Monday, 16 January 2012

Unraveling the Obesity-Cancer Connection

Gary Taubes from Science

Growing breast cancer cells in the lab has been a revelation to Vuk Stambolic. The protocol he follows is decades old and widely used, but there’s a puzzle at its core. The recipe calls for a large dose of glucose, a growth factor called EGF, and insulin. Add these to tissue culture, and tumor cells will be fruitful and multiply. A curious thing happens if you try to wean the tumor cells off insulin, however: They “drop off and they die,” says Stambolic, a cancer researcher at the University of Toronto in Canada. “They’re addicted to [insulin].”

What makes this so “bizarre,” Stambolic says, is that this behavior is totally unlike that of the healthy breast cells from which these tumor cells are derived. Normal cells are not sensitive to insulin - or at least not nearly to the same degree. They don’t have insulin receptors, and they lack key elements of the insulin signaling pathway necessary to make insulin outside the cell immediately relevant to what goes on inside. Indeed, normal cells thrive without insulin. By contrast, the tumor cells in culture can’t live without it.

Insulin, a hormone produced in the pancreas, is more commonly known for its role in diabetes. But its reputation may be changing. Insulin and a related hormone known as insulin-like growth factor (IGF) are now at the center of a growing wave of research around the world aimed at elucidating what many scientists consider to be their critical role in fueling a wide range of cancers. Elevated levels of insulin and IGF are also the leading candidates to explain a signifi cant correlation in epidemiology that has gained attention over the past 30 years: Obese and diabetic individuals have a far higher risk than lean healthy people of getting cancer, and when they do get it, their risk of dying from it is greater. And now that obesity and diabetes rates are skyrocketing, the need to understand this link has become far more urgent.

The correlation between obesity and cancer can be found in the medical literature going back for several decades. But it wasn’t until 2004 that two cancer epidemiologists put it all together, says Robert Weinberg, a cancer researcher at the Massachusetts Institute of Technology (MIT) in Cambridge. An article that year in Nature Reviews Cancer by Rudolf Kaaks, then of the International Agency for Research on Cancer, and the late Eugenia Calle of the American Cancer Society “laid down a challenge to the rest of us … to determine why obesity is such an important determinant of cancer risk,” Weinberg says.

The message of this research is straightforward, Kaaks says: Excess body fat seems to account for between one-quarter and one-half of the occurrence of many frequent cancer types—breast, colorectal, endometrial, renal cell, and adenocarcinoma in the esophagus, in particular. Kaaks adds, “The list is growing.”

“The magnitude of the effect is huge,” in large part because obesity and diabetes are now so common, says Michael Pollak, an oncologist at McGill University in Montreal, Canada. It seems that cancer “loves the metabolic environment of the obese person,” Pollak says. Epidemiologic studies have also found that not only is type 2 diabetes associated with increased cancer incidence and mortality but so are circulating levels of insulin and IGF.

Recent drug studies have sharpened the picture: Type 2 diabetics who get insulin therapy or drugs to stimulate insulin secretion have a significantly higher incidence of cancer than those who get metformin, a drug that works to lower insulin levels. There’s a large and growing body of evidence implicating insulin and IGF in cancer, Pollak says, “and it’s causing a lot of people to stay up at night thinking about it.”

Ravenous for Glucose
The focus on obesity, cancer, and hormones has kindled a wide interest in the metabolism of cancer cells and particularly in work done in the 1920s by the German biochemist and later Nobel laureate Otto Warburg. Warburg observed that tumor cells can survive without oxygen and generate energy by a relatively ineffi cient process known as aerobic glycolysis. This conversion of cancer cell metabolism to aerobic glycolysis has been known as the Warburg effect ever since. It is akin to how bacteria generate energy in the absence of oxygen, although cancer cells do it even when oxygen is present (hence “aerobic”). Rather than converting glucose to pyruvate and burning that with oxygen in the cells’ mitochondria, the pyruvate is converted to lactate in the cells’ cytoplasm outside the mitochondria, and no oxygen is used. The process yields only one-ninth the energy, four ATP molecules instead of 36, from each molecule of glucose. One result is that cancer cells have to burn enormous amounts of glucose to thrive and multiply.


That insulin and IGF may be the relevant “something else” that fuels cancer is a relatively new idea. But the evidence has been accumulating for decades. In the mid-1960s, researchers demonstrated that insulin acts as a promoter of growth and proliferation in both healthy and malignant tissues. By the late 1970s, C. Kent Osborne, then at the National Cancer Institute, and his colleagues reported that a line of particularly aggressive breast cancer cells were “exquisitely sensitive to insulin” and that breast cancer cells express insulin receptors, even though the cells from which the tumors derive do not.