Good Calories, Bad Calories

insulin in its environment. Having a greater number of insulin receptors than healthy cells, as one report noted, might confer “a selective growth advantage to tumor cells.”

“Selective growth advantage” speaks directly to the process of Darwinian evolution that is considered the controlling force in tumor development. We can think of human cells as existing in a microscopic ecosystem, living in harmony with their environment, and balanced, as are all species, between the opportunities for growth and proliferation and the processes that lead to aging and death. In such an environment, the billions of cells that eventually constitute a tumor will be the descendants of a single cell that has accumulated a series of genetic mutations, each adding to its proclivity to proliferate unfettered by any of the normal inhibitions to growth. The process in which a healthy cell eventually results in malignancy is a gradual evolution driven by a series of mutations in the DNA of the genes, each bestowing on the cell either the inclination to multiply or a breakdown in the control and repair mechanisms that have evolved to counter precisely such potentially deleterious mutations. The descendants of such a mutant cell would inherit this fitness advantage over other cells in the tissue, and so, within a few years, a single such mutant cell will leave millions of descendants. As one of those descendants in turn gains, purely by chance, yet another advantageous error or mutation, its descendants will now come to dominate.

Each new mutation-bearing cell constitutes a new species, in effect, that is better suited to prevail in its local cellular environment. Eventually, with this continued accumulation of what to the body as a whole is simply bad luck, a single cell will come to possess precisely that set of mutant genes that drive it and allow it to grow and proliferate without limit. Because each single hit of genetic damage alone is not sufficient to produce a cancer cell, the accumulation of just the right half-dozen hits (actually, the wrong half-dozen hits) takes years or decades, which is why virtually all cancers become more common as we age.

Cancer researchers now believe that these cancer-causing mutations occur as errors in the replication of DNA during the process of cell division and multiplication. Each one of us is likely to experience some ten thousand trillion cell divisions over the course of our lives, constituting an “enormous opportunity for disaster,” in the words of the MIT molecular biologist Robert Weinberg, author of the textbook The Biology of Cancer. This suggests that cancer-causing mutations are another unavoidable side effect of aging, which is why our cells have also evolved to be exceedingly resistant to genetic damage. They have sophisticated mechanisms to search out defects in newly replicated DNA and repair them, and other mechanisms that actually prompt a cell to commit suicide—programmed cell death, in the technical terminology—if the repair mechanisms are incapable of fixing the damage that occurred during replication. Alas, with time, these programs, too, can be disabled by the proper mutations.

Within this Darwinian environment, insulin provides fuel and growth signals to incipient cancer cells. Its more lethal effects, however, might come through the actions of insulin-like growth factor (IGF). Growth hormone itself is secreted by the pituitary gland and works throughout the body; IGF is secreted both by the liver and by tissues and cells throughout the body, and it then works locally, where concentrations are highest. Most tissues require at least two growth factors to grow at an optimal rate, and IGF is almost invariably one of the two, and perhaps the primary regulator.

Insulin-like growth factor is sufficiently similar in structure to insulin that it can actually mimic its effects. IGF can stimulate muscle cells to take up blood sugar, just as insulin does, though not as well. Researchers now believe that IGF serves as the necessary intermediary between the growth hormone secreted by the pituitary gland, and the actual amount of food that is available to build new cells and tissues. If insufficient food is available, then IGF levels will stay low even if growth-hormone levels are high, and so cell and tissue growth will proceed slowly if at all. Add the necessary food and IGF levels increase, and so will the rate of growth. Unlike insulin, which responds immediately to the appearance of glucose in the bloodstream and so varies considerably from hour to hour, IGF concentrations in the circulation change only slowly over days or weeks, and thus better reflect the long-term availability of food in the environment.

Since the mid-1970s, researchers have identified many of the molecules that play a role in regulating the strength of the growth and proliferation signals that IGF communicates to the cells themselves. There are several different insulin-like growth factors, for instance, and they bind to specific IGF receptors on the surfaces of cells. The more IGF receptors on a cell’s surface, the stronger the IGF signal to the cell. If insulin levels are high enough, insulin will stimulate the IGF receptors and send IGF signals into cells as well as insulin signals.^*64

IGF and its receptors appear to play a critical role in cancer. In mice, functioning IGF receptors are a virtual necessity for cancer growth, a discovery that Renato Baserga of Thomas Jefferson University says he “stumbled” upon in the late 1980s, after nearly forty years spent studying the growth processes of normal and cancerous cells. Shutting down the IGF receptor in mice will lead to what Baserga calls “strong inhibition, if not total suppression of [tumor] growth” it is particularly lethal to those tumors that have already metastasized from a primary site elsewhere in the body.

In the bloodstream, virtually all insulin-like growth factors are attached to small proteins that ferry them around to various tissues where they might be needed. But the IGFs, when attached to these proteins, are too large and unwieldy to pass through the walls of blood vessels and get to the tissues and cells where the IGF might be used. At any one time, only a small percentage of IGF in the circulation is left unbound to stimulate the growth of cells.

These binding proteins constitute yet another of the mechanisms used by the body to regulate hormonal signals and growth factors. Insulin appears to depress the concentration of IGF-binding proteins, and so high levels of insulin mean more IGF itself is available to effect cell growth—including that of malignant cells. Anything that increases insulin levels will therefore increase the availability of IGF to the cells, and so increase the strength of the IGF proliferation signals. (Insulin has been shown to affect estrogen this way, too, one way in which elevated levels of insulin may potentially cause breast cancer.)

The role of IGF in cancer appears to be fundamental, albeit still controversial. As is the case with insulin, IGF has been found in the laboratory to enhance the growth and formation of tumor cells directly; IGF signals prompt cells to divide and multiply. (This effect seems to be particularly forceful with breast-cancer cells when IGF and estrogen are acting in concert.) IGF has an advantage over other growth factors that might play a role in cancer because it can reach tumors either through the bloodstream—after being secreted by the liver—or as a result of production by nearby tissue. There’s even evidence that tumors can stimulate their own further growth and proliferation by secreting their own insulin-like growth factors. In the early 1980s, cancer researchers discovered that tumor cells also overexpress IGF receptors, just as they overexpress insulin receptors. The surfaces of tumor cells have two to three times as many IGF receptors as healthy cells, which makes them all that much more responsive to the IGF in their immediate environment.

This is another way in which cancer cells gain their all-important survival growth advantage, suggests Derek LeRoith, whose laboratory at the National Institute of Diabetes and Digestive and Kidney Diseases did much of this research. The extra insulin receptors will cause cancerous cells to receive more than their share of insulin from the environment, which will convey to the cell more blood sugar for fueling growth and proliferation; the extra IGF receptors will assure that these cells are supplied with particularly forceful commands to proliferate. Another critical role of IGF in the development of cancer may be its ability to inhibit or override the cell suicide program that serves as the ultimate fail-safe mechanism to prevent damaged cells from proliferating.