Dr. Philip A. Wood, professor in the Metabolic Signaling and Disease Program at the Diabetes and Obesity Research Center in Orlando
Burnham Scientists Study How Obesity Leads to Often-Fatal Disease
ORLANDO—With the obesity epidemic reaching new heights in the United States, scientists at the Burnham Institute for Medical Research at Lake Nona are interested in learning how fatty acids may lead to an optimal environment for cancer cell growth.
“Obesity isn’t just an aesthetic problem,” said Philip A. Wood, professor in the Metabolic Signaling and Disease Program at the Diabetes and Obesity Research Center in Orlando, and author of How Fat Works (Harvard Press, 2006). “It’s becoming recognized as a common co-morbidity with several disease states, including cancer. There’s tremendous interest to more fully understand the mechanistic connections between obesity and cancer.”
Accumulating data support the notion that cancer should be added to the increasing list of obesity-related diseases or disease processes, such as nonalcoholic fatty liver disease, insulin resistance, type 2 diabetes and cardiovascular disease, said Wood.
“Cancers associated with obesity include some of the most prevalent types, including colon, breast, prostate and endometrial,” he said. “The study of this has led to more questions: is there a ‘cause and effect’ relationship with the obese state, a condition of excess fatty acids, and increasing the risk of cancer or increasing the virulence of cancer—that is, being more invasive and metastatic? Or do they happen to occur together as independent events?”
Even though obesity is widely recognized as a risk factor for developing type 2 diabetes, the process is often associated with excessive adipose tissue, particularly visceral adiposity, which provides a continual source of excess fatty acids for the body to respond to, especially the liver, Wood explained.
“Could it be that the excess fatty acid environment of obesity likewise has a direct role in promoting the development or modifying the aggressiveness of cancer? Thus, there are many shared factors and biomarkers of interest between patients with obesity, insulin resistance, metabolic syndrome, type 2 diabetes and those with cancer,” he said.
With that in mind, PAI-1 is a potential marker, which has been shown in a potential chain of events directly linking fatty acid stimulated PAI-1 expression via SMAD-4 activation, which was associated with migration of breast cancer cell lines in culture.
“SMAD4 was stimulated by excessive fatty acids in the medium, notably the ubiquitous dietary omega-6 fatty acid—linoleic acid—as well as oleic acid to a lesser extent,” he said, noting that linoleic acid is a common omega-6 fatty acid found in the Western diet, particularly in foods prepared from plant-derived polyunsaturated fats, such as safflower oil. “It’s of interest that a recent American Heart Association Panel reports that when at least 5 to 10 percent of energy is derived from omega-6 fatty acids, this reduces the risk of cardiovascular disease relative to lower intakes. Thus, it remains to be seen if this recent recommendation affects cancer risks. Oleic acid, another common dietary fatty acid found enriched in olive oil and canola oil, is likewise of interest because it’s often associated with more healthful properties regarding raising HDL-cholesterol and lowering LDL-cholesterol. Thus, it may help improve the dyslipidemia found commonly in obesity.”
PAI-1, also elevated in obesity-related conditions, is considered a common risk factor for myocardial infarction associated with metabolic syndrome, said Wood.
“Increased PAI-1 concentrations are a potential contributor in the pro-thrombotic state found in these patients, as well as a prognostic biomarker for breast cancer, as described in the journal Laboratory Investigation. Although further clarification of the mechanisms remains to be defined, (the authors) essentially fulfill a ‘Koch’s Postulates’-like score card in their experiments,” said Wood. “They showed that MDA-MB 231 breast cells are stimulated to produce more secreted PAI-1 via fatty acid (linoleic acid, and to a lesser extent oleic acid) stimulation, which was clearly associated with increased aggressiveness as measured by the migration assay. Other fatty acids with different chain lengths and saturation states had no effect as far as PAI-1 expression or cell migration.”
Also, the linoleic acid migration was inhibited by expression of antisense RNA against PAI-1, Wood said.
“SMAD4 appeared to be the mediator of this fatty acid-stimulated event, and that was further elucidated by showing that SMAD4-deficient MD-MB-468 breast carcinoma cells lacked the response,” he said. “In my mind, these studies raise a number of interesting issues regarding fatty acids, PAI-1 concentrations and cancer. Are there additional mechanisms involving fatty acid metabolism that would affect cancer cell behavior? For example, there’s a lot of interest in the role of excess fatty acids in the development of insulin resistance in normal cells such as hepatocytes or muscle cells.”
Without delving deeper into the discussion, Wood summed up by saying it was striking that obesity-related phenotypes such as metabolic syndrome share features with cancer prevalence and specifically including increased concentrations of fatty acids and PAI-1. He also added that the similarities make it more difficult to sort out “cause and effect.”
Wood said a number of labs at Burnham are working on solving riddles involving obesity. “For example, does obesity cause poor sleep patterns, or is it the other way around? We’ve developed complete teams to tackle a very complex problem,” he said. “Collectively, all of our heads put together are coming up with important work, which will hopefully lead to a new drug.”