summarize this "As you might have gathered by now, we tend to think of cancer as primarily a
genetic disease, driven by mutations of unknown cause. Clearly, cancer cells
are genetically distinct from normal human cells. But for the last century or
so, a handful of researchers have been investigating another unique property
of cancer cells, and that is their metabolism.
In the 1920s, a German physiologist named Otto Warburg discovered that
cancer cells had a strangely gluttonous appetite for glucose, devouring it at up
to forty times the rate of healthy tissues. But these cancer cells weren’t
“respiring” the way normal cells do, consuming oxygen and producing lots of
ATP, the energy currency of the cell, via the mitochondria. Rather, they
appeared to be using a different pathway that cells normally use to produce
energy under anaerobic conditions, meaning without sufficient oxygen, such
as when we are sprinting. The strange thing was that these cancer cells were
resorting to this inefficient metabolic pathway despite having plenty of oxygen
available to them.
This struck Warburg as a very strange choice. In normal aerobic
respiration, a cell can turn one molecule of glucose into as many as thirty-six
units of ATP. But under anaerobic conditions, that same amount of glucose
yields only two net units of ATP. This phenomenon was dubbed the Warburg
effect, and even today, one way to locate potential tumors is by injecting the
patient with radioactively labeled glucose and then doing a PET scan to see
where most of the glucose is migrating. Areas with abnormally high glucose
concentrations indicate the possible presence of a tumor.
Warburg was awarded the Nobel Prize in Physiology or Medicine in 1931
for his discovery of a crucial enzyme in the electron transport chain (a key
mechanism for producing energy in the cell). By the time he died in 1970, the
weird quirk of cancer metabolism that he had discovered had been all but
forgotten. The discovery of the structure of DNA by James Watson, Francis
Crick, Maurice Wilkins, and Rosalind Franklin in 1953 had caused a seismic
paradigm shift, not just in cancer research but in biology in general.
As Watson recounted in a 2009 New York Times op-ed: “In the late
1940s, when I was working toward my doctorate, the top dogs of biology
were its biochemists who were trying to discover how the intermediary
molecules of metabolism were made and broken down. After my colleagues
and I discovered the double helix of DNA, biology’s top dogs then became its
molecular biologists, whose primary role was finding out how the information
encoded by DNA sequences was used to make the nucleic acid and protein
components of cells.”
Nearly forty years into the War on Cancer, however, Watson himself had
become convinced that genetics did not hold the key to successful cancer
treatment after all. “We may have to turn our main research focus away from
decoding the genetic instructions behind cancer and toward understanding the
chemical reactions within cancer cells,” he wrote. It was time, he argued, to
start looking at therapies that targeted cancer’s metabolism as well as its
genetics.
A handful of scientists had been pursuing the metabolic aspects of cancer
all along. Lew Cantley, now at Harvard’s Dana-Farber Cancer Center, has
been investigating cancer metabolism since the 1980s, when the idea was
unfashionable. One of the more puzzling questions he has tackled was why
cancer cells needed to produce energy in this highly inefficient way. Because
the inefficiency of the Warburg effect may be the point, as Cantley, Matthew
Vander Heiden, and Craig Thompson argued in a 2009 paper. While it may
not yield much in the way of energy, they found, the Warburg effect generates
lots of by-products, such as lactate, a substance that is also produced during
intense exercise. In fact, turning glucose into lactate creates so many extra
molecules that the authors argued that the relatively small amount of energy it
produces may actually be the “by-product.”
There’s a logic to this seeming madness: when a cell divides, it doesn’t
simply split into two smaller cells. The process requires not only the division
of the nucleus, and all that stuff we learned in high school biology, but the
actual physical materials required to construct a whole new cell. Those don’t
just appear out of nowhere. Normal aerobic cellular respiration produces only
energy, in the form of ATP, plus water and carbon dioxide, which aren’t
much use as building materials (also, we exhale the latter two). The Warburg
effect, also known as anaerobic glycolysis, turns the same amount of glucose
into a little bit of energy and a whole lot of chemical building blocks—which
are then used to build new cells rapidly. Thus, the Warburg effect is how
cancer cells fuel their own proliferation. But it also represents a potential
vulnerability in cancer’s armor.
