Sometimes the simplest solutions can achieve surprisingly significant results. Using an inverted Olympus culture microscope, researchers from the University of Michigan (UM; Ann Arbor) were able to track down the cells responsible for neurofibromatosis type 1 (NF1), an incurable condition of the peripheral nervous system that afflicts one in 3500 Americans. Though most cases are mild, the disease can lead to disfigurement, learning disabilities, blindness, skeletal abnormalities, loss of limbs and, occasionally, lethal malignancies. NF1 causes benign tumors to grow around peripheral nerves; in 3% to 5% of the cases, the tumors later become malignant (neurofibromas).
An inverted Olympus microscope image of mouse Schwann cells is shown in red with the cell nuclei stained blue. (Courtesy of University of Michigan/Nancy Joseph)
Researchers have long wondered which cell types trigger formation of neurofibromas: Schwann cells, which form the protective myelin sheath around nerve fibers, or stem cells that give rise to Schwann cells during fetal development? The answer has implications for the development of drug therapies.
In a study published in the Feb. 5 Cancer Cell, UM scientists Nancy Joseph and Jack Mosher tried to determine if deleting the NF1 gene causes neural crest stem cells to persist beyond birth and form neurofibromas in mice. They studied seven mouse models that had various mutations of the NF1 gene and other genes known to contribute to the formation of neurofibromas and malignant peripheral nerve sheath tumors.
“The surprise was that we didn’t see neural crest stem cells persist after birth in regions where the tumors formed, even with the NF1 deletions,” Joseph says. “That argues against a stem-cell origin.”
This study, when combined with related work done in Yuan Zhu’s lab in the UM Medical School (also published in Cancer Cell, Feb. 5), led the researchers to conclude that Schwann cells, not neural crest stem cells, proliferate to form the tumors. Zhu and his colleagues were able to show that a specific type of Schwann cell, called a non-myelinating Schwann cell, is the likely source of potentially cancerous neurofibromas.
“One of the difficulties of NF1 is that it is hard to predict when tumors will grow and which tumors will turn malignant. You don’t want to use a very aggressive therapy because some tumors will never grow,” Zhu says. “With this insight into the initiation of the disease, we can develop strategies to prevent the tumors from forming.”