Tumor Cell Egress from Lymphovascular Spaces, and Metastatic Spread

00:00 So, came back to our invasion in metastasis. Tumor cell is also in the circulation to help them with their eventual egress. They surround themselves with other cell types in the circulation such as platelets. To get out, they have to adhere to the basement membrane as is shown there. They have to break down the basement membrane and extravasate into the tissue and they have to induce new blood vessel formation so that they have adequate nutrition at that site. So, kind of what I just said in graphic form, we talk about in words. So platelet interactions can actually improve tumor cell survival and extravasation. Platelets are able to adhere to various parts of the vascular bed. How did the tumor cells bind to the endothelium? Well they may use CD44 or a number of other adhesion molecules, CD stands for cluster of differentiation 44. And the same adhesion molecules are actually used by lymphocytes when they want to stick in a particular vascular bed. The basement membrane has to be degraded with the same elaboration of proteases that it took for the tumor to get in to the vasculature. That's what it has to do to get out. Additional points, the tumor does induce a stromal production that's part of that wound that will not heal with angiogenesis and the recruitment inactivation of fibroblast to lay down matrix. Interestingly enough, kind of predicting where tumors might metastasize too. They will frequently deposit in the very first capillary bed that they encounter, not always, but frequently. So if I have a colon cancer and it gets in to the blood supply, the very next capillary bed it's going to encounter is going to be in the liver.

01:59 And that's why liver is a major site of metastasis of malignancy anywhere in the GI tract, things going in to the portal circulation and they stick in that first capillary bed. However, other tumors have specific tropisms. They go to certain places, it's called seed and soil; seed is a tumor, soil is a place where they grow best. And some tumors, for various reasons, have a predilection to go to certain sites. This will involve specific endothelial adhesion molecules because the tumor has to know as it's circulating. "Gee, am I in bone? Am I in lung? Am I in brain? Am I in adrenal? That's going to be specific adhesion molecules there. And there will also be specific chemokines and attractants. So interestingly enough, in the seed and soil hypothesis where the seed and soil mechanism of metastasis.

02:51 Prostate cancer likes to go to bone. Haven't exactly worked out all the mechanisms in which adhesion molecules and chemokines that elects to go to bone. Lung cancer, for whatever reason, likes to go to brain and to adrenals. Hmm, we don't completely understand that but we do know that tumors tend to have a tropism or they can go to the nearest capillary bed where they stick and crawl across and do their thing. So, big picture points to take away from this whole discussion about metastasis and invasion and the other clever things that tumors can do. Tumors drive their own angiogenesis and stromal development. They need a reasonably good blood supply to bring in nutrition and oxygen. So that's why they drive angiogenesis. And the stroma is part of that process because the vessels are leaky and we will get a scar formation just as if we had a wound.

03:48 Number of factors can drive this, the ones that we know the most about and probably is one of the most important is vascular endothelial growth factor. But keep in mind there are many other angiogenic factors that will drive the same process. For a tumor to metastasize, it has to be a decathlete, it has to be able to do multiple things quite well and in any individual cell it needs to be able to release itself from adjacent cells. It needs to be able to crawl across a basement membrane. It needs to degrade extracellular matrix. It needs to crawl across the basement membrane of the endothelial cells.

04:29 Separate those endothelial cells, crawl into the bloodstream, survive in the bloodstream, avoid being destroyed by the immune system, stick somewhere else, crawl across again, and set up shop in a new place. There are multiple steps that must be intact for tumor to metastasize so that's why it's a relatively rare event. And finally, tumors are very clever, they have multiple different mechanisms that they can use to evade host immunity.

05:00 And because tumors are constantly proliferating with genetic instability, they are acquiring the necessary mutations or the necessary upregulation of various components in order to learn all these tricks and to be so darn clever. And with that, we finished kind of the big picture points having to do with metastasis and tumor genesis.