Breaking the Mucus Barrier Unveils Cancer Cell Secrets

Abstract

Measuring the mechanical strength of mucus layers surrounding cancer cells offers clues to better ways to treat cancer, and also suggests why some cancer cells are more resistant to drugs than others, according to a report in the January 2010 online issue of the journal Applied Physics Letters (available: http://link.aip.org/link/applab/v97/i26/p263703/s1). Researchers led by Kai-tak Wan, associate professor of engineering at Northeastern University, Boston, Massachusetts, say that uptake of cytotoxic drugs by typical tumor cells is limited by the dense dendritic network of oligosaccharide mucin chains that forms a mechanical barrier. “Mucins are high molecular weight glycoproteins having oligosaccharides attached to a protein backbone core by O-glycosidic linkages, and are approximately 50%–80% carbohydrates in terms of total molecular mass,” the authors state. “The long chain molecules are naturally produced in a wide range of host tissues including the gastrointestinal tract, lungs, kidneys, ovaries, breast, and pancreas.” This tangled brush forms a physical barrier and, when over-expressed, can prevent drugs from reaching the underlying cancer cells. Over-expressed mucus also makes it easier for cancer cells to break away from surrounding cells and metastasize. According to Wan, healthy tissues naturally secrete mucus to protect against infection. Cancer cells, however, produce far more mucus than healthy cells. Study co-author Robert B. Campbell, an associate professor of pharmaceutical sciences at Massachusetts College of Pharmacy and Health Sciences, Worcester, Massachusetts, has been investigating the use of chemical agents that limit the formation of this tangled mucus barrier to allow chemotherapeutic agents to permeate the barrier. To determine how well those agents work, Wan used the nanoscale tip of an atomic force microscope to push against the mucus barrier. The less resistance it encountered, the less tangled the barrier. Six types of mucinous human in vitro adenocarcinoma models were investigated: pancreatic Capan-1; breast ZR-75-1; colorectal Colo-205; lung Chago-K-1; ovarian (wide type [WT]) SK-OV3 WT; and ovarian (multidrug resistant [MDR]) SK-OV3 MDR. A nonmucous cancer cell type derived from the brain, U87-MG, served as a negative control for the study. Benzyl-α-GalNac (analog of N-acetylgalactosamine) was used to inhibit type-O-glycosylation and to reduce the carbohydrate chains associated with the protein backbone of mucin. The chemotherapeutic agent significantly reduced the energy needed to pierce the mucus barrier in lung, breast, colorectal, pancreatic, and wild type (natural) ovarian cancer cells. However, the treatment barely registered any change in MDR ovarian cancer cells. It currently remains unclear how those cells resist drugs that ordinarily eliminate wild-type ovarian cancer, but Wan's research points to an important difference: the mucus layer formed by the 2 types of cells reacts differently to the same chemical treatment. “Although the mechanical barrier alone is certainly not the only mechanism that hinders drug transport, it at least contributes quite significantly to ineffective cytotoxic drug therapy,” the authors state. “The studies reported herein offer additional support for the development of clinical and pharmaceutical approaches to combat mucin overexpression in tumors during cancer chemotherapy.”