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

by Jason Fung

between these two regions is the area known as the hypoxic zone, where cells receiving barely enough oxygen to survive activate an enzyme called hypoxia-inducible factor (HIF1).

First, HIF stimulates the release of vascular endothelial growth factor (VEGF), which promotes the growth of new blood vessels.

Second, HIF makes it easier for the normally stationary cells to become more mobile.

Third, because oxygen is scarce, HIF reprograms the cell’s metabolism from OxPhos and toward glycolysis.

16 In essence, HIF is responsible for the phenomenon known as the Warburg effect, yet another key hallmark.17

This package of changes induced by HIF improves survival in a low-oxygen environment.

Compared to normal cells, which live in an environment with a pH of 7.2 to 7.4, tumors generate a surrounding microenvironment of pH 6.5 to 6.9.19 Why do cancer cells put so much effort into acidifying their surroundings?20 Because the acidity give the cells a huge survival advantage. Normal cells are injured in an acidic environment and undergo apoptosis, while cancer cells tolerate the acidity fairly well.

There are two ways to win: get better or make your competitor worse. Both work. Cancer is playing a cellular Game of Thrones. You win or you die.

Even when oxygen is freely available, cancer continues to use glycolysis because it offers the singular survival advantage of pumping out lactic acid (the Warburg effect).

the increased lactic acid from the Warburg effect: Suppresses normal cell function; Degrades the extracellular matrix, facilitating invasion; Provokes inflammatory response and growth factor secretion; Reduces immune response; and Increases angiogenesis.

Cancer didn’t choose glycolysis over OxPhos (the Warburg effect) by accident. It’s not a mistake. It’s a logical choice because of the survival advantage offered by lactic acid.

19 INVASION AND METASTASIS

THERE IS NO word in the cancer lexicon more terrifying than metastasis. The National Cancer Institute defines metastasis as “The spread of cancer cells from the place where they first formed to another part of the body.”

This single distinguishing feature makes cancer more lethal than virtually any other disease in existence. A fact highlighting the severity of this phenomenon: metastases are responsi...

Cancers are categorized as either benign or malignant. Both types of cancer behave identically in all respects, except that benign cancers lack this metastatic ability and therefore cause almost no significant disease.

how does this metastatic process happen?

The metastatic cascade occurs in two steps: invasion of surrounding tissue and metastasis to distant sites.

First, cancer cells must break free from the original tumor mass, which may occur e...

Second, the cancer must invade through the basement membrane of the normal tissues.

Once through, it can spread to surrounding tissues, local lymph nodes, or past blood vessel walls in a process called intravasation.

INVASION Primary tumor formation. Local invasion. Intravasation.

METASTASIS Survival in circulation. Extravasation. Survival at distal site.

These first three processes (primary tumor formation, local invasion, and intravasation) can be considered together as the process of invasion.

The hypoxic, acidic environment around the cancer created by the Warburg effect clears a path for invasion.4 Believe it or not, this is the easy part for cancer cells.

To metastasize, the cancer cells must survive the journey in the bloodstream, leave the blood vessel to invade a foreign organ, and then learn how to survive and thrive in that new environment.

The bloodstream is a harrowing, hostile environment, with a million ways for cancer cells to die. Natural killer cells of the innate immune system hunt down and attack them immediately. This part of the immune system is called “innate” because the killer cells are naturally programmed to attack cancer on sight.

cancer does not randomly accumulate the ability to invade and metastasize; it evolves that ability.

CIRCULATING TUMOR CELLS AND MICROMETASTASIS

Metastasis is an extraordinarily inefficient process. Given the almost insurmountable problems of metastasis, the majority of cancer cells sen...

Cancer cells reproduce every one to two days, but the doubling time of tumors is sixty to two hundred days, implying that the vast majority o...

TUMORAL EVOLUTION AND SELF-SEEDING

This is not the end of the story; it’s only the beginning. The evolution of the cancer cell is an iterative process (see Figure 19.1). The new CTCs face another round of intense selection pressure. Most of the new CTCs are also killed, but once again, a few rare mutants who developed enhanced survival mechanisms in the bloodstream return to reseed the primary tumor site.

These genetic mutations are anything but random—this is the Darwinian process of natural selection. The cancer cells are evolving.

Figure 19.1: Evolutionary paradigm of cancer cells.

Each iteration selects for more survivability...

The self-seeding process explains the genetic diversity with the primary tumor site—known as intratumoral heterogeneity (ITH).

With enough time and tumoral evolution, the cancer cells can now survive the bloodstream journey reasonably well and land in the different organs. Again, that foreign landscape will be hostile soil to the cancer cells. They start by establishing a colony, a micrometastasis that can stay dormant for decades.

Metastasis creates a new branch in the cancer’s evolution. The metastatic site shows completely different genetics from the primary tumor,16 which reflects the particular challenges of surviving in that metastatic site. Because most cancer cells die when trying to metastasize, very few cells survive, and this restricts genetic diversity,17 a phenomenon known in biology as “bottlenecking.”

The factor that shapes cancer from beginning to end is the most powerful force in biology: evolution.

Cancer paradigm 3.0, the evolutionary model, can be divided into three phases: Transformation: The normal cell’s first step toward cancer is an evolutionary response to chronic, sublethal injury. The cancer phenotype develops as a survivalist mechanism that requires rejecting multicellular life. This is the seed of cancer. Progression: The nutrient sensors insulin, mTOR, and AMPK influence growth factor availability and provide a fertile environment for cancerous proliferation. This is the soil. Metastasis: The early shedding of cancer cells into the bloodstream exposes the cells to intense selection pressure for survival. As the primary tumor site is reseeded by its own progeny, natural selection pressure favors more aggressive and primitive traits.

20 THE STRANGE STORY OF CANCER

The evolutionary paradigm offers astonishing new insight into cancer’s genesis, from transformation, progression, and metastasis to treatment and recurrence. The focus shifted from purely genetics (the seed) to the environment (the soil) and the interaction of the two.

let’s briefly recap the story of cancer, using the example of a smoker who develops a lung cancer that metastasizes to the liver.

Unicellular genes that enhance competition and survival are precisely those genes that cause cancer in multicellular organisms.

Because cancer is a dormant part of ourselves, and a known ever-present danger, multicell organisms have evolved potent anticancer strategies, including DNA repair, apoptosis, the Hayflick limit, and immune surveillance.

Natural killer (NK) cells are a part of our innate immune system that—surprise, surprise—naturally kills tumor cells.

NK cells constantly patrol the body like a vigilant police force, looking for potentially cancerous cells. Orders? Shoot to kill. If the anticancer d...

Cancer results from the loss of cooperation between cells and proceeds in three stages: transformation, progression, and metastasis.

TRANSFORMATION

The chronic sublethal smoke damage exerts a potent selection pressure, and the cell must activate the rarely used ancient survival subroutines from unicellularity to save itself.