Acidic Microenvironments in Tumors Aid Tumor Cell Survival, Researchers Find

 

ScienceDaily (Sep. 6, 2012) — Researchers at Moffitt Cancer Center and colleagues at the University of South Florida and Wayne State University have discovered that tumor cell survival relies on adaptation to acidic conditions in the tumor microenvironment. Their research investigating the effects of acidity on breast and pancreatic cancer cell lines revealed the importance of autophagy in acidic microenvironments and suggests that a successful treatment strategy might be based on this autophagic dependence.

The study appears as the cover story for the Aug. 15 issue of Cancer Research, a publication of the American Association for Cancer Research.

“Cancer progression is a multistep process strongly influenced by the physical properties of the tumor microenvironment,” said Robert J. Gillies, Ph.D., corresponding author of the study and chair of Moffitt’s Department of Cancer Imaging and Metabolism. “Both low oxygen and high acidity can be cytotoxic. Our research suggests that adaptation to these stressful conditions involves autophagy allowing cancer cells to survive, proliferate and eventually metastasize to secondary sites.”

According to the authors, not much is known about cell survival mechanisms under acidic conditions, but it has been demonstrated that acidosis can alter gene expression leading to cell types that are adapted for growth and survival in low pH conditions. Identifying low pH survival mechanisms would “give further insight into tumor progression and potentially introduce novel therapeutic strategies,” researchers said.

In this study, the researchers tested cancer cell lines under acidic conditions to learn more about autophagy and cellular adaptation. They noted that normal cells in the acidic environment can respond to acidic stress by increasing cell death pathways, thus introducing the need for survival and adaptive mechanisms by cancer cells.

The researchers also noted that their experiments were carried out under atmospheric oxygen levels and they found that the cell’s stress response could lead to chronic autophagy even when nutrients and oxygen were in adequate supply.

“We found that cells subjected to transient and chronic low pH growth conditions demonstrate elevated markers for autophagy and are dependent on this process for prolonged survival in acidic environments,” explained Jonathan W. Wojtkowiak, lead author of the study and postdoctoral fellow at Moffitt. “A hallmark of cancer is the ability of cancer cells to evade apoptosis. Autophagy supports this by playing a tumor promoter and survival role under certain circumstances during different stages of tumorogenesis.”

Their study demonstrated the importance of autophagy in low pH-adapted breast and pancreatic cancer cell lines and the dependence of these cells on autophagy for survival to acidic tumor microenvironment. According to the researchers, they identified a potential therapeutic strategy of using an autophagy inhibitor, one that does not affect cells under neutral conditions.

Funding for the study came from National Institutes of Health grants R01 CA077575, U54 CA143970 and R01 CA 131990

Limiting Carbs, Not Calories, Reduces Liver Fat Faster, Researchers Find

Limiting Carbs, Not Calories, Reduces Liver Fat Faster, Researchers Find

ScienceDaily (Apr. 19, 2011) — Curbing carbohydrates is more effective than cutting calories for individuals who want to quickly reduce the amount of fat in their liver, report UT Southwestern Medical Center researchers.

“What this study tells us is that if your doctor says that you need to reduce the amount of fat in your liver, you can do something within a month,” said Dr. Jeffrey Browning, assistant professor of internal medicine at UT Southwestern and the study’s lead author.

The results, available online and in an upcoming issue of the American Journal of Clinical Nutrition, could have implications for treating numerous diseases including diabetes, insulin resistance and nonalcoholic fatty liver disease, or NAFLD. The disease, characterized by high levels of triglycerides in the liver, affects as many as one-third of American adults. It can lead to liver inflammation, cirrhosis and liver cancer.

For the study, researchers assigned 18 participants with NAFLD to eat either a low-carbohydrate or a low-calorie diet for 14 days.

The participants assigned to the low-carb diet limited their carbohydrate intake to less than 20 grams a day — the equivalent of a small banana or a half-cup of egg noodles — for the first seven days. For the final seven days, they switched to frozen meals prepared by UT Southwestern’s Clinical and Translational Research Center (CTRC) kitchen that matched their individual food preferences, carbohydrate intake and energy needs.

Those assigned to the low-calorie diet continued their regular diet and kept a food diary for the four days preceding the study. The CTRC kitchen then used these individual records to prepare all meals during the 14-day study. Researchers limited the total number of calories to roughly 1,200 a day for the female participants and 1,500 a day for the males.

After two weeks, researchers used advanced imaging techniques to analyze the amount of liver fat in each individual. They found that the study participants on the low-carb diet lost more liver fat.

Although the study was not designed to determine which diet was more effective for losing weight, both the low-calorie dieters and the low-carbohydrate dieters lost an average of 10 pounds.

Dr. Browning cautioned that the findings do not explain why participants on the low-carb diet saw a greater reduction in liver fat, and that they should not be extrapolated beyond the two-week period of study.

“This is not a long-term study, and I don’t think that low-carb diets are fundamentally better than low-fat ones,” he said. “Our approach is likely to be only of short-term benefit because at some point the benefits of weight loss alone trounce any benefits derived from manipulating dietary macronutrients such as calories and carbohydrates.

“Weight loss, regardless of the mechanism, is currently the most effective way to reduce liver fat.”

Other UT Southwestern researchers involved in the study were Dr. Shawn Burgess, senior author and assistant professor of pharmacology in the Advanced Imaging Research Center (AIRC); Dr. Jonathan Baker, assistant professor of pathology; Dr. Thomas Rogers, former professor of pathology; Jeannie Davis, clinical research coordinator in the AIRC; and Dr. Santhosh Satapati, postdoctoral researcher in the AIRC.

The National Institutes of Health supported the study