Posted: March 22, 2011
Tumor Suppressor Function of Mig-6 and its Limitation of EGFR Signaling is Lost in Some Cases of Glioblastoma Multiforme
Researchers1 expanded on data generated by The Cancer Genome Atlas (TCGA) by describing how the loss of a protein called Mig-6 suppresses tumor growth, thereby affecting the development of glioblastoma multiforme (GBM). The work may eventually help clinicians identify patients who will respond better than other patients to new treatments.
Scientists have known that Mig-6 acts as a tumor suppressor in various tissues. It alters the molecular signaling pathways within cells, including the epidermal growth factor receptor (EGFR) pathway, which is abnormally active in GBM. EGFR is a protein found on the surface of some cells that, when bound by epidermal growth factor, sends signals for the cell to keep growing. EGFR is overexpressed in almost half of GBM tumors, so it plays a significant role in GBM development.
Mig-6 is a Tumor Suppressor That is Lost in GBM
Because of Mig-6’s involvement with EGFR, the scientists decided to explore how it contributes to GBM growth. The group found that the Mig-6 gene was deleted in 13 percent of their own collection of GBM tumors and in 18 percent of the TCGA-collected tumors. They also found reduced expression of the Mig-6 gene and its protein product in half of their collection of tumors. It appeared that loss of Mig-6 eliminates its tumor suppressor role and allows GBM tumors to grow uncontrolled.
To confirm Mig-6’s role as a tumor suppressor, the scientists altered Mig-6 levels within cell line models of cancer, which are cells that are grown in the laboratory and are genetically identical to the tumor from which they were taken. By adding Mig-6 to GBM cells lines that were lacking it, they found that GBM cell growth slowed. When they removed Mig-6 from a separate group of GBM cells, the cells grew and divided faster. They concluded that Mig-6 normally works to keep cells from growing out of control.
Loss of Mig-6 Leads to Enhanced EGFR Signaling
The researchers then tested whether Mig-6 affects cell growth by interacting with EGFR. Removing Mig-6 from GBM cells resulted in increased activation of EGFR and the molecular pathways it communicates with. After EGFR is activated and sends its growth signals into the cell, it is shuttled to special cell compartments where it is destroyed. This mechanism ensures that EGFR signaling is turned off before it sends too many commands for the cell to grow, which might lead to cancer. Taking Mig-6 out of GBM cell lines leads to delayed EGFR destruction. These findings suggest that Mig-6 is needed to limit EGFR signaling that contributes to uncontrolled cell growth.
When the scientists added Mig-6 back into GBM cells lacking it, the opposite happened: EGFR activation decreased, while its destruction increased. Using high-powered microscopes, the scientists were able to peer into the cells to visualize how Mig-6 affects EGFR’s destruction. They observed that after EGFR is activated, it moves from the cell surface to the cell interior, where it makes contact with special cell compartments that will take it to be destroyed. Mig-6 accompanies EGFR to these compartments.
When cells were depleted of Mig-6, EGFR did not appear in the compartments. After Mig-6 was added back into cells, the EGFR once again showed up near the compartments. The scientists concluded that Mig-6 is required for EGFR destruction. They also found another protein, called STX8, which acts as an escort along with Mig-6 to ensure that EGFR is destroyed.
Scientists believe that in some cases of GBM, abnormally low levels of Mig-6 allow for EGFR hyperactivity, which drives tumor growth. A class of drugs designed to enhance EGFR delivery to cellular compartments where it is destroyed is currently in clinical trials. Patients who have Mig-6 deletions may be especially sensitive to these drugs. This new knowledge could help clinicians select patients most likely to respond in these drug trials.
1Ying, H., Zheng, H., Scott, K., Wiedemeyer, R., Yan, H., Lim, C., Huang, J., Dhakal, S., Ivanova, E., Xiao, Y., et al. (2010) Mig-6 controls EGFR trafficking and suppresses gliomagenesis. Proc Natl Acad Sci USA. 107(15):6912-6917. Read the full article.