00:02
The final paraneoplastic syndrome I
want to talk about here is cachexia,
also an incredibly common
manifestation of malignancy.
00:09
How does this happen?
So it's a multifactorial syndrome, we're
going to have a bunch of boxes in a minute
so you'll see all the different
ways that this can happen.
00:18
Characterized by loss of body weight,
greater than 10% of your body weight
and it's often associated with
reduced food intake, patients are just
anorexic and not interested.
00:30
And there's also going to be systemic inflammation.
00:32
Again, malignancy will drive systemic inflammation.
00:36
It's an increased catabolism of fats and
proteins, so there's more proteolysis
going on than there is protein synthesis going
on and we'll talk about those mechanisms shortly.
00:46
There's also increased lipolysis to break
down fat versus the generation of fat.
00:52
And again, we'll talk about mechanisms.
00:55
So how is this happening?
Again, multiple molecular mechanisms.
00:58
And if you just say it's tumor necrosis
factor, IL-1, IL-6, all those cytokines,
you are going to be right.
01:06
The inflammation elicited by tumors will
drive the predominant forms of cachexia.
01:15
There's also different proteins elaborated by the
tumor, including a zinc alpha two glycoprotein,
that we will call ZAG in the subsequent
slide, that will engender lipolysis.
01:29
And in some ways, this makes some sense
if you're a tumor cell, you want to have
the massive breakdown to
provide nutrition to the tumor.
01:37
And as a consequence, however,
you're taking away fat from the host.
01:42
And then there's also a factor made by tumor
cells called proteolysis inducing factor,
which will cause protein degradation.
01:48
And again, these last two, ZAG and PIF,
P-I-F are going to be important for the tumor
because this now mobilizes nutritional
stores, amino acids, triglycerides, etc.
02:02
that the tumor can use because it's
very inefficiently using metabolites.
02:09
So the lipolysis, the cachexia that takes
away adipose tissue is driven in part by ZAG,
that zinc alpha-2 glycoprotein
elaborated by the tumor.
02:20
There's also because of the
inflammatory milieu that's going on,
we have inhibition of lipoprotein lipase.
02:26
And finally, there is the Cori cycle.
02:29
Oh boy, now we're getting to metabolism.
02:31
I'll show you on the next
slide what this is all about.
02:34
But there are Cori cycle leads to kind
of a futile cycling and loss of energy.
02:40
How does that happen?
Alright, so the normal Cori cycle.
02:46
In exercise in skeletal muscle,
we have a certain amount of ATP
that we can use and if you exceed that, you go
into aerobic glycolysis and you make lactate.
02:58
Okay, and that's why if you work really hard,
and then you stop, there'll be a little acidosis
and you might even get muscle
cramping because of that.
03:06
But we know this is going to happen.
03:07
This is kind of planned evolutionarily,
it's going to make some excess lactate.
03:11
That lactate tend to go to the liver,
and it takes energy in the liver
but that lactate will then
be converted back to glucose,
and that glucose can be
utilized by the skeletal muscle.
03:22
So this is the Cori cycle.
03:25
Note that it takes energy to do this.
03:27
Now if we substitute in place of that
exercising skeletal muscle, tumor.
03:33
Oh my goodness, remember the tumors,
you have this so called Warburg effect
so even in the presence of adequate oxygen, they
prefer to do what's called aerobic glycolysis.
03:45
They will not go down the TCA cycle.
03:49
They will generate happily, tons and
tons and tons of lactate inefficiently
because they're just doing glycolysis and
not sending things down the TCA cycle.
04:00
When that happens, now we're
generating tons of lactic acid
takes energy by the liver to
convert it back into glucose,
that the tumor is going to be using inefficiently.
04:12
So with a large tumor mass, we're
using up tons of ATP in the liver
in order to maintain that tumor.
04:23
The skeletal muscle component of cachexia
so there's decreased protein synthesis
and increased protein catabolism.
04:30
This is due to the PIF, the proteolysis
inducing factor made by the tumors.
04:35
It's also a secondary consequence
of all those inflammatory cytokines
that are engendered by the tumor as well.
04:42
The activation of NF Kappa B will lead to
the ubiquitination of myofibrillar proteins
that will then target them
for proteasome degradation.
04:53
And with the loss of the skeletal muscle,
systemically, there is profound weakness.
04:57
There can be diminished respiratory function,
after all the diaphragm is a skeletal muscle
and that will be a major factor
leading to shorten survival.
05:05
So patients who get cachectic will die earlier.