Gautham Venugopalan, PhD, of the University of California, Berkeley, bioengineering lab of Daniel Fletcher, PhD, described how applying compressive force to malignant breast epithelial cells growing within a laminin-rich 3-D extracellular matrix caused them to turn into highly organized, growth-arrested acini, the milk-secreting spherical structures that are central to breast tissue.
This "phenotypic reversion" was accomplished without pharmacological agents, noted Dr. Venugopalan. Research collaborators included Kandice Tanner, PhD, and Mina Bissell, PhD, of the Lawrence Berkeley National Laboratory in Berkeley.
During a woman's reproductive life, breast tissue continuously grows, shrinks, and remodels in a highly regulated fashion. When this process breaks down, growth becomes abnormal.
Although genetic mutations are the classic explanation for differences between healthy and malignant cells but they don't tell the whole story because malignant cells treated with certain drugs will grow into organized acini that appear very similar to the healthy acini, even though they remain genetically malignant. This indicates that malignant cells have not completely "forgotten" how to be healthy, since they can be guided back into their "normal" growth program by giving them the right cues, according to Dr. Venugopalan.
Could mechanical force also reprogram malignant cells? The researchers seeded malignant breast epithelial cells into a 3-D laminin-rich extracellular matrix and used an elastic chamber to apply a compressive force. Over time, the compressed malignant cells grew into more organized, healthy-looking acini that resembled normal structures, even without the addition of exogenous drugs.
However, when the researchers added a drug that blocked E-cadherin, a transmembrane protein that helps cells adhere to their neighbors, the compression lost all effect, and the cells returned to their disorganized malignant appearance.
Previous studies have shown that healthy breast cells rotate as they form acini to help them organize into spherical structures, according to Dr. Venugopalan. This coherence is lost in malignant cells, so the researchers investigated whether rotation was affected by compression. By performing time-lapse microscopy over several days, they found that compression was inducing rotation in the malignant cells, further suggesting the importance of cell-cell communication during growth.
"Our findings suggest that external forces can encourage malignant cells to re-enter the correct morphogenetic program," said Dr. Venugopalan.
"Externally applied forces can phenotypically revert malignant breast epithelial structures," Monday, Dec. 17, 2012, 2−3:30 pm, Session: Tumor Microenvironment, presentation: 1673, poster: B1444, Exhibit Halls A-C
American Society for Cell Biology
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