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.