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The Warburg Effect - Basis of the PET scan

Cancer research is increasingly becoming the field of interest among researchers. The reason is simple; healthcare is based on trying to overcome the inevitable, but here is an entity that seemingly has only a negative outcome. In order to find a solution to something, the problem needs to be delineated, and that’s where the trajectory of current research is heading:

Understanding cancer.

Efforts are underway simultaneously on how to diagnose, prognosticate, and manage these conditions better and on accurate follow-up to pick up recurrences. This was how Positron Emission Tomography, popularly called the PET scan, came into being; a very important tool to pick up metastasis and recurrences.

So how exactly does this PET scan work? Well for that, we need to understand a little bit about a cancer cell’s metabolism, more specifically to a concept called, the Warburg Effect.

The Warburg Effect, described by Otto Warburg in the early 20th century describes how the cancer cells use aerobic glycolysis as a source of their energy, rather than oxidative phosphorylation which is the more efficient process of cellular respiration.

Now before we understand the Warburg Effect itself, let’s talk a little about this 6-carbon molecule that seems to be the centre of this whole story: Glucose.

Glucose, a simple carbohydrate, is used by most of the cells as fuel to produce energy in the form of ATP. After a meal, the food that we eat gets broken down by the enzymes in the gut to simpler molecules that can be absorbed, one of which is glucose, and under the influence of Insulin, glucose gets transported into cells for energy production or storage as glycogen.

To produce ATP, glucose needs to undergo a series of reactions inside the cell, from glycolysis in the cytoplasm, to the citric acid cycle and finally the oxidative phophorylation reactions in the mitochondria to produce ATP. At the end of this process, one molecule of glucose is used to generate 36 molecules of ATP. That’s a fairly efficient system.

In cancer cells however, even in the presence of oxygen, the cells don’t prefer to go through this entire process; it stops at glycolysis. The energy yield is only 2 ATP. This is called “aerobic glycolysis”, and this is exactly what the Warburg effect is.

 
Warburg effect.jpg
 

Logically, a question pops up in our head:

Why does a rapidly dividing mass of disorganised cells opt a less efficient system?

When any cell divides, along with its genetic material being duplicated, all its cellular organelles and the cell membrane also need to get duplicated. So that means lipids, nucleic acids and other structural proteins need to be synthesised, and all these raw materials needed for these actions need to be pumped into the dividing cell.

In cancer cells, the end product of glycolysis, pyruvate, is shunted to creating all the molecules required to create 2 new cells, thus dividing faster than a non-cancerous cell, giving it a distinct survival advantage. Recent studies have suggested that the mutations responsible for carcinogenesis also up-regulate the mechanisms required for glucose uptake. Curiously, this glucose hunger is seen even in embryonic cells, which also tend to be rapidly dividing cells.

So, cancer cells are glucose hungry, and divide faster than a normal cell and this concept of “glucose hunger” forms the basis of PET scan. A radio-labelled glucose molecule is injected into the patient; naturally, the cancer cells pick these molecules up first, and this uptake is recorded by gamma cameras that show where the cancer cells are.

This increased glucose uptake and utilisation also explains why people with advanced malignancies have a loss of weight, a phenomenon called cancer cachexia and and depriving glucose is being researched as a potential therapy for cancers with high rates of cell division.

Author: Anirudh Murali (Facebook)

Sources and citations

1. 1. Kumar, Vinay, et al. “Chapter-5: Neoplasia.” Robbins Basic Pathology, 9th ed., Elsevier-Saunders, 2013, pp. 195–196
2. Seyfried, T N, et al. “Metabolic Therapy: a New Paradigm for Managing Malignant Brain Cancer.” Cancer Letters., U.S. National Library of Medicine, 28 Jan. 2015, www.ncbi.nlm.nih.gov/pubmed/25069036/.