival signals will mutate and greatly shift that balance in favor of survival even in conditions where a cell should undergo death like DNA damage. Hallmark 4: Replicative Immortality Telomeres are the caps on the end of each chromosome. Think of them like the little caps on the end of your shoe strings. They have a specific length. Each time a cell replicates, the telomere gets slightly shorter.  After several generations of replication, you can exhaust the telomere. After the telomere runs out, the cell can no longer replicate. This is called the Hayflick limit. Cancer cells mutate to turn on the telomerase enzyme which extends the telomeres after each replication giving them attributes of stem cells. Stem Cells have the enzyme Telomerase which adds more sequences to the end of the Telomere. This give them immortality. Hallmark 5: Genomic Instability This hallmark is considered one of the first mutations to occur. Genetic Instability makes the cell unstable and allows for the rapid and progressive mutations from one generation to the next. This is when the cell loses the ability to quality check its DNA when it replicates like the p53 protein or DNA repair proteins. We said that a cell makes about one mistake each time it replicates the DNA. Most of them are caught and corrected. Genetic Instability occurs when something mutates to stop this quality check or the DNA Damage Repair pathways. Some of the genetic instability leads to errors in the actual chromosome like gene deletions, duplications and translocations. These are called gene rearrangements and they alter the DNA. Many of these errors are common to specific types of cancer.  One such example is the Philadelphia Chromosome. It's a translocation between Chromosome 9 and 22. A portion of each chromosome is cut and placed on the opposite chromosome. Hallmark 6: Reprogramming Metabolism Cancer cells will mutate their ability to take up glucose to power their rapid replication. It is shown that Cancer cells will uptake glucose at 100x the rate of normal cells.  Since the tumor usually forms in the tissue where there is no or little oxygen, cancer cells will often rewire their metabolism to make them anaerobic. The cellular respiration cycle has several processes of glycolysis, the Krebs cycle and the Electron Transport Chain. The later two use oxygen to break down glucose and make ATP which the cell uses for energy. The process of Glycolysis does not require oxygen which allows cancer cells to use this part of the process to produce energy for survival in a low oxygen environment of the tissue. This takes the glucose and breaks it down into Lactic Acid instead of Pyruvate which gets used in the rest of the process. Hallmark 7: Angiogenesis The next hallmark of cancer is the creation of new blood vessels. This is also the first step toward metastasis. The blood vessels provide a connection for the tumor to the circulation and the rest of the body.  Tumors need a lot of nutrients to drive their growth. They will release Vascular Endothelial Growth Factor (VEGF) which will act on the endothelial cells of nearby blood vessels. This will cause them to create new routes of blood vessels toward those signals. Hallmark 8: Tumor Promoting Inflammation The tumor will hijack the inflammation process and use it to promote its own growth. It releases signals like IL-4 that switches the immune system away from a cellular response that could kill the tumor toward one of a humoral response. The tumor will release signals to recruit neutrophils which can degranulate and damage nearby healthy cells, clearing the way for the tumor to expand and grow.  The helper T cells and macrophages in the area can also release growth signals which help drive the growth of tumor cells. The tumor not only learns to avoid the immune system, but it uses the immune system to do its bidding. Hallmark 9: Evading Immune Destruction Tumor cells must learn to evade immune destruction. The immune system is designed to find and kill mutated cells. The tumor can develop many mechanisms by which it will block the immune response.  The first is that the tumor will promote the creation of T regulatory cells. It does this by secreting cytokines like IL-10 and TGF-beta. This will cause T helper cells to switch into induced T regs. They will then release cytokines which will shut down the immune response toward the tumor. The macrophages in the area will be switched away from the M1 phenotype which kills tumor cells and to the M2 phenotype so they release TGF-beta which promotes growth for the tumor. The tumor cells can express ligands on their surface that can deactivate cytotoxic T cells and Macrophages. They can express PD-L1 which will stop cytotoxic T cells from killing them. The constant activation of these T cells without the ability to kill lead to them becoming exhausted, causing them to fail to respond at all. The tumor cells can also express CD47 which will prevent any M1 macrophages from killing them. Hallmark 10: Invasion and Metastasis The last Hallmark for cancer is the ability to invade nearby tissue and travel to distant tissues and set up secondary tumors. Normally, cells are anchored to where they belong by cell adhesion molecules.  They hold the cell in place. A mutation in these cellular adhesion molecules will allow the cells to break free from their normal tissue and invade nearby tissue. If there are blood vessels nearby, they can also travel through the blood to distant sites and spread. This process is called metastasizing. The statistics show that 90% of cancers become fatal once they are metastatic. During the process of metastasis, the cells must undergo a transition from a normal Epithelial cell into a Mesenchymal type stem cell. This process is called the Epithelial to Mesenchymal Transition (EMT). They will travel throughout the body in search of a place that will allow a new tumor to grow. The circulation is a toxic place for the circulating tumor cells as the immune system can respond to them. The places where secondary tumors will spring up are common based on the type of cancer. The main four are Brain, Bone, Liver and Lung. Those are the four sites where secondary tumors will often show up. |
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