Cancer and Metabolism

 
 
 
 

Vocabulary

 

cell	generate	cause of death
patient	lights up	approach (2)
effect	scientist	metabolism
observe	invasion	know/knew/known
piece	diagnosis	eat/ate/eaten
peace	lactic acid	take advantage
scan	pancreas	Nobel laureate
label	glucose	therapeutics
organ	step (2)	take it a step further
oxygen	major (2)	far/further/furtherest
convert	run out of	carbon dioxide
access	survival	PET imaging
muscle	enzyme	lead/led/led
burn	buildup	feel/felt/felt
lactase	molecule	point of view
ATP	glycolysis	concentrate
DNA	divide (2)	make/made/made
RNA	blueprint	microscope
mutate	concrete	carbohydrate
starve	block (3)	insulation
cellular	pyruvate	biosynthetic
detail	screen (2)	pathway (2)
alter	pathway	deliver (2)
glucose	shrink (2)	find/found/found
genetic	share (2)	see/saw/seen
design	sensitive	tell/told/told
detect	based on	mass spectrometer
invade	figure out	as you can see
route	multiple	personalized
rewire	strategy	inefficient
protein	enzyme	take advantage of
breathe	avenue (2)	begin/began/begun

 
 
 
 
 

Video

 

 
 
 
 

Transcript

I love candy!

Does anyone else like candy? A lot of you. Well so do cancer cells. Cancer cells love sugar.

As many of you know, cancer remains the second leading cause of death in the United States, which means we still need better therapeutics for our cancer patients.

Today I’d like to tell you about an exciting new approach to cancer therapy based on sugar metabolism. We’ve actually known for a long time that cancer cells love sugar.

Almost a hundred years ago in 1924 a famous German scientist and Nobel laureate named Otto Warburg observed that cancer cells eat a lot more sugar than normal cells. So this observation that cancer cells love sugar is known as the Warburg Effect.

And the Warburg effect tells us that normal cells can stop after just one piece of candy — but cancer cells can’t stop eating candy.

.     .     .     .     .     .     .     .

And we do take advantage of the Warburg Effect for diagnosis of cancer through PET imaging: here’s a PET scan of a patient with pancreatic cancer. The patient was given radioactively-labeled glucose, which lights up when it concentrates in an organ.

The pancreas normally doesn’t light up because it normally doesn’t like to eat so much sugar. But in this case the patient has cancer cells in the pancreas; it’s eating up all the sugar, concentrating it and causing it to light up in the PET scan. And we’re able to diagnose the patient.

So it’s good that we’re taking advantage of sugar metabolism and the Warburg Effect for cancer diagnosis. But I want to take it a step further and use it for therapy.

Well in addition to eating a lot more sugar cancer cells also metabolize sugar differently. There are two major ways to metabolize sugar.

.     .     .     .     .     .     .     .

One way is to use oxygen, which we breathe in and convert it to carbon dioxide, which we breathe out.

If we don’t have enough access, if we don’t have access to enough oxygen, we can also convert sugar to lactate also known as lactic acid; and we’ve all experienced this during exercise when we’re unable to deliver enough oxygen to our muscles. We run out of breath and we start getting lactic acid buildup, and we feel that muscle burn.

From an energy point of view it’s much better to metabolize sugar using oxygen because you can generate up to 36 energy molecules called ATP’s. If you convert sugar to lactate, you only generate up two.

Well normal cells take sugar, use oxygen and convert sugar to carbon dioxide, generating a lot of energy molecules.

But cancer cells eat a lot more sugar, and they convert most of it to lactate — even when they have plenty of oxygen available and they don’t generate much energy.

So why would cancer cells use such an inefficient metabolism?

.     .     .     .     .     .     .     .

Well to answer this question, we have to think about what a cancer cell needs. A cancer cell needs to grow and divide and make more cancer cells. And you can’t make more cancer cells simply with energy, just as you can’t build a new house simply with electricity.

So yes we can make energy from sugar, but we can make other things like DNA and RNA, which serve as the genetic blueprints for the cell, just as you will need a blueprint to build a house. You can also generate carbohydrates, proteins and fats, just as you will need building blocks, concrete, insulation and other items to build a house.

And we think that the Warburg effect supports all these biosynthetic pathways that generate cellular building blocks. And if we want to take advantage of the Warburg Effect we have to understand it in more detail.

So our favorite form of sugar is called glucose. And glucose is metabolized mainly through a pathway called glycolysis, which has many steps that eventually generates a metabolite called pyruvate.

Without oxygen you can generate lactate from pyruvate. With oxygen you can generate carbon dioxide. Now the enzyme that generates pyruvate is called pyruvate kinase, and it’s altered in all cancer cells.

.     .     .     .     .     .     .     .

There are actually two major forms or isoforms of pyruvate kinase: M-1 and M-2. M-1 is found in many normal adult cells, meaning these cells are no longer growing. M-2 is found in every cancer cell study to date. But to make things more complicated, it’s also found in some normal growing cells.

