Scientists have found that a protein naturally produced and secreted by the body can make the difference between an average mole and the deadly melanoma, a type of skin cancer that appears as a coloured mark.
Michael Green, a Howard Hughes Medical Institute investigator at the University of Massachusetts Medical School, says that the natural anti-cancer agent IGFBP7 might serve as a targeted chemotherapy for metastatic melanoma if it could be produced and delivered to tumours.
AdvertisementHe says that IGFBP7 might also be used to treat other cancers with mutations in the oncogene known as BRAF.
"This is a natural mechanism by which cells try to prevent cancer. The secretion of this protein gets lost in the formation of cancer. But, because it is secreted, it might also be converted to a therapeutic," Green said.
The researchers say in their study report, published in the journal Cell, that mutations that leave BRAF permanently activated are found at high frequency in human cancers. Such mutations are particularly prevalent in melanoma, they add.
During the study, the researchers conducted a genome-wide screen of cells made to express the BRAF mutation (known as BRAFV600E) found in both melanoma and moles, and then disabled other genes in search of those that would allow the cells to begin dividing as they would in cancer.
They found that the mutation in cells leads to the synthesis and secretion of IGFBP7, which acts on that cell and its neighbours to inhibit the BRAF-driven signal and induce cell senescence and death.
They also found that IGFBP7 delivered to human melanoma cells could slow their growth, suggesting that the protein might help fight other BRAF mutant tumours as well.
The researchers injected mice with human melanoma cells both with and without the activated BRAF mutation, and then injected the animals at the tumour site with IGFBP7 or a control chemical. The protein substantially suppressed the growth of tumours, but only those with the abnormal form of BRAF.
Based on their findings, the researchers came to the conclusion 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. Inhibitors of BRAF have been developed but unfortunately have performed poorly in clinical trials," the researchers concluded.
"We have shown that IGFBP7...efficiently induces (cell death) in BRAFV600E-positive melanoma cell lines. The selective sensitivity of BRAFV600E-containing human cancer cell lines to IGFBP7, and the ability of IGFBP7 to suppress BRAFV600E-positive tumour growth in mice, suggest that IGFBP7 may have a role in treating malignancies harbouring activating BRAF mutations," they added.
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