Meanwhile, Gutmann's lab had conducted extensive research showing how the environment immediately surrounding NF1 brain tumors known as gliomas influences their formation and maintenance. Most NF1 brain tumors occur in the optic pathway, the region of the brain that relays information from the retinas to the visual cortex in the back of the head. These tumors generally stop growing after patients reach puberty. Both characteristics suggest that in NF1 patients something that encourages cancer formation, and growth is present in the optic pathway during a specific time of life.
Rubin and Gutmann decided to collaborate to see if that something was CXCL12, the protein that binds to CXCR4 to activate it. Rubin checked for elevated CXCL12 activity levels in human tumor samples and found higher levels in the tumors and in normal tissue inside the tumors. He also found that the optic pathway generally had higher levels of CXCL12 activity than other brain regions.
Next, Rubin took brain cells called glia from Gutmann's mouse model of NF1 and exposed them to CXCL12. Normal mouse glia died after exposure to CXCL12. In contrast, glia from the mouse model divided and grew in response to CXCL12.
Rubin then linked that effect to levels of a compound known as cyclic adenosine monophosphate (cAMP). Lower cAMP levels meant cells thrived after exposure to CXCL12. Higher levels meant they died in response to it. He also found the optic pathway has much lower levels of cAMP than any other brain region, and that lower cAMP levels were associated with loss of function of the neurofibromatosis gene, which causes NF1.
"My lab had previously shown that loss of this gene made glia more likely to grow and divide, a
|Contact: Michael C. Purdy|
Washington University in St. Louis