Our next session, we will discuss emerging hallmarks of cancer. So these are hallmarks 6-8 and these hallmarks enable a cancer cell to be more fit for competing, surviving and reproducing within the host, the human body. So just a recap of the first five that we've covered as well as the next one which is alter metabolism. So, the first five hallmarks are replicative immortality, genome instability, evading growth suppression, sustain proliferation, resist cell death, and alter metabolism. One of the key ways a cancer cell differs from a normal cell is its metabolism. We will discuss this alter metabolism in cancer. And how it allows cells to obtain energy from alternate sources that a normal cell typically does not use. Hallmark Number 6, Altered Metabolism, the re-programming energy metabolism has been identified as an emerging hallmark in cancer cells. For cancer cells to sustain uncontrolled proliferation, they must make adjustments to their energy production. Cancer cells do this by finding and using alternative sources and alternate metabolic pathways. Normal cells typically break down glucose in a process called glycolysis and converts it to pyruvate, which provides adenosine triphosphate, or ATP, for the cell. This is largely done in the mitochondria. However, cancer cells are very different, where they can convert glucose to lactate irrespective of oxygen. Molecular cancer research also reveals a number of activating mutations and enzymes that help exacerbate this process. This allows cancer cells to divert metabolites for useful anabolic processes such as mitosis. Here's a look at a cancer cell metabolism next to a normal cell metabolism. One of the first scientists to make this observation was Otto Warburg and this is known as the Warburg Effect. Whereas a normal cell takes in glucose, breaks it down by glycolysis to pyruvate and mitochondria undergoes the Krebs cycle which produces 36 ATP molecules in CO2. Whereas a cancer cell undergoes aerobic glycolysis, produces low ATP and lactate which is important for cell proliferation and biomass incorporation. Physicians have long exploited this fact about cancer. I have been able to use it to image tumors in the human body by using Fluorodeoxyglucose or FDG by a Positron Emission Topography. On the left side of your screen, you can see a patient's colon cancer tumors, which take up xylose or glucose, they also take up the FDG and you can image this by pad imaging. And on the right side of your screen, you can see the molecule FDG and its chemistry. Imaging will be discussed in more detail in a later lecture. So this leads us to our next hallmark, which is avoiding immune destruction. This is another emerging hallmark that allows cancer cells to be more fit and to survive in the host. But to better understand this hallmark, let's take the quick review of the human body and the immune system. The immune system is a system of many biological structures and processes within humans that protects us against disease. To function properly, an immune system must detect a wide variety of agents from viruses and parasitic worms to distinguish the body's own healthy tissue from foreign tissue. Here in this cartoon you can see organs of the immune system such as the thymus, lymph nodes, spleen, appendix, bone marrow and lymphatic vesicles. Several cells are produced by each of these organs shown here. So lymph nodes can produce T cells, which get their name because they mature in the thymus. Myeloid cells become macrophages and they are produced in largely every organ in the body. Dendritic cells, as well as B cells which present antibodies and secrete cytokines. All of these cells are vitally important to protecting the host from foreign invaders. Avoiding immune destruction that ever allowed immune system destroys viruses in other foreign cell types in the human body. Cells of the immune system that engulf and destroy foreign particles are B cells, T lymphocytes or T cells, macrophages and natural killer cells. However, cancer cells are able to protect themselves from attack from the T cells and other cell types by up regulating a protein that is well studied in cancer biology called programmed death-ligand 1. Programmed death-ligand 1 is shown here on the blue cell as well as programmed death-ligand 2 or PD L1 and PD L2 respectively. These proteins are transmembrane meaning that they are extra cellular and intracellular. And they play a major role in suppressing immune system during particular events such as pregnancy, tissue allographs, autoimmune disease, and other disease states such as hepatitis. Normally the immune system reacts to foreign antigens as well as foreign cells to trigger proliferation of antigen-specific CD8 T cells shown in the orange peach colors cell type. T cells express PD-1 and when it contacts PD L1 it serves as a checkpoint to tell T cells to stop proliferating to prevent auto-immunity. Cancer cells are very clever and they up regulate PD L1, interact with PD-1 so T cells cannot attack them. This is a very key way in how tumor cells are able to evade the immune system. There are on going studies and FDA approved drugs that antagonize PD-1 so the T cells can now attack tumor cells. The next hallmark also involves the immune system, and this is known as tumor-promoting inflammation. We will discuss how inflammation can aid tumor growth and lead to subsequent tumor movement and metastasis. So the tumor microenvironment is often infiltrated with an adoptive immune cells that enable tumors to mimic inflammatory conditions that are seen in normal tissues. Current Molecular Cancer Research indicates that this tumor associating inflammation may aid in tumor growth. Additionally, inflammation is seen in early stages of several neoplastic diseases. Early inflammation can release chemicals into the tumor microenvironment that may lead to mutations, and enable cells to accelerate the formation of tumor. As well as cells to undergo what is known as the epithelial to mesenchymal transition, or EMT, and invade. This is shown on this cartoon here where you have immune cells shown on the left that secrete cytokines. And then those cytokines regulate the immune cell proliferation and accumulation. These cells also secrete proteases, which are degrading enzymes that break down proteins, particularly those found in the extracellular matrix. Cancer cells can also secrete factors such as chemokines to immune cells. And immune cells can secrete these factors back to cancer cells which leads to increases in cellular motility, to cell movement, cellular survival, and a process called angiogenesis that we'll talk about in future slides. All of this enables tumor cells to grow and survive and invade. So that is it for this section. I think you can appreciate the emergent cellular hallmarks of cancer. You will now have a short quiz and in the next session we'll discuss angiogenesis and metastasis.
