Many of us have heard about metastatic cancer. It is the type of cancer we all fear, as it is difficult to predict where and when a tumor will migrate. Scientists are working to not only cure cancer, but prevent metastasis of cancer to other sites in the body. This is because it is easier to treat tumors when they are at a confined location and it can be impossible to track down and kill every cancer cell.
In order to prevent cancers from spreading, it is important to understand how it occurs. In tissue such as skin or bladder, the cells act as a barrier or lining. They perform this function by being uniform in shape and tightly connected, like bricks in a wall. These cells are called epithelial cells. In cancer, the epithelial cells lose their uniform shape and tight connections, becoming less attached and more motile. In this way, the cells are able to separate and travel away from the tumor to metastasize. When cells behave in this manner, they are described as mesenchymal. This change in cell shape and behavior is called the epithelial to mesenchymal transition, or EMT.
Dr. Jing Yang at the University of California, San Diego, received the John J. Abel Award in Pharmacology given by ASPET for her pioneering work researching the mechanisms of cancer metastasis. As a postdoctoral fellow, Yang discovered that the protein Twist1 was essential in regulating the epithelial to mesenchymal transition in cancer. This transition actually occurs normally in the body during development as a method for cells to travel to their correct locations in the embryo. “Tumors don’t invent anything new,” says Dr. Yang. “They use what evolution already gave them. They just activate them at the wrong time, in the wrong place and at the wrong dose. If you look at what situation the epithelial cell is able to move, really this is the program that allows stationary epithelial cells to be able to migrate and invade as a single cell.”
At first, it was difficult to prove that epithelial cells became mesenchymal in order to metastasize to a secondary site. When tissue from metastatic sites in human cancers was tested, the cancer cells looked epithelial, not mesenchymal. Dr. Yang proposed that the cells first became mesenchymal in order to gain their migratory capabilities, but reverted to an epithelial type in order to settle at the new tumor site. In other words, the cancer cells underwent the epithelial to mesenchymal transition to metastasize, and then the mesenchymal to epithelial transition (MET) to establish a second tumor. This would make sense, because a cell that is trying to establish itself in a new site would not need migratory capabilities any more.
In order to determine if cancer cells must undergo EMT, followed by MET, in order to metastasize and establish at a secondary site, Yang and her team created a system in which mice were induced to have skin cancer, with the whole body exposed to EMT signals. If the cancer cells did not need to transition from a mesenchymal to epithelial phenotype, they would be able to metastasize anywhere in the body. However, if MET was required, the cancer cells would not be able to establish at distant sites. She also created a model in which EMT was promoted only at the primary tumor site. If cells migrated from this mesenchymal environment and established themselves as epithelial cells at a distant site not receiving EMT signals, it would indicate that EMT is initially required for cancer cells to metastasize, but that it must be reversed for the cells to settle at a secondary site.
In mice with pro-EMT signals throughout the whole body, the cells were unable to metastasize to different sites. Only in the mice with pro-EMT signals restricted to the initial tumor site were the cancer cells able to migrate and found new tumors. This was because the cells were able to undergo first EMT, travel to a different site, and then establish there using MET to revert back to epithelial-like cells. In the other mice, the cells were able to undergo EMT, but not the reverse in order to found new tumors.
Dr. Yang and her team have also been able to capture cancer cells circulating in the blood stream, in a sense getting a snapshot of cancer metastasis. They identified that the cells in the process of metastasis were the mesenchymal type. This further confirmed their hypothesis that cancer cells must acquire mesenchymal characteristics in order to migrate away from the tumor and travel through the blood stream to a new site.
These findings have direct clinical implications, as anti-EMT drugs have been proposed to prevent cancer metastasis. While the cells at the initial tumor site would not be able to leave and establish secondary tumors, any cells that had already acquired mesenchymal characteristics and were traveling through the body would be encouraged to revert to an epithelial type and settle down at a new site. Until techniques are available to track down all cancer cells, both those established and circulating in the body, drugs that alter EMT should be used with caution.