The Hedgehog gene, first studied in fruit flies, got its name because during embryonic development, the mutated version causes flies to resemble a spiky hedgehog. The pathway plays a major role in controlling normal fetal and postnatal development, and, later in life, helping normal adult stem cells function and proliferate.
The Johns Hopkins scientists first tested 19 human glioblastomas removed during surgery and frozen immediately, and found Hedgehog active in five at the time of tumor removal. They also found Hedgehog activity in four of seven glioblastoma cell lines.
Next, the team used cyclopamine, chemically extracted from corn lilies that grow in the Rocky Mountains, to inhibit Hedgehog in cells lines growing on plastic or as neurospheres, round clusters of stems cells that float in liquid nutrients. This reduced tumor growth in the cell-laden plastic by 40 to 60 percent, and caused the neurospheres to fall apart without any new growth of the cell clusters.
The researchers also pretreated mice with cyclopamine before injecting human glioblastoma cells into their brains, resulting in cancer cells that failed to form tumors in the mice.
Other researchers have shown that radiotherapy fails to kill all cancer stem cells in glioblastomas, apparently because many of these cells can repair the DNA damage inflicted by radiation. The Hopkins team suggests that blocking the Hedgehog pathway with cyclopamine kills these radiation-resistant cancer stem cells.
In previous laboratory experiments, Eberhart used cyclopamine to block Hedgehog using medulloblastoma cells, the most common brain cancer occurring in children.
Along with childhood brain cancers, cyclopamine has shown early promise in treating skin cancer; rhabdomyosarcoma, a muscle tumor; and multi
|Contact: Vanessa Wasta|
Johns Hopkins Medical Institutions