CSB327 Lecture 16 Notes

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Cell and Systems Biology
Maurice Ringuette

CSB327 Lecture 16 Notes (November 26, 2012) – Ovarian cancer metastasis 1 – Lecture topics • Ovarian cancer is a complicated disease. I am going to focus on a matrix-centric viewpoint (e.g., how the cancer cells behave and their interaction with the matrix). • A large number of cells in the heart are fibroblasts that can be transformed into myofibroblast (e.g., excessive ECM deposition). Even though volume wise, the cardiomyocytes take up more space, the fibroblasts are responsible for the matrix that makes the heart. 2 – Lecture outline • One of the famous problems with ovarian cancer is that it presents so late. Women don’t show metastatic disease or symptoms until they begin to have a build up in the peritoneal cavity (e.g., the cavity that lines the organs). It fills up with fluid as a result of metastasis and begins to swell. This is when women start feeling discomfort. By that time, it is a bit late. • I will use ovarian cancer as a prototype for peritoneal metastasis. Unlike a lot of cancers, it doesn’t spread through the vascular network except in very late stages. It primarily damages the peritoneum. The stroma plays a very critical role in the peritoneal wall. 4 – Peritoneal metastasis is distinct from haematological metastasis • This is like a breast cancer cell that originated from a mammary gland going to bone. • This is a long process. The odds of making it there are small compared to when you have peritoneal metastasis. Why is this a critical and vast feed-forward process and difficult to handle? 5 – Peritoneal metastasis • It stays within the abdominal cavity. In the viscera (e.g., guts), this would be covered by a peritoneal wall, then dermis and skin. • It used to be though that ovarian cancer cells were born in the ovary because of a cyclic wounding and renewal that occurs during ovulation that as the repair process progressed, you had some of these epithelial cells stuck in an environment (e.g., hormonal rich stroma of the ovary) and given enough time with ROS, they transform into malignant cells, broke out of the ovaries and seeded in the peritoneum. • We now know that the fallopian tube is one of the major sources of ovarian cancer. There are two sources in the literature. A lot of people argue that maybe it is the fallopian tube that is the most common source of ovarian cancer. 6 and 7 – Peritoneal metastasis • Gastric cancer also applies to what we know about ovarian cancer because they both stay within the peritoneum. The early polyps can be removed. If the polyps grow, they will eventually penetrate past the BL, release into the peritoneum and metastasize around the peritoneal cavity. • Do not memorize these stages. This slide is to show you that ovarian cancer and gastric cancer are two examples where they restrict themselves to the peritoneum. They don’t go through blood vessels. • This can be bad if you perforate the intestine pre-maturely during surgery. You can make the cancer spread. 8 – Peritoneal metastasis • They exfoliate from the primary site. They float around in the peritoneum and will stick to different sites within the peritoneum. I am going to talk about the peritoneal wall and the omentum (e.g., where the cells seed). • They are carried by peritoneal fluid to secondary sites and throughout the viscera. 9 – Peritoneal metastasis • It is fairly rapid and efficient. • Patients succumb to secondary peritoneal metastases. In other words, the primary site of tumour formation is not the cause of death. The seeding on the intestinal wall causes major issues. The intestinal adhesions will begin to block the intestinal tract. o There are a lot of secondary metastases. The advanced metastatic cancer cells are really hard. These metastases express a lot of protein, matrix molecules, remodel matrix, and extremely fibrotic. 10 – Peritoneal metastasis • Why is it such a poor prognosis? o It is one of the most deadly diseases of women. This is because it is diagnosed late. You can have a good success rate early before the spread. However, once it spreads, it becomes aggressive. • Chemotherapy resistance is common. Patients may respond to drugs initially, but eventually, drug resistant disease resurfaces. • This is a rapid fast-forward process. • Why are we focused on ovarian cancer? There’s not much you can do about the intial genetic event that might have triggered the transformation of these cells. Can we make life miserable for these cells as they are starting to seed on the wall to block angiogenesis and block interaction with the matrix? This is achievable at the stages where women present with the disease. You can’t do prognostic stories when there are no symptoms. Cont’d • Why ovarian cancer? o Other cancers