The Cancer Code: A Revolutionary New Understanding of a Medical Mystery

by Jason Fung

Mitochondria are highly susceptible to damage and, to stay healthy, are constantly remodeling. To maintain high-quality mitochondria capable of carrying out apoptosis, two things must happen: old or damaged mitochondria are removed through a process called mitophagy, and new mitochondria are created.

Mitophagy is closely related to the cellular process called autophagy, which was brought to prominence by Nobel laureate Dr. Yoshinori Ohsumi.

Autophagy is a regulated, orderly process of degrading cellular components to be recycled into new ones.

Autophagy definition.

Autophagy functions as a cellular housekeeper and is controlled mainly through the nutrient sensor mTOR.

When lots of nutrients are available, mTOR is high, putting the cell into “growth” mode, so autop...

Without mitophagy and the removal of old mitochondria, new on...

The major signal to generate new mitochondria is the nutrient sensor AMPK.9 When overall energy availability is low, AMPK is high, which sti...

Animals exposed to intermittent fasting showed a striking benefit in mitochondrial networks.

To maintain healthy mitochondria, you don’t need more nutrients, but you periodically need fewer nutrients.

Damaged cells allowed to persist may turn cancerous because of the selection pressure to survive. These cells should have been culled but were not.

The periodic removal of older or damaged cells forms one of our primary anticancer defenses.

On the other hand, nutrient deprivation—especially protein deprivation—lowers mTOR and activates autophagy. This takes the cell out of growth ...

Any combination of increased growth factors or decreased cell death (apoptosis) will allow progression of a cancerous cell toward growth.

High blood insulin (hyperinsulinemia) causes the metabolic diseases of obesity and type 2 diabetes and, through PI3K and IGF-1, facilitates a disease of growth cancer. But the idea that cellular metabolism might be important in cancer is not new. Over a century ago, one of history’s greatest biochemists, Nobel laureate Otto von Warburg, proposed that the key to understanding the origins of cancer was to look at its metabolism.

PART V METASTASIS (Cancer Paradigm 3.0)

18 THE WARBURG REVIVAL

Otto Warburg’s specific research interest was cellular energetics,

How did cancer cells differ in their energy metabolism from normal cells?

Normally, cells may generate energy in the form of adenosine triphosphate (ATP) in two different ways: oxidative phosphorylation (OxPhos), also called respiration; and glycolysis, also called fermentation.

OxPhos, which occurs in the mitochondrion, burns each glucose molecule with oxygen to generate thirty-six ATP. Without oxygen, normal cells must resort to glycolysis, which generates only two AT...

Normal cells do not function well in an acidic environment.

In 1923, Warburg noticed with some amazement that fast-growing rat tumor cells used no more oxygen than regular cells.

The cancer cells were instead using ten times more glucose and producing lactic acid at seventy times the rate of normal tissues (see Figure 18.1).

Warburg calculated that tumor cells converted an astounding 66 percent of the glucose they took up to lactate.2

Figure 18.1: Use of glucose and production of lactic acid in normal...

Despite the ready availability of oxygen, cancer cells were generating energy using the less efficient glycolysis pathway. This surprising process ...

Aerobic glycolysis (glycolysis in the presence of lots of oxygen) is unique to cancer.

Even in situations where cells grow quickly and require large amounts of energy, such as during wound healing, the Warburg effect is not found. But why? It seems very strange.

Think about it. We know that cancer can be distinguished by four hallmarks: It grows. It is immortal. It moves around. It uses the Warburg effect: it deliberately uses...

Why on earth would cancer choose a less efficient manner of energy extraction?

about 80 percent of all known cancers use the Warburg effect. Whatever the reason, it is critical to cancer’s genesis and not merely a metabolic mistake.

In a famous 1956 research paper titled “On the Origin of Cancer,” Warburg hypothesized that the anomalous switch to aerobic glycolysis is so bizarre that it must be cancer’s inciting event.

Cancer was not being forced to use glycolysis, it was choosing it. But why?

Efficiently generating energy (ATP) is an advantage only under conditions of scarcity. If there is a lot of glucose around, then why does it matter if each glucose produces only two ATP instead of thirty-six? Glycolysis produces ATP less efficiently but more quickly.

In the time that normal cells metabolize one glucose to thirty-six ATP, cancer cells metabolize eleven glucose molecules to twenty-two ATP and twenty-two lactic acid. Because lactic acid can be converted to ATP one to one, this gives cancer a potential total of forty-four ATP. Cancer cells ...

OxPhos is advantageous only when glucose is scarce, but given the recent obesity and type 2 diabetes epidemics, glucose levels tend to run high, not low. So, the OxPhos “advantage” of energy efficiency is largely illusory in this current environment.

The fact that almost every known cancer uses this pathway suggests that it is neither coincidence nor a mistake, but integral to cancer development. It must confer some selective advantage. But what?

During glycolysis, only a small percentage of carbons are completely burned for energy. The leftover carbons can be metabolized into carbon building blocks to make new amino acids and fatty acids.

Consider this analogy: Building a house requires both energy (the hard work of the builders) and materials (bricks). Having builders but no bricks is useless. Similarly, rapidly growing cells require both energy (ATP) and materials (carbons).

OxPhos generates pure energy alone, which does not...

Glycolysis better supports rapid growth because it provides both energy and materials, while OxPho...

THE WARBURG REVIVAL

The pathways that govern a cell’s growth and its metabolism had always been considered distinct. But Lew Cantley’s groundbreaking research linked the well-known metabolic hormone insulin directly to growth pathways through PI3K. Cancer cell growth and metabolism were inextricably linked by the exact same genes and hormones.

Cancer cells can’t stop growing, but they also can’t stop eating. Does cancer grow because it can’t stop eating, or does it eat because it can’t stop growing? Most likely, both.

Cancer cells love eating glucose, but not exclusively. The metabolic pathways of the amino acid glutamine are also disrupted in cancer.

Amino acids are the building blocks of proteins, and glutamine is the most abundant amino acid in the blood. Some cancer cells consumed more than ten times the normal amount of glutamine.

Some cancers, such as neuroblastoma, lymphoma, and kidney and pancreatic cancer, appeared so “addicted” to glutamine that they s...

Warburg believed that cancer was solely dependent on glucose for energy, but this was not entirely true. Cancer can also metabolize glutamine, and more recent studies show that cancer may...

The large volume of lactic acid produced during the Warburg effect was not a waste product, as previously assumed, but a major benefit, providing the cancer cell with a significant survival advantage.

LACTIC ACID