Cachexia as a Paraneoplastic Syndrome

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.