Tumors: Wounds that Do Not Heal

by Richard Mitchell, MD

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    00:00 So, important points about tumor vessels, they're abnormal. That's what the headline says, must be true. So, they are not uniform in terms of their distribution. If we look at a typical vascular bed, we have an artery that branches into arterioles into a nice capillary bed and then into post-capillary venules into a vein and we're off. Well, it is not quite exactly that uniform distribution of those vessels because there is that aberrant expression of the growth factors. So there is a loss of that normal arteriolar capillary venule architecture and we'll actually get a lot of irregular branching and arteriovenous shunting. These vessels are very prone, once they form, to also collapse. And so the tumor may outgrow its blood supply. What's it actually doing is having an abnormal blood vessel supply that's not very reliable and can potentially be easily compressed by edema or other parts of the tumor doing it's thing. So, there is continuous growth. Again, we have taken away the normal regulatory things like hypoxia and acidosis. Once this stuff is upregulated, VEGF is being produced by mutant p53, then we have ongoing growth and endothelial cell proliferation. Again, it's kind of uncontrolled. The endothelial cells are normal. They are not tumor, they are not mutated, but they're responding to this kind of deluge of growth factors that will cause them to sprout and do all the things we've talked about. There is a very important lack of maturation, and one of the other elements that I haven't emphasized but I will now, in order to get vessels to mature into nice tubes, it's not, you know you don't want just a sheath of endothelial cells, you want tubes of endothelial cells. That maturation process involves smooth muscle-like cells called pericytes. Not a parasite, not like malaria but pericytes p-e-r-i cytes. And those pericytes are going to be important for the maturation into nice functional tubes. A lot of tumor vasculature lacks that. So that also makes the vessels kind of immature and extremely leaky. Also, there is no nervous innervation. We are not growing nerves along with the tumor vasculature. And you are probably well aware that nervous input is very important for regulating tone of the vessel, how much the arterioles contract or relax to allow blood in. We don't have any of that normal control mechanism because nerves aren't coming in as well. The vessels deluge with this VEGF, which is also known as vascular permeability factor. Hey, they're continually leaky. So, in a tumor bed of vessels, there's going to be a lot of edema fluid which is also going to impact the ability of, for example, chemotherapy to get in. And then they lack the normal vasomotion. So normally, arteries squeeze and we have capillaries that can respond with some degree of pericytes and dilate or constrict, none of that is happening.

    03:19 Okay so these vessels, suffice it to say, are abnormal. Well, how abnormal are they? That abnormal. So, previously we'd shown in the last lecture artery into capillaries, back to venules and then out. This is nothing like that. We have things going every which way. It's like a very bad day in Boston traffic. Okay, and we don't have the normal organization with the normal pericytes. Now, there will be some adjacent normal cell or normal vasculature and that's where the endothelial cell precursors are coming from that can also come from circulating precursors. They are being called in by the tumor.

    04:06 Somewhere over on the right hand side of this picture is the tumor that's inducing this neovascularization, angiogenesis. The cellular proliferation is being driven by the angiogenic factors. We will get the migration, we will get apoptosis to some extent because it's a very abnormal signaling process. The specialization may or may not happen. That would known to be expected within a particular vascular bed. And there will be ongoing endothelial cell necrosis. The cells will be potentially be dying as well because of this abnormal concentration gradient of growth factors. So the evolving network is very metastable, it's unstable and we can get compression of parts of the vessels, we may get expansion of parts of the vessels. You may have forward flow for a while and then backward flow at another time so it's a very unstable network. Consequently, there is abnormal function coming in to this vascular bed and feeding the tumor it still is usually sufficient to keep the tumor alive. And the growth of the vessels is totally inappropriate for the location. So just so you can think about this in a certain way, we're looking down an aerial view of Chicago. See how regular the streets are; they run north south and east west. Someone with a very mathematical mind said that's how streets should be constructed. That's a normal vasculature. On the right hand side, that's where I live.

    05:43 That's Boston. And the streets and the roads in Boston were built around in pre-existing cow paths, honest to God, and however the cow meandered around that's where they built the street and so it looks like a tumor vasculature. So it's just a way to think about it.

    06:01 Okay, so again to make this analogy about tumors being wounds that don't heal, both tumors and wounds generate stroma by very similar mechanisms. So you will have increased VEGF expression that will allow incredibly increased amounts of protein and plasma leakage from these leaky vessels. Remember it's also the vascular permeability factor. That fibrin will support the ingrowth of fibroblast and support the blood vessel ingrowth of course. That's what it's trying to do. The fibroblasts are coming in because that's the usual scheme of things when the body lays down new blood vessels in wound healing. You are calling in the fibroblast as well. They are going to march in along this abnormal vasculature, march out, and will be able to form new matrix. It will be mature but it won't be quite normal. In wound healing, that eventually the matrix will remodel and you'll end up with scar. Okay and that's terrific. But if we have ongoing stimulation, if we never turn off the wounding response that we've talked about previously, then you have desmoplasia, you have abnormal stromal formation and that's going to be around tumors.

    07:25 Just to make the point, again, so this is the 3rd or 4th time so it must be important.

    07:30 Right? Tumors are like wounds that will not heal. We're looking here at edema, at the leakiness of the vessels in a wound versus the leakiness of vessels in a tumor. And if we have injury and we have initial wound formation, initially the vessels that are going to heal that wound and turn into scar are leaky. Yeah, that's what they're supposed to do, that's an important part of the healing process. But that eventually goes away. So the green line comes down to very low levels of edema influx. However, in tumors, they just keep making more and more and more the fact that they never turn it off so the leakiness persists over a long period of time. And the scarring persists over a long period of time except it's desmoplasia, not a scar. And with that, we've kind of giving you hopefully a flavor for tumor angiogenesis and tumor stromal formation.

    About the Lecture

    The lecture Tumors: Wounds that Do Not Heal by Richard Mitchell, MD is from the course Tumor-host Interactions.

    Included Quiz Questions

    1. Nonuniform distribution, loss of arteriole-capillary-venule structure, and irregular branching
    2. Uniform distribution, loss of arteriole-capillary-venule structure, and irregular branching
    3. Nonuniform distribution, preserved arteriole-capillary-venule structure, and irregular branching
    4. Nonuniform distribution, loss of arteriole-capillary-venule structure, and regular branching
    5. Uniform distribution, preserved arteriole-capillary-venule structure, and regular branching
    1. They lack pericytes.
    2. They lack endothelial cells.
    3. They lack epithelial cells.
    4. They lack connective tissue.
    5. They lack a stromal matrix.
    1. Replacement of fibrin with a matrix
    2. Decreased vascular endothelial growth factor (VEGF) expression
    3. Decreased vascular permeability factor expression
    4. Decreased fibroblast recruitment
    5. Increased macrophage recruitment
    1. Arteriovenous shunting
    2. Arteriovenous hierarchy
    3. Arteriovenous homogeneity
    4. Arteriovenous maturation
    5. Arteriovenous continuity

    Author of lecture Tumors: Wounds that Do Not Heal

     Richard Mitchell, MD

    Richard Mitchell, MD

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