that start from a primary tissue and metastasize to secondary sites, then looking at the secondary sites, you can analyze the change in the reactive stroma associated with the cancer. • One of the advantages in ovarian cancer is that you have ready access to the peritoneal cavity. You can treat ovarian cancer by IP (intra-peritoneal injections). • The second thing about ovarian cancer is that it is a matrix centric metastasis. It has to interact with the matrix to being to proliferate and form metastatic secondary sites. o They eventually cause major problems wherever they seed. If they seed on the intestinal tract, they will grow and block the intestinal tract, which is severe. • The peritoneum is a cavity that overlaps with the visceral organs of the body. • The fallopian tube epithelia can give rise to ovarian cancer, as well as the ovaries. • In the process of the progression, the women will start feeling discomfort (e.g., distension of the stomach) because the vasculature becomes very leaky as a result of secretion of things like VEGF by the cancer cells and inflammatory response. You get build up of the ascites fluid that has to be drained. • As well as trying to block the seeding on the wall of the peritoneum, if we could block ascites fluid production that fills up the abdominal cavity, that would reduce the pain. 11 – Peritoneal metastasis structure • What does a peritoneal wall look like? • This is looking outwards from the intestine. You see the peritoneal cavity and the peritoneal wall. This is a special type of cell called mesothelial cells that have a character of mesenchyme and epithelial. They are easy to tweak one way or the other. These cells line the stroma that is part of the connective tissue of the peritoneal wall. o A cancer cell from a fallopian tube or ovary sees a wall of cells first. It will not see the matrix at this stage. The mesothelia is acting as a protective barrier. • Under the mesothelial cells, you see a collagen rich matrix containing fibronectin. Laminin is part of the BL that these cells make. There is a BL followed by a collagen rich environment as well as fibronectin. • These cells that you see act as a protective barrier. A cancer cell will not seed onto this. • What do the cancer cells that spread in the peritoneum love to bind to? • If you coat plates with different types of ECM molecules and use a variety of different cancer cell types, you can see that BSA is the control. They do not bind effectively. o When you look at collagen I, there is a tremendous increase in their ability to stick to collagen I. It still likes collagen IV, fibronectin and laminin, but not as much. • The star of the show is collagen I. Where is collagen I? There is a stroma that is enriched in collagen I underlying the mesothelial cells. • The mesothelial cells line the peritoneum and act as a protective barrier. The mesothelial cells secrete proteoglycans and HA. The mesothelial lining the cavity facing the organs is very slippery. It prevents things from sticking together and makes life miserable for the cancer cells to adhere to. • The mesothelial cells needs to have something to happen to it to expose the collagen, FN, LM rich ECM. 12 – Peritoneal metastasis • Collagen I is the preferred substratum for ovarian cancer cells and gastric cancer cells. • You can begin to study how the behaviour of these cells are on different matrices. • The monoclonal antibody against IgG is a control. This is not targeting any molecule. o At 0 hours, you see cellular aggregates. The cancer cells are tightly packed.  Spheroids are important to the progression of cancer. o At 24 hours, the cells spread. For collagen I, the cells are really dispersed. They like to bind and spread on the collagen matrix. • The monoclonal antibody against β1 integrin. o After 24 hours, for collagen I, when you have a neutralizing antibody that will block the activity of β1 integrin, you see no spreading compared to the control experiment. This suggests that this integrin-dependent migration on collagen I can be blocked by antibodies.  Why do you use β1 antibody? It is the most common. What is the favoured integrin for collagen? β1. This is consistent with their adhesion and spreading. o There is no major change in LM, CIV and FN. • BSA is another control. The cells don’t stick to albumin. 13 – Peritoneal metastasis • The peritoneum has lymphatic portals for draining the peritoneal fluid under normal standards. There is a specialized tissue called the omentum (fold-like) that covers the visceral organs. The omentum is like a flap. For example, gut, omentum folds over gut and peritoneal wall. The omentum is a multi-functional tissue and is involved in the immune response. It is abundant in milky spots. • There are milky spots in the
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