Dartmouth Medical School professor William Kinlaw discussed evidence that the introduction of conjugated linoleic acid into breast cancer cells decreases tumor metastasis at Tuesday’s pathology seminar at Dartmouth-Hitchcock Medical Center.
Kinlaw’s research involves the “lipogenic tumor phenotype,” which characterizes the “addiction” of many tumors to fatty acids. His research has focused on disrupting the lipid metabolic pathway and thus minimizing cell growth in several forms of breast cancer and liposarcoma.
Liposarcoma is a malignant adipocyte, or fat cell, that forms a mesenchymal tumor within a body cavity that can grow to a remarkably large size. This rare form of cancer responds poorly to traditional cancer treatments such as chemotherapy and radiation, and is not well-understood biochemically. T47D cells, a common form of breast cancer, the rarer but deadly “triple-negative” MDA-MB-231 breast cancer cells, and the “immortal” HeLa cancer cell line were all part of the analysis.
Most research on possible treatments is directed towards interfering with the high rate of glucose uptake and fatty acid production by cancer cells, which is necessary for their rapid growth.
“It’s not just glucose metabolism that’s abnormal in the tumors … there are a host of mitochondrial abnormalities that have several fascinating effects,” Kinlaw said.
Kinlaw’s research sheds light on one of these effects, specifically the truncation of the citric acid cycle, which leads to a release of citric acid into cytosol and the formation of excess fatty acids. This process may form a “back door” for tumors to acquire fatty acids in addition to lipogenesis, the process of converting glucose into fatty acids. Lipolysis is the process that allows tumor cells to utilize these excess fatty acids. The lipoprotein lipase enzyme cleaves the circulating lipids into fatty acids, such as palmitate, which are necessary for tumor cell growth and survival.
Conjugated linoleic acid (CLA) is a fatty acid, specifically produced in the digestion system of ruminants. It is available to humans through dietary dairy and meat products, and commercially, as a weight loss supplement. CLA has been known to inhibit metastasis by up to 50%. In an informal poll at DHMC, one out of six breast cancer patients were taking CLA supplements.
However, the mechanism behind CLA’s anticancer effects has not been understood until recently.
Kinlaw used the “milk fat depression” syndrome in dairy cows as an analogy to illustrate CLA’s effect on lipid metabolism. Researchers have found that the necessary gene factor S14 was inhibited in cows that failed to produce any milk fat in their milk. In previous studies, this syndrome was induced in cows that had been given excess CLA, either through dietary supplements or direct injection into bovine mammary epithelium. Kinlaw sought to reproduce this phenomenon in breast cancer cells and murine adipocytes, whose genetic markers are nearly identical to those of liposarcoma.
The results were promising. Excess CLA silenced S14 expression and lipogenesis in the cancer cells, thus inhibiting growth of both types of breast cancer cells and adipocytes. Co-addition of palmitate revived the cell growth rate. On the other hand, the HeLa cells were unaffected by CLA infusion because they lack the target pathway of lipogenesis.
Tumor cells appear to have a capacity for monitoring the level of fatty acid availability. In the presence of excess fatty acids, lipogenesis is switched off inside the cancer cell, limiting palmitate production, and reducing tumor growth. The results not only point to a new possible treatment method for breast cancer and liposarcoma, but also provide new understanding of the lipogenic pathway that aids tumor growth.
Listen to a DUJS Podcast of William Kinlaw’s lecture here