[MUSIC] Hi, my name is Ken Valkenburg, and I'm a cancer researcher at Johns Hopkins School of Medicine. I'm going to talk to you about cancer metastasis. So I've entitled this module Metastasis, The Real Killer. Because metastasis is usually the thing that causes death in cancer patients. And we'll get into why that is and how it happens throughout this module. These are the objectives for the module. The first one is to understand the lethality of metastasis. The second one is to describe the TNM system for cancer staging. Then, to identify the major steps of the metastatic process. And finally, to explain the principle of metastatic homing and the seed and soil hypothesis. So, the first section that we'll go over an introduction of metastasis. And we will describe and define metastasis. So, metastasis can be broken down into two parts. Meta meaning to alter something or something beyond. And stasis meaning a state of inactivity or stagnation. Put together, metastasis is changing or moving beyond something stationary. In clinical terms, we use metastasis to refer to the process which tumor cells go from a primary tumor such as a prostate tumor to a different organ such as bone. Prostate cancer growing in the prostate is an example of a primary tumor. Whereas prostate cancer cells that have gone to the bone and begun growing there is an example of a metastatic prostate tumor. In other words, if someone has cancer cells growing in their bone, they may not necessarily have bone cancer. It only matters where those cancer cells originated. If they originally grew in the prostate, for example, then that cancer would be referred to as prostate cancer even though it's in the bone. Some terms to know that I'll be using in this lecture are on the right side of the slide, metastasize is the actual act of a cell going from a primary tumor to a secondary site. Metastatic is an adjective describing a cancer that metastasizes. And metastases refers to multiple metastatic tumors. So let's focus on the primary tumor first. You've heard of the words benign and malignant in reference to cancer. The very definition of a malignant tumor is a tumor that has tumor cells that have the ability to invade neighboring tissue and metastasize. Benign tumors may grow to a certain extent but as long as they do not develop the ability to metastasize, they remain benign. Benign tumors can become malignant however and we'll talk about that in future slides. In this course, Dr. Zarif previously discussed and defined the hallmarks of cancer. Each of these hallmarks promotes metastasis. Sustained proliferation, replicative immortality, and evading growth suppression allows for cancer cells to grow uncontrollably into a tumor mass big enough to invade neighboring tissue. Genome instability and an altered metabolism causes cells to become more aggressive and mobile. The ability of cells to resist cell death and avoid immune destruction allows for them to survive harsh conditions in the metastatic journey. And tumor promoting inflammation promotes metastasis by bring certain immune cells to the primary tumor that actually engage with tumor cells and cause them to leave the primary site and enter circulation. And angiogenesis, the formation of new blood vessels, provides a way for tumor cells to leave the primary site and enter the bloodstream. In short, all of the hallmarks promote metastasis and are extremely important for it to occur. Let's delve into the history of metastasis a little bit. Melanoma and metastases were found in 2000 year old skulls from Peru, and other metastatic lesions have been recorded as well throughout history. The actual word metastasis was used to first describe metastatic tumors in breast cancer patients who were lactating. They called it metastasis of milk. Associating metastasis with cancer diagnoses and treatment was first done in 1829 and the process of tumor dissemination later in 1858. Since then, cancer researchers have discovered much about the process and the nature of metastasis, but there is still much to learn. We know that all solid tumors can metastasize. Liquid cancers like leukemia do not metastasize because there is no primary tumor. And most people who die of cancer will die because they have a metastatic tumor. Some cancers are diagnosed infrequently with metastatic cancer, such as breast and prostate. Likely due to better screening methods, which can find tumors before they become metastatic. Some tumors however are difficult to screen and detect, and therefore become metastatic by the time they are diagnosed. You can see the number of deaths worldwide due to the six most common cancers. Breast, prostate, lung, colon, liver and stomach, which we have described before. That metastatic cancer is still a huge problem worldwide. In addition, this chart shows that in general the metastatic disease is the real killer for cancer patients. Non-metastatic cancers are much less lethal in general. Let me walk you through this chart. A five year survival rate refers to the percentage of patients that are still alive five years after the diagnosis. So for non-metastatic prostate cancer, 100% of patience are alive five years after diagnosis. For metastatic prostate cancer, only 29% of patients are still alive after five years. A similar dramatic difference can be seen in each of the other six cancers So now that we know that metastasis is the biggest killer in cancer, how does cancer actually kill people? One way is through the loss of tissue function due to a tumor growing in an organ, and damaging or blocking its natural function. And example of this is a metastatic tumor growing in the brain and causing loss of regular brain function. Excessive bleeding can cause irreversible problems for cancer that can lead to death. An embolism is the blockage of an artery, and if this happens in the lung, you likely have a pulmonary embolism. It could result in death. Cancer patients are also more prone to infection, partially due to the cancer's effect on the immune system, and partially due to the effect of chemotherapy on the immune system. Speaking of cancer treatment, chemotherapy and radiation can cause irreparable damage to various organ systems. This includes treatment that manage pain which metastatic cancer patients tend to feel a lot of. Cachexia is a term that generally means weakness and wasting away due to severe chronic illness, and cancer is certainly that. Metastatic cancer can also disrupt ion balances throughout the body. And bone metastasis in particular can cause severe hypercalcemia which is excessive amounts of calcium in the blood stream which can be fatal in severe cases. So that's it for section a, which is just an introduction to metastasis. And I think you can appreciate the lethality of metastasis in cancer. In the next section, we'll discuss the system that is used to stage cancer, in which metastasis plays a big role.
