Tumor Angiogenesis

00:00 Hey, welcome back. We've been talking about normal wound healing. We have been talking about normal angiogenesis. Well, tumors use the same general pathways, they're just not quite as organized in doing so and so it's important that you understand how tumors engender new vasculogenesis, new blood vessel growth in, and the stroma that they build around them so that we can think about how we might treat that or how we might use that as an Achilles heel in treating malignancy. With that kind of initial introduction, let's begin. This is where we are in terms of our roadmap. We talked about the biology of neoplasia, we talked about some normal angiogenesis and wound healing. Now we're going to get into tumor angiogenesis and a stroma. So here is the fundamental issue. Tumors, if they don't have a good blood supply to supply them, they can only get to a certain size, maybe 1-2 mm in cross sectional diameter. That's because the middle of that becomes relatively hypoxic.

01:06 There isn't enough nutrition or oxygen to supply the central portion of a tumor that's grown to a certain size. So there will be necrosis due to hypoxia and also to loss of nutrition.

01:19 So the tumor if it wants to be successful, I mean and that's what it wants to do, it needs to engender new blood vessel growth into it and it will release a number of factors; vascular endothelial proliferation factors, vascular endothelial growth factors, basic fibroblast-derived growth factors. There is many of them, maybe 20 different ones overall.

01:43 They are secreted into the extracellular matrix around the tumor and then they will drive the process by which that nearby vessel that is intact will grow and respond to the growth factors and now supply the tumor with new blood vessels. So some of the activities that will happen because of these growth factors in particular VEGF, vascular endothelial growth factor also known as vascular permeability factor. But VEGF has all the necessary activities to drive angiogenesis. So the little balls that's VEGF being secreted into the extracellular matrix and there is a gradient. When you reach a certain sufficient high level, we will have the endothelial cells at that point break down their basement membrane, that's what's happening here. They will begin to proliferate and migrate and mature to form a blood vessel that will be able to provide adequate nutrition and oxygen to the tumor. And that's basically what tumor angiogenesis is all about, it's the tumor being successful and allowing it to grow more and more. Well there is also another consequence. Now that we have an intact vasculature that's kind of saddled up to the tumor pumping in, the tumor can also use that as a means of egress so cells can potentially now enter into the vasculature they couldn't access before. So, it is also a double edge sword as far as the host is concerned because not only have we provided new blood supply to the tumor, but it's also allowing for metastatic spread. So, what are the various factors that can drive this? I already said there are probably 20 different vascular growth factors, the ones that will be on the board examinations that you'll hear most commonly because we actually now have antibodies that block them is vascular endothelial growth factor. It also increases vascular permeability and that's what's being indicated here. The vessels are quite leaky and so previously it also been called vascular permeability factor. There is a normal physiologic expression as we've talked about before driven by things like hypoxia and acidosis, certain cytokines, sex hormones, etc. but the tumor is doing this for its own nefarious reasons. Important too, we had thought that if we just block VEGF alone with antibodies, monoclonal antibodies, that would be the end of the game, we'd be able to starve tumors. Well, it turns out that there are many other angiogenic factors and even if we block one, the tumor can upregulate the expression of others. So this might be a good target for therapy. We just haven't figured out how to keep ahead of the tumor changing what factors it generates. In terms of the tumor angiogenesis and the genetic regulation of expression of things like VEGF, it turns out that mutant p53 and other activated oncogenes such as RAS in our tumor will potently upregulate the expression of the angiogenic factor such as VEGF. And importantly, it also once that p53 is mutated or RAS is upregulated now we uncouple the angiogenesis from the environmental cues. So it isn't totally driven at that point by hypoxia or acidosis. The tumors just cranking up the stuff and it will actually lead to abnormal vasculature. And it's important because angiogenesis as we've already indicated in the previous slide, precedes invasion. So, without a nearby tumor bed, tumor cannot get out of that tumor bed into the host vasculature.