The worst cancer cells don't sit still. Instead they metastasize—migrate from their original sites and establish new tumors in other parts of the body. Once a cancer spreads, it is harder to eliminate. A study by developmental biologists offers a fresh clue to how cancer cells acquire the ability to invade other tissues—a prerequisite for metastasis. It reveals that invasion requires cells to stop dividing. Therefore, the two processes— invasion and proliferation—are mutually exclusive. The finding could inform cancer therapies, which typically target rapidly proliferating cancer cells.
David Matus of Stony Brook University and David Sherwood of Duke University turned to a transparent worm to elucidate this invading process. During the worm's normal development, a cell known as the anchor cell breaks through a structure called the basement membrane, which initially separates the uterus from the vulva. The process is similar to how human cancer cells invade basement membranes to enter the bloodstream, which carries them to distant sites. So biologists have adopted Caenorhabditis elegans as a metastasis model organism, which they can easily image and genetically manipulate.
After turning on and off hundreds of genes in C. elegans, Matus's team found a gene that regulated anchor cell invasion. When it was turned off, the anchor cell failed to invade the basement membrane. But the anchor cell also did something unexpected: it began to divide. Conversely, when the researchers inhibited cell proliferation, the anchor cell stopped dividing and began to invade again. Further experiments showed that halting cell division was both necessary and sufficient for invasion. Although anecdotal observations by pathologists have suggested this either/or situation might be the case, the new study is the first to uncover the genetic mechanism that explains why these two processes must be mutually exclusive. The results were published in October in the journal Developmental Cell.
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The study also explains the long-standing but mysterious observation by cancer biologists that the invading front of many tumors does not contain dividing cells; instead the invasive cells lead the dividing cells behind them and push forward into healthy tissue as the tumor grows in size. “This research changes how we think about cancer at some level,” Matus says. “We think of cancer as a disease of uncontrolled cell division, and in fact, many cancer drugs are designed to target these dividing cells. But our study suggests that we need to figure out how to target these nondividing cells, too, as these are the ones that are invasive.”
Before the insight makes its way into cancer treatments, however, it will need further testing. “Now we can take that simple model and go to more complex systems—like breast cancer tumors,” says Andrew Ewald, a cancer cell biologist at Johns Hopkins University. Metastatic breast cancer alone accounts for about 40,000 deaths every year in the U.S., but the five-year survival rate is nearly 100 percent if caught before the cancer spreads.
