[MUSIC] Welcome to lecture six in our series, Understanding Cancer Metastasis. In the last several lectures you have gained an understanding of the sequential steps of metastasis, and some of the biology of how metastasis occurs. In this lecture, we would like to focus on the morbidity and mortality associated with metastasis. How cancer hurts and kills patients. At the end of this module you will be able to number one, recognize how cancer metastasis causes morbidity or harm, and mortality or death. Number two you will be able to describe the role of cytokines in metastasis. Number three, you will be able to recognize what cancer cachexia is. And number four, you will be able to explain Virchow's Triad. In this first section, we will describe the distribution of metastasis or, in other words, where do the cancers actually spread. To understand this we'll go back to Stephen Paget. As you may remember, as I hope you remember, he wrote a paper in 1889 on the distribution of secondary growths in the cancer of the breast, where he analyzed 735 fatal cases and argued that the distribution of metastases cannot be due to chance. Paget recognized that metastatic patterns did not simply follow blood flow distribution as suggested by Virchow. He referred to cancer cells as seeds in the way the distributed throughout the body must be understood by studying the properties of the soil of the secondary organs. Remember that famous quote, when a plant goes to seed, its seed is carried in all directions, but they can only live and grow if they fall on congenial soil. We refer to cancer cells going to different organ sites as homing. The table and figure demonstrate that specific cancers go to specific metastatic sites. For example, breast cancer most frequently goes to bone, lung, liver, and brain. Prostate cancer most frequently goes to the bone, liver, and lymph nodes. Lung cancer most frequently goes to bone, liver, adrenal gland and brain. Colon cancer is most often found when it metastasizes in the liver, lung and peritoneum. Liver cancer when it metastasizes most frequently goes to the peritoneum or lining of the abdominal cavity, the lungs and the bone. And stomach cancer most frequently goes to liver, lung, and peritoneum. Let's first look at metastasis to specific organs and the specific problems they cause. Specific organs that have specific symptoms associated with them that are most commonly seen in cancer patients are the brain, the liver, the bone, and the lung. Brain metastases are most frequently seen in patients who have lung cancer, breast cancer, melanoma or skin cancer, colon and kidney cancer. The symptoms include headache, seizures, or dizziness. In this patient here, you can see that a Metastasis grew over a long period of time from 2007 to 2014. But you can see as that cancer got big in 2014, it shifted the brain around. This causes increased intracranial pressure which causes headache. It can cause a seizure or dizziness. But that mass effect leads to increased intracranial pressure which can actually cause the rest of the body to shut down, ultimately causing death. Brain metastases, if possible, are treated with radiation or surgery to remove them. The liver is a frequent sight of metastases from solid tumors. These solid tumors include colon, lung, breast, melanoma, stomach and pancreas. It takes a lot of metastases to cause liver damage. And that's why even when you have a liver metastasis, it takes many liver metastases to actually cause liver morbidity or mortality. If you get enough metastases like seen in the patients here, in the upper left hand figure you can see a radiograph showing the many cancer deposits. In the lower left hand corner you can see what those deposits of tumor look like in a autopsy. In the right side demonstrates what that looks like microscopically. Suffice it to say you need a lot of cancer in the liver to cause damage. And in fact, it's estimated that you can replace 90% of the liver with cancer and still have normal liver function. If enough of the liver is damaged you can get jaundice, which means turning yellow, you can have nausea, and the liver enlargement itself can cause pain. Ultimately, the cause of death for a patient can be liver failure. But, again, you literally have to destroy 90% of the liver before that happens. Bone Metastases are very common in many solid tumors. The most common origins for bone metastases are prostate, breast, kidney, lung and thyroid. Bone metastases occur in almost 100% of patients with metastatic prostate cancer, and over 50% of women who suffer from metastatic breast cancer have bone metastases. These bone metastases can cause pain simply by growing in the bone and pushing on the nerves of the bone. They can cause fracture, meaning the bone will break. If those metastases occur in the back bone and they're growing, they can actually compress the spinal cord and cause paralysis or nerve pain. Generally a single fracture or spinal cord compression can cause morbidity but does not kill the patient with cancer. However if you get many, many bone metastases that are causing pain, the only way you can control that is with pain medications. Patients can die eventually because they spend all their time sleeping from the use of pain medications. They can also cause cachexia, and we will address these in the next section. Finally, let's talk about lung metastases. Again, the lung is a common place for many solid tumors to spread. Most common origins of lung metastases include the bladder, colon, breasts, prostate, as well as sarcomas. Just like in the liver, it takes a lot of metastases to cause symptoms. If symptoms do occur, they include cough, shortness of breath, and coughing up of blood. Enough metastases can cause respiratory failure. It should be emphasized that, just like liver cancer, it takes a lot of lung metastases to cause respiratory failure. For example, the lung that you see in the upper panel has many metastases, as you can see from the white spots in the lung. But this patient would typically not have any symptoms. And certainly, the patient shown in the radiograph, who has only one metastases in the lung as noted by the box, would not have any symptoms at all.
