When an ovarian tumor begins to spread, its first targets are the other organs within the abdominal cavity, which are protected by a layer of epithelial cells known as the mesothelium. Now, scientists have discovered how ovarian cancer cells breach that barrier to create new tumors -- brute force. According to a study published online today (June 14) in Cancer Discovery, ovarian cancers use proteins involved in cellular movement to muscle their way past the cellular barrier.
“You can use the analogy of a snowplow,” said Ernst Lengyel, associate professor of gynecologic oncology at the University of Chicago, who was not involved in the research. In essence, he said, the tumor cells shovel healthy mesothelial cells out of their way to get to underlying organs.
In the early stages of metastasis, tumor cell clusters called spheroids break off from the ovary and float through the abdominal cavity until they encounter the abdominal cavity walls or nearby organs such as the stomach, liver, and intestines. But until now, scientists did not know how the tumor cells penetrated the mesothelium that surrounds these organs to form the secondary tumors characteristic of metastasis.
To determine the method of invasion, cell biologist Marcin Iwanicki of Harvard Medical School and his colleagues observed the movement of cultured mesothelial cells after addition of a tumor spheroid. Time-lapse microscope images showed that as the tumor cells attached to the surface of the mesothelial cell layer and began to multiply, they forced the mesothelial cells to the side. Further experiments showed that the connections between the mesothelial cells were weakened and the cells began actively migrating away from the tumor cells.
To determine how the cancer was driving this process, the researchers inhibited expression of various tumor cell proteins and watched for any effects on tumor penetration. Three proteins -- myosin II, talin I, and an integrin protein -- were all required in order for the tumor cells to pass through the mesothelium. The precise mechanism of cell layer penetration remains unclear, said Joan Brugge, chair of the Department of Cell Biology at Harvard Medical School and principal investigator on the study, but based on the known cellular function of these proteins, the researchers hypothesized that the 3-protein complex works by gripping the extracellular matrix and pushing the tumor cells between mesothelial cells, physically driving the cancer into the new organ.
“I think it’s an elegant study,” said Lengyel, who co-authored a Cancer Discovery editorial on the study. “They explain the first step of ovarian cancer metastasis.”
The next challenge is to confirm the results in vivo, said Brugge. “We’re starting to interact with some clinicians to understand whether there’s a correlation between the in vitro assay and the properties of the tumors in the gut,” she said. If there is, Brugge said, the results may one day lead to therapies that prevent the spread of tumors throughout the abdominal cavity.
M.P. Iwanicki, et. al. "Ovarian cancer spheroids use myosin-generated force to clear the mesothelium," Cancer Discovery, doi: 10.1158/2159-8274.CD-11-0010, 2011.