So in the last section of this lecture we will discuss the Cellular Hallmarks of Cancer numbers 9 and 10. These hallmarks prepare the cancer cell to move and to metastasize to distant sites in the human body. So far we've covered these eight cellular hallmarks of cancer and tumor cells the process of angiogenesis, which is the formation of new blood vessels is critical for sustained tumor growth and subsequent metastasis. We will discuss this hallmark in the next couple of slides, Induction of Angiogenesis. All tumor cells require a blood supply to grow to a significant size. Cancer cells are able to do this by using pro-angiogenic factors such as vascular endothelial growth factor, also called VEGF in the field of cancer research,to become activated in tumor cells, and signal to endothelial cells to grow and make new blood vessels. In previous hallmarks, we talked about the help of immune cells in cancer and tumor genesis. Immune infiltrating cells such as macrophages can also secrete VEGF to induce angiogenesis. Unabated angiogenesis enables tumor expansion and local invasion through delivery of oxygen and nutrients and production of growth factors that largely benefit tumor cells. Here's a look at angiogenesis here. Tumor cells have the black nuclei and the normal cells have the blue nuclei in the cartoon. Tumor cells also grow geographically farther away from the blood vessels than normal cells, because they have a faster growth rate and therefore need more oxygen. So new blood vessels form from already existing blood vessels and reach to the tumor cells. This can continue as the tumor grows larger, and larger, and larger. Because this process is not natural, these new blood vessels are often poorly made and are leaky, meaning that blood leaks out of these vessels and they don't have a strong integrity. And therefore become easy for tumor cells to get into and to get out of them. This provides an outlet largely for tumor cells to get into the bloodstream and into the lymphatics, and metastasize to distant sites. So that brings us to our last hallmark, which is hallmark number 10, and that is the activation of invasion and metastasis. Hallmark number 10, activation of invasion and metastasis. Several things must occur before you get metastatic lesion in several cancer types. These steps are shown here. The first one, cell to cell and cell-extracellular matrix interactions are altered. Changes or loss of structural proteins that keep cells bound to the extra cellular matrix, which are integrins and other adhesion proteins. There are a loss of genes or mutation of genes that are seen in metastatic lesions. Known as metastasis suppressor genes. So they are different from tumor suppressor genes whereas you lose a tumor suppressor, you get tumor formation. When you lose these genes, you get metastasis. You also have a recruitment of immune cells which would covered in a previous hallmark and then, you get epithelial-to-mesenchymal transition as we abbreviated in EMT And here's a closer look at EMT. So as you can see, on the far left, you have normal cells that are cuboidal and stationary, bound to the extracellular matrix by, integrins, and other adhesion molecules. And they're bound to each other by E-cadherin and other cell-to-cell junctions. There's a loss in that over time, as you can see as you go further to the right of the cartoon, and you have a gain of Mesenchymal proteins. Several are of study, such as N CADherin or Neuro CADherin, is increased in these cell types. And then you have a change or loss in integrin adhesion to the extracellular matrix. This causes the cells to be more stretched out and to function quite differently than a normal cell would. So these cells become more invasive and begin to invade or move into surrounding tissues. So we've covered nine hallmarks previously. And the first hallmark was replicative immortality followed by genomic instability. And so genomic instability produces a daughter cell with the mutation. And that cell gives rise to other daughter cells. And then you end up with a hyperplastic legion which typically is the primary, or the first legion seen in several adenocarcinomas. And then you have cancer in situ that is accompanied by inflammation As well as the invasion of the immune system and resistant to cell death. And then you get invasive cancer that is triggered by loss of cell cell contacts, cell ECM contacts, as well as increased and intrinsic factors within the cell that cause the cell to move From it's original space in the organ to a distant space in the organ. Invasive carcinoma is highlighted in the box here. But now we will discuss metastasize which is a long process that we'll be discussing in great detail in a later lecture. But I would like to highlight key steps during metastasis. The first step being invasion, breaking through the extracellular matrix or ECM. And this is local tissue invasion as well. So as cells become more aggressive and more mobile and motile, they can gain cellular properties that allow them to break through the protective extracellular matrix. They break out of the extracellular matrix and go into the newly formed blood vessels via hallmark number nine angiogenesis and are able to get into the blood vessels more easily. Please note that there's a difference between cell movement and invasion. Think of movement as walking across a room versus invasion is using a elevator to go down to the first floor if you're on the ninth floor of a building. So invasion pushes the severity of the cancer to a higher level. The next step in metastasis or key step in metastasis is a step called intravasation. Cancer cells intravasate in to a blood vessel, usually by pushing their way through the vascular endothelial cells shown in this cartoon. This, again, ties us back to hall mark number nine, angiogenesis. And you can now appreciate the process of angiogenesis, and how it can promote Cancer cells to get into the blood stream more easily given that these blood vessels typically are poorly formed. The next step for a cancer cell to be fit enough to survive in the human body, is being able to survive during systemic circulation. So cancer cells must in a traverse venous system and they have to be able to get to the heart back out of the lungs, back to the heart and band through the arterial system where could go everywhere and wind up anywhere. Although sometimes a circulating tumor cell or CTC may just stop in the lungs and never really enters the arterial system, these could develop lung metastasis. During the transition through the circulation CTC must survive various sources of death and cellular stresses that a normal cell just simply would not be able to endure. And the last key step in metastasis is extravasation. These are when cells get out of the lymphatic system and set up secondary tumor sites in the distant organ. Once a cancer cell can begin to grow a metastatic tumor in a secondary site, this tumor follows many of the same hallmarks as previous tumors do, such as replicative immortality, resistant cell death, avoiding immune surveillance, alter metabolism, as well as other cellular features. The larger the secondary tumor becomes, the more problems it can cause. And you will discuss this in upcoming lectures that are focused directly on metastasis. As a recap, here are all ten cellular hallmarks of cancer. The first one we covered was replicative immortality which involve telomeres and telomerase. The second one was genome instability which involve the production of daughter cells that beared genetic mutations, alterations and deletions and these cells were able to continuously divide. The third hallmark we covered was evasion of growth suppression. And the fourth, resisting cell death, followed by sustained proliferation. And we covered how hallmarks 325 all work together to allow tumor agenesis. Emerging hallmarks that we discussed, were alter metabolism by the Warburg effect, where cancer cells can use alternate sources for energy. They are able to avoid the immune destruction, as well as use tumor promoting inflammation to their advantage. To induce movement, cancer cells are able to induce angiogenesis as well as induction of invasion and metastasis. These 10 cellular hallmarks are what distinguish a cancer cell from a normal cell. I hope you can all now appreciate how a cancer cell is very different from a normal cell, and also how these hallmarks make a cancer cell more fit to survive and proliferate in a perfect host, the human body. Looking ahead, upcoming lectures will include metastasis, as well as imaging, diagnosis, and staging of cancer. I hope you guys enjoyed this lecture. Thank you very much. [MUSIC]