So what I did in the laboratory was to delete pyruvate kinase M-2 from both normal and cancer growing cells and see what would happen.

And here’s what I found: normal cells grow well, as you can see in the yellow line with pyruvate kinase M-2. And when I delete it, they completely stop growing as you can see in the red line.

When I do this to cancer cells, they’re able to grow with or without M-2. So how they are doing this? Has their metabolism changed? Are they rewiring their metabolism in order to do this?

We have to be able to look at their metabolites. And we can’t just put them under a microscope and look at metabolites; it’s too small.

.     .     .     .     .     .     .     .

So we need very expensive and sensitive experiments. I’ve been told that this looks like a Slurpee machine, but this is actually a very expensive instrument called a mass spectrometer. And it can detect thousands of metabolites based on a molecule’s mass.

These are instruments that Otto Warburg did not have; but we have access to them. And we can study cancer metabolism in great detail. And I want to show you my data using this instrument.

But before I do, I don’t want you to look at the words; I want you to look at the colors. Is it black or do you see a lot of colors? If it’s black that means no metabolites are changing. If you see a lot of colors, the metabolites are changing.

So let’s take a look.

As you can see, these cancer cells are completely changing their metabolism; they’re increasing their metabolites in yellow and decreasing their metabolites in blue, so that they can still grow without M-2.

.     .     .     .     .     .     .     .

So it’s like this: if cancer cells are invading what this Wharton Center at Michigan State University, and we figure out that they’re coming in through Wilson Road.

So what do we do well we block Wilson Road we delete that road so they can’t get in. And what do they do? They find a new way in; they rewire their route. Even though it has more traffic and it’s more indirect, they still find the way in.

So without M-2, normal cells stop growing, and cancer cells continues to grow by rewiring their metabolism.

So what I’m doing now in the laboratory is blocking multiple roads at once. Multiple genes so that cancer cells stop growing, while normal cells continue to grow.

So we just talked about glycolysis and pyruvate kinase; but metabolism is much more complicated than this. And I want to give you an idea of that.

So I’m going to shrink glycolysis and move it to the upper left corner of your screen. And now I’m going to fill in the rest of your screen.

So take a deep breath . . . and let it out.

.     .     .     .     .     .     .     .

As you can see, metabolism is very complicated — and this is still just a simplified map of metabolism.

And remember: cancer cells came from normal cancer cells. So some pathways are shared and some pathways are different, which means we have to understand normal, complicated metabolism, as well as cancer complicated metabolism.

But this is a very exciting avenue for therapy because here are just some of the enzymes that are mutated, deleted or somehow altered in cancer cells.

So these are all potential targets for therapy.

.     .     .     .     .     .     .     .

So here’s our research strategy.

First I want to identify all the key metabolic pathways that help cancer. Then I want to do deeper mechanistic studies that tell us exactly how each pathway is helping cancer cells. Does it help their survival, their growth or their invasion or something else?

Then I want to take all of this information and use it to design personalized therapy, because as you know, all individuals are different with their own genetics, diets and environments.

So we have just begun to understand different metabolism and cancer and taking advantage of it for therapy. There are many different types of cancers with all kinds of mutations.

But they all have one thing in common they all have to eat. Cancer cells have altered sugar metabolism and I want to starve cancer.

*     *     *     *     *     *     *

 

Questions

Bite. “I LOVE candy!” Was the speaker being frank, honest and truthful; sardonic, cynical and sarcastic; or all of the above? Why did she say this? Was she promoting and marketing the processed (junk) food industry?

Chew. In 2014, the presenter, Dr. Sophia Lunt, discovered a relationship between cancer cells and sugar. True or false? What is the Warburg Effect?

Saliva. Can the Warburg Effect be used to locate, identify and diagnose cancer?

Enzyme. Is there a metabolic difference between walking, jogging and sprinting?
What is the difference between walking and sprinting?

Swallow. Do normal cells and cancer cells have different metabolic pathways? Do they have the same or different metabolism? Do they metabolize differently?

Esophagus. The speaker used an analogy to clarify a metabolic process. Is this right or wrong?

Gastric Juice. What are the isoforms of pyruvate kinase? What can you say about children and adults?

Hydrochloric Acid. Does the speaker use another analogy? What analogy does she use?

Digest. Metabolic pathways, enzymes, mutations, cells, tissues and food sources are all simple and straightforward. Is this correct or incorrect?

Chyme. Is the speaker searching for a single panacea for every single ailment for every single individual? Does she give any definite advice or suggestions for her audience?
 
 
 
Bile. How common is cancer in your country? Is it a leading cause of death?

Pancreatic Juice. Is the public very concerned (and frightened) of cancer?

Duct. What is the anecdotal evidence as to the causes of cancer?

Lymph Nodes. Has there been a lot of research on cancer?

Gut Bacteria. Are certain groups more susceptible or vulnerable to cancer; and others less like to have cancer?

Amino Acids. Are the folk remedies and treatments for cancer?

Glucose. What might happen in the future?