Hypoxia-inducible factor

cancer.

But the HIF-1-alpha, it's Often, I mean, it's not something that we can measure, but it's often something that's abnormal because of just relative states of hypoxia.

You don't need to be anemic.

You don't need to be a COPD patient who's hypoxic.

You can have a relative state of hypoxia in the tissue itself.

And if that's because of inflammation and oxidative stress, HIF-1-alpha gets released.

which then leads to the final common pathway of inflammation, which is NF-kappa-beta.

And now you've got problems.

And this isn't a like, look what I know, but This is one mechanism that we know, right? When you exercise, you elicit some form of oxidative stress and changes in tissue partial pressure, so like how much oxygen is there.

And then this stimulates something called HIF-1-alpha, which is a potent angiogenic growth factor.

So it stimulates the release of something called VEGF.

I did my dissertation on this area, so this is why I know this.

No, this is fascinating.

I'm glad you brought that up because it's cool to touch on.

So HIF-1-alpha is activated by the delta of oxygen.

So not necessarily the presence of or lack thereof, it's the delta.

It pretty much becomes difficult.

And diabetes does impair angiogenesis, okay? One of the pathways that becomes particularly important here involves HIF-1 alpha, okay? I did a whole episode on this, okay? So think of H- [chuckles] HIF-1 alpha as one of the part cell's response systems to low oxygen.

And when the tissue becomes hypoxic, HIF-1 alpha helps activate those genes involved in adapting to the environment.

And then one of the most important downstream signals of this is VEGF.

VEGF is vascular endothelial growth factor.

And vascular endothelial growth factor tells endothelial cells we need new blood vessels here.

And conceptually, hypoxia will activate the HIF-1 alpha, and that will cause VEGF, and that will cause the endothelial response, and that will cause angiogenesis.

But here's the fascinating part.

And we needed to do that in a setting of where tumors were – were able to be looked at on treatment.

And that really required both a good genetic model of kidney cancer that is a VHL dependent model, because we know obviously that the whole reason why TKIs work in kidney cancer uniquely is because of VHL dependency and HIF dependency.

And the second was that we wanted to be able to do it sort of longitudinally in an immunocompetent system where we could track tumors over time and look at resistance and sensitivity.

And that required immunocompetent models.

What tends to grow in mice and what tends to grow in vitro is sort of the more de-differentiated one.

Now, we proved in this study that they retained the hallmarks.

They had the HIF-1, they had CA9, they had GLUT-1, all the things that we know make them bonafide VHL-dependent, HIF-dependent tumors.

But they're very de-differentiated, unfortunately.