[*1]
This remains a controversial view in mainstream cancer circles, but it has
gotten harder and harder to ignore the link between cancer and metabolic
dysfunction. In the 1990s and early 2000s, as rates of smoking and smokingrelated cancers declined, a new threat emerged to take the place of tobacco
smoke. Obesity and type 2 diabetes were snowballing into national and then
global epidemics, and they seemed to be driving increased risk for many
types of cancers, including esophageal, liver, and pancreatic cancer. The
American Cancer Society reports that excess weight is a leading risk factor
for both cancer cases and deaths, second only to smoking.
Globally, about 12 to 13 percent of all cancer cases are thought to be
attributable to obesity. Obesity itself is strongly associated with thirteen
different types of cancers, including pancreatic, esophageal, renal, ovarian,
and breast cancers, as well as multiple myeloma (see figure 7). Type 2
diabetes also increases the risk of certain cancers, by as much as double in
some cases (such as pancreatic and endometrial cancers). And extreme
obesity (BMI ≥ 40) is associated with a 52 percent greater risk of death from
all cancers in men, and 62 percent in women.
I suspect that the association between obesity, diabetes, and cancer is
primarily driven by inflammation and growth factors such as insulin. Obesity,
especially when accompanied by accumulation of visceral fat (and other fat
outside of subcutaneous storage depots), helps promote inflammation, as
dying fat cells secrete an array of inflammatory cytokines into the circulation
(see figure 4 in chapter 6). This chronic inflammation helps create an
environment that could induce cells to become cancerous. It also contributes
to the development of insulin resistance, causing insulin levels to creep
upwards—and, as we’ll see shortly, insulin itself is a bad actor in cancer
metabolism.
This insight comes courtesy of further work by Lew Cantley. He and his
colleagues discovered a family of enzymes called PI3-kinases, or PI3K, that
play a major role in fueling the Warburg effect by speeding up glucose uptake
into the cell. In effect, PI3K helps to open a gate in the cell wall, allowing
glucose to flood in to fuel its growth. Cancer cells possess specific mutations
that turn up PI3K activity while shutting down the tumor-suppressing protein
PTEN, which we talked about earlier in this chapter. When PI3K is activated
by insulin and IGF-1, the insulin-like growth factor, the cell is able to devour
glucose at a great rate to fuel its growth. Thus, insulin acts as a kind of cancer
enabler, accelerating its growth.
Source: NCI (2022a).
This in turn suggests that metabolic therapies, including dietary
manipulations that lower insulin levels, could potentially help slow the growth
of some cancers and reduce cancer risk. There is already some evidence that
tinkering with metabolism can affect cancer rates. As we have seen,
laboratory animals on calorically restricted (CR) diets tend to die from cancer
at far lower rates than control animals on an ad libitum (all-they-can-eat) diet.
Eating less appears to give them some degree of protection. The same may
hold true in people: one study of caloric restriction in humans found that
limiting caloric intake directly turns down the PI3K-associated pathway,
albeit in muscle (which is not susceptible to cancer). This may be a function
of lowered insulin rather than lower glucose levels.
While it’s tricky to impossible to avoid or prevent the genetic mutations
that help give rise to cancer, it is relatively easy to address the metabolic
factors that feed it. I’m not suggesting that it’s possible to “starve” cancer or
that any particular diet will magically make cancer go away; cancer cells
always seem to be able to obtain the energy supply they need. What I am
saying is that we don’t want to be anywhere on that spectrum of insulin
resistance to type 2 diabetes, where our cancer risk is clearly elevated. To me,
this is the low-hanging fruit of cancer prevention, right up there with quitting
smoking. Getting our metabolic health in order is essential to our anticancer
strategy. In the next section, we’ll look at how metabolic interventions have
also been used to potentiate other kinds of cancer therapy.
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