Program in Gene Function and Expression; Program in Molecular Medicine
Medical Subject Headings
Animals; Apoptosis; Cell Growth Processes; Cell Line, Tumor; Colorectal Neoplasms; Epigenesis, Genetic; Gene Silencing; HT29 Cells; Humans; Insulin-Like Growth Factor Binding Proteins; Melanoma; Mice; Mice, Inbred BALB C; Mice, Nude; Proto-Oncogene Proteins B-raf; Recombinant Proteins; Signal Transduction; Survival Rate; Xenograft Model Antitumor Assays; ras Proteins
Genetics and Genomics
We recently identified the secreted protein IGFBP7 as a factor required for an activated BRAF oncogene to induce senescence or apoptosis in primary human cells. In human melanomas containing an activating BRAF mutation (BRAF-positive melanomas), IGFBP7 is epigenetically silenced, which seems to be a critical step in melanoma genesis. Restoration of IGFBP7 function by the addition of recombinant IGFBP7 (rIGFBP7) induces apoptosis in BRAF-positive human melanoma cell lines, and systemically administered rIGFBP7 markedly suppresses the growth of BRAF-positive primary tumors in xenografted mice. Here we further evaluate the role of IGFBP7 in the treatment of BRAF-positive melanoma and other malignancies. We find that in human metastatic melanoma samples IGFBP7 is epigenetically silenced and at an even higher frequency than that found in primary melanomas. Using a murine experimental metastasis assay, we show that systemic administration of rIGFBP7 markedly suppresses the growth of metastatic disease and prolongs survival. An analysis of the NCI60 panel of human cancer cell lines reveals that in addition to melanoma, IGFBP7 induces apoptosis in several other cancer types, in particular colorectal cancer cell lines. In general, IGFBP7 induces apoptosis in human cancer cell lines that have an activating mutation in BRAF or RAS, and that are sensitive to chemical inhibition of BRAF-MEK-ERK signaling. Significantly, systemically administered rIGFBP7 blocks the growth of colorectal tumors containing an activating RAS or BRAF mutation in mouse xenografts. The results presented here, in conjunction with those from previous studies, justify the further development of IGFBP7 as an anticancer agent.
Rights and Permissions
Citation: Mol Cancer Ther. 2009 Nov;8(11):3009-14. Epub 2009 Oct 27. Link to article on publisher's site