A protein naturally produced and secreted by the body can make the difference between your average mole and melanoma, which killed more than 8,000 people in the United States last year, reveals a new study in the February 8 issue of the journal Cell, a publication of Cell Press.
If this natural anti-cancer agent, called IGFBP7, can be produced and delivered to tumors, it might serve as a targeted chemotherapy for metastatic melanoma, a condition which is "basically untreatable" today, said Michael Green, a Howard Hughes Medical Institute investigator at the University of Massachusetts Medical School. It 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," Green said. "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."
Mutations that leave BRAF permanently activated are found at high frequency in human cancers, the researchers explained. Such mutations are particularly prevalent in melanoma, where they occur in as many as 70 percent of cases. Those mutations, which are also found in some colorectal, ovarian and lung cancers, have been linked to cell proliferation and tumor growth.
Yet activating BRAF mutations are also present in up to 82 percent of benign moles (which go by the clinical term "nevi"). Pigmented moles progress to melanoma only very rarely, and studies have shown that the same BRAF mutations tied to cancer also cause pigment-producing human melanocytes to undergo senescence and cease dividing.
"How, then, does an activated BRAF oncogene induce uncontrolled proliferation in melanoma and senescence in benign nevi?" Green's team wanted to know. They suspected that melanomas might feature a second defect that inactivates the senescence otherwise induced in response to the mutant BRAF.
To find those factors, the researchers conducted a genome-wide screen of cells made to express the BRAF mutation (known as BRAFV600E) found in both melanoma and moles. They then disabled other genes in search of those that would allow the cells to begin dividing as they would in cancer.
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 researchers concluded. "Inhibitors of BRAF have been developed but unfortunately have performed poorly in clinical trials.
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 tumor growth in mice, suggest that IGFBP7 may have a role in treating malignancies harboring activating BRAF mutations."
The researchers include Narendra Wajapeyee, Howard Hughes Medical Institute, Programs in Gene Function and Expression and Molecular Medicine, University of Massachusetts Medical School, Worcester, MA; Ryan W. Serra, Howard Hughes Medical Institute, Programs in Gene Function and Expression and Molecular Medicine, University of Massachusetts Medical School, Worcester, MA; Xiaochun Zhu, Howard Hughes Medical Institute, Programs in Gene Function and Expression and Molecular Medicine, University of Massachusetts Medical School, Worcester, MA; Meera Mahalingam, Department of Dermatology, Boston University School of Medicine, Boston, MA; and Michael R. Green, Howard Hughes Medical Institute, Programs in Gene Function and Expression and Molecular Medicine, University of Massachusetts Medical School, Worcester, MA.
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