all right welcome back so this video is about again organo tropism worgen tropism organ honing so vide us a breast cell the breast cancer cell predictably go to the lung in the liver and the brain and why do some other tumors spread to different organ site what's with the seed and soil why does one tumor go to a particular place and that's three main factors that I want you to appreciate actually before I talk about those I'm gonna talk about a historical perspective people have been thinking about this a lot and one of the hypotheses is called the seed and soil hypothesis may be a tumor cell will grow particular well particularly well in a secondary organ that kind of looks like itself and some people have postulated maybe if they came from the germline tissue right so the Me's abarim ectoderm those kind of things they came from the same tissue maybe they're more alike and there is a better soil for the cells to thrive in once they get there we don't really know how much this is true a lot of this is conjecture there's three main factors that we know for sure that that will affect whether a cell goes to a particular organ and the first one we have right here is where it arrests in the circulation depending on where you depending on where the cell enters the circulation will largely determine of which capillary bed it crawls out of okay so here's a simplified version of my my circulatory system my lungs right here my heart and here's my brain and here's some tissues right so and so again wherever I put the set wherever the cell enters it is literally the first capillary bed that you would that you might encounter so I give you an example the in a mouse for instance kay now I'm going to tell you about that my research presentation if we want to have a chance of a brain metastasis it cancer cell that travels to the brain I touched my head because you don't know where the brain is right so here's the brain the but we do is we inject cells in to the left ventricle of the heart and from this left ventricle it gets pumped up da order and hits the capillary beds of the brain okay where it arrests and so you're more likely to get a brain metastasis if you're shooting for a lung metastasis okay what you would do is you can inject it in the tail vein okay so the tail has a really nice big vein and if you inject the cells in the tail vein it gets returned and then ends up in the pulmonary capillaries right here it is more likely to form a long metastasis so wherever the first capillary bed is the first pass organ as we say that it encounters that is a large factor - of where it will end up so again here's a cartoon my red blood cells don't have a nucleus they're small they're squishy again it kind of looked like an indented donut you can sort of like squish them around they can squeeze through capillaries tumor cells comparatively are big even though they're not big on an actual scale they are bigger and they're not meant to squeeze through capillaries that's not what they're supposed to do okay and so they can tend to get stuck in these capillary beds right so that's the first part first pass organ secondly it has to do with the tumor cells ability to express genes inappropriately especially transcription factors which are usually there for embryonic development and twist is one of those transcription factors I got this from a paper - so in this paper they showed that so again twist is a transcription in an embryonic transcription factor that allows for motility of cells so that kin cells can crawl around and form a three-dimensional human being as you were developed okay so an adult's twist is a differentiated organ twist is turned off but apparently the egg pression ok the inappropriate we expression of twist enables extravasation so here we have cancer cells again you see how like we can image this oops inside I want to get a pointer okay image this inside the living animal so here we have a cancer cell that is stuck in a capillary at timepoint 0 30 minutes 60 minutes nothing is happening you see the blue cell in the green blood vessel right here so the blood vessels in green the cancer cell in blue and then we add twist this transcription factor that enables the cell to turn on metalloproteases and these metalloproteases are able to dissolve the adhesion molecules between the endothelial cells right so here in green my endothelial cells my blood vessel cells and it's the inappropriate expression of metalloproteases via this twist transcription factor that allows these cells to crawl out okay so where do they end up well first organ how do they crawl out they express inappropriately metalloproteases and allowed them to crawl out okay do all of them do it nope you could also die in there but that's one way of doing it and then lastly which tissue they go there has to not to do with the integrity of the endothelium in this organ okay how tight in other words how leak proof are the blood vessels of this particular organ and so we see this in breast cancer a lot the first side of metastasis and breast cancer it's generally bone metastasis okay and one of the reasons why that might be is if we look at the integrity of the of the bone right here of the blood vessels in the bone they actually have fenestrations openings through in the in the endothelial cells right here in blue is failure cells are supposed to form the blood vessels but bone cells actually have slightly open blood vessels may get fairly easy for this cancer cell to come out right here okay and so part of the reason why that is is because in this bone marrow right here are these stem cells the cells that are gonna make more blood cells white blood cells red blood cells right those are the stem cells of our blood cells well they have to get into the blood somehow well there's these openings these fenestrations so that these him hematopoietic stem cells as we call them so a stem cells of red and white blood cells can actually crawl in there so these openings make it easier for cancer cell to crawl out hence bone is a likely site of metastasis the brain on the other hand is protected by a blood-brain barrier okay you might have heard of that that prevents a lot of substances to actually get into the brain including unfortunately chemo therapies so most chemo therapies that we can give a patient they will reach tissues like the lung and the liver just fine but they won't make it into the brain because the brain vasculature is so selective of what gets in and what doesn't because of this blood-brain barrier let's compare so here's our endothelial cell which compared to the bone excuse me is tightly closed no fenestrations okay around these these endothelial cells around the blood vessel cells is another kind of cells called an endothelial cell I'm sorry the parasite the parasites have these feet right which can wrap around and so they almost go all the way around here and basically form a second layer a second cellular sheet on the on the blood vessels that makes it a double cell wall and that makes it hard to penetrate certainly for cancer cells do you see these guys right here it'll go stuck inside no chance that coming out and even if they did penetrate the first and the second line of defense right here the brain has its own immune system called astrocytes right here microglia I'll tell you about these a little bit later but these guys right here have their feet firmly planted on the parasite so even if these guys get out they would be right there the immune system is right there so crawling out of a blood vessel in the brain is a very unlikely event and it's partly due to the integrity of the endothelium of the blood vessel organization if you will in various organs so these are three factors that affect which organ a blood base a cancer cell might eventually come out all right we'll be right back