So let's think a little bit about how tumor invasion has to happen. Normal cells are held
together by a variety of things forming here at 1 single cell layered epithelium. And there
are cadherins that connect cells to each other. Those will be forming the desmosomes.
That spot weld cells one to another. They are also attached to the underlying basement
membrane. So there are a number of laminin receptors binding to laminin in the extracellular
matrix that will hold the cells down. Okay, and now they are attached one to another.
There are also fibronectin receptors that are going to be useful for binding to other cell
types or other extracellular matrix types further down below the basement membrane.
So you can see the fibronectin down below. Those are usually in place in a normal epithelium
in case there is wounding and that fibronectin can bind to the wound and can allow for
migration proliferation and other things. Okay, but we're really concerned about the cells
attaching one to another thru cadherins and attaching to them underlying basement thru
the laminin receptor. Cell goes bad. Another green cell. And you see that it has lost its
attachment, its cadherins with the neighboring normal cells. So that allows it to detach from
its neighbors, that's the first mutation that has to happen if you're going to be invasive.
And then, you want to upregulate your laminin receptor expression so you can start
clawing your way through that matrix you bind very avidly and you will use that to kind
of pull yourself through in the basement membrane into the underlying matrix. You're
also going to need to release a variety of proteases, type 4 collagenase, that's going to
break down basement membrane and also plasminogen activator that's going to break
down other extracellular matrix elements. That's going to allow you to degrade that so
that you can crawl through and you're going to ooze your way through after having
degraded the extracellular matrix. And remember, we also had those fibronectin receptors,
those are now able to bind to the fibronectin that's out there. Having the cell move in a
particular direction has to do with the formation of autocrine motility factors near the
leading edge so they spewed out and they go (sniff) "That smells good, I'm moving
towards that, I spew more out (sniff), smells good, and I move towards that." So that's
how you have a directional migration out of the epithelial layer and into the underlying
stroma. So, the tumor has to crawl out. We've seen how that can happen. You have to
have the reverse of that process when you crawl out of the back end. So the
lymphovascular invasion is the reverse of the tumor invasion step. An important feature
too is that just because you made it to the circulation, big deal, you've got to survive
immune surveillance. There are lots of lymphocytes and other cells in there that can
actually make it quite difficult for the tumor to survive. And for those of you who do
culture media experiments, you only use about a 20% of serum concentrations for your
petri dishes. These cells have to survive in 100% serum and many cells won't survive that
as well. And there's going to be antitumor immunity. There's going to be a gulled of
immune cells that are cocirculating with the tumor cells. So it is not an easy process to be
successful. Let's talk about antitumor immunity. So we've talked about the decathlon that
metastatic cells have to run in order to be successful in getting to a new site, let's talk
about how you evade antitumor immunity.