The screen turned up 17 genes including many of the "usual suspects"genes already known to play a role in the cell cycle and cell death pathways, Green said. But the presence of the secreted protein IGFBP7 among those factors came as a complete surprise.
Expression of BRAFV600E in cells leads to the synthesis and secretion of IGFBP7, they report, which acts on that cell and its neighbors to inhibit the BRAF-driven signal and induce cell senescence and death.
Moreover, they found that IGFBP7 delivered to human melanoma cells could slow their growth. That finding raised the possibility that the protein might fight BRAF mutant tumors as well.
They injected mice with human melanoma cells both with and without the activated BRAF mutation. The mice were then injected at the tumor site with IGFBP7 or a control chemical. The protein substantially suppressed the growth of tumors, they show, but only those with the abnormal form of BRAF.
Lastly, they report that normal skin melanocytes express low but detectable levels of IGFBP7. In contrast, nevi carrying the BRAF mutation express high levels of IGFBP7, consistent with the finding that the mutant BRAF in melanocytes increases the protein's levels. Significantly, they found, expression of IGFBP7 was not detectable in BRAFV600E positive melanomas.
Based on their findings, the researchers proposed that loss of IGFBP7 expression allows escape from BRAFV600E-mediated senescence and is a critical step in the genesis of melanoma.
"Activated BRAF-positive metastatic melanoma is an aggressive disease that is refractory to conventional chemotherapeutic agents and lacks adequate treatment options," the researc
|Contact: Cathleen Genova|