The essence of MADM is its unambiguous labeling of mutant cells with green fluorescent protein, which allowed Zong's team to probe into pre-clinical, tumor-initiating stages that are inaccessible to researchers using conventional tools. "Our system lets us watch the action from the beginning, to watch every direction, every hand off or pass, before a tumor forms," Zong said.
"Another key feature is the concurrent creation of a normal red cell whenever a mutant green cell is generated. In effect, we can compare every player's movement with or without the ball -- the mutations," he said. "If they are doing the same thing, we know they are not attacking. If they are doing different things, we know something is wrong, and should focus our attention to tackle the particular player, the cell type, to prevent a tumor from advancing down the field."
In the current research, funded primarily by the National Institutes of Health, two prevalent mutations found in human glioma patients, p53 and NF1, were introduced into neural stem cells (NSCs) "just like snapping the ball to the quarterback," Zong said. "And to our surprise, the quarterback didn't run, although NSCs have been implicated in gliomagenesis by other research groups using conventional genetic methods."
Further analyses of all cell lineages derived from neural stem cells clearly demonstrated that OPCs are the cell of origin since mutant green OPCs over-populate their normal red counterparts by 130-fold before any visible signs of tumor can be detected. "Therefore," Zong said, "the quarterback role of the NSCs seems to be merely passing the ball to the running back -- the OPCs -- which will then score the touchdown.
To convincingly show that OPCs have intrinsic scoring ability independent of the mutation-passing process from NSCs, researchers in the Zong lab also introduced p53 and NF1 mutations directly into OPCs.
|Contact: Jim Barlow|
University of Oregon