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Efficacy of IGFBP7 for treatment of metastatic melanoma and other cancers in mouse models and human cell lines.

ABSTRACT: 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.

SUBMITTER: Wajapeyee N

PROVIDER: S-EPMC2783755 | biostudies-literature | 2009 Nov

REPOSITORIES: biostudies-literature

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Efficacy of IGFBP7 for treatment of metastatic melanoma and other cancers in mouse models and human cell lines.

Wajapeyee Narendra N Kapoor Varun V Mahalingam Meera M Green Michael R MR

Molecular cancer therapeutics 20091027 11

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 admini ...[more]

PMID: 19861408

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Project description:Melanoma can progress rapidly from a slow-growing surgically curable lesion to aggressive metastatic disease, with high mortality and poor response to current therapies. The mechanisms underlying melanoma progression and resistance to therapeutic agents are not well understood. There are few treatment options for melanoma once it has metastasized, and new biomarkers that aid diagnosis, predict clinical outcome, and suggest new therapies are required. This aim of this study was to invesigate the molecular basis of melanoma biology and heterogeneity by defining genomic characteristics that correlated with tumour phenotype in a novel panel of 25 cell lines derived largely from New Zealand patients with metastatic melanoma. The goals of this study were to (i) stratify melanoma cell lines by using global gene expression profiling ; (ii) correlate gene expression profiles with invasive potential; and (iii) identify new prognostic markers and therapeutic targets that might aid clinical cancer diagnosis and management. Two-colour spotted oligonucleotide microarrays were used to measure global gene expression in metastatic melanoma cell lines against a common universal reference. Biological replication was achieved by performing replicate arrays on a subset of randomly selected cell lines, in which the replicate total RNA samples were isolated from different vials of cells at different passage numbers, grown by different researchers, and often in different laboratories. Further, NZM01 and NZM02 were derived from different tumours from the same patient at different surgeries, and NZM07.2 and 07.4 were derived from the NZM07 cell line. The array hybridisations were peformed in three batches. Technical replication was achieved by using intra- and inter-batch replicates with different RNA samples from 6/25 of the cell lines: NZM04, 2 x batch 1, 1 x batch 2; NZM22, 2 x batch 1; NZM40, 1 x batch 1, 1 x batch 2; NZM06, 1 x batch 1, 1 x batch 3; NZM09, 1 x batch 1, 1 x batch 2; NZM15, 1 x batch 2, 1 x batch 3.

Dataset Information

Efficacy of IGFBP7 for treatment of metastatic melanoma and other cancers in mouse models and human cell lines.

Publications

Efficacy of IGFBP7 for treatment of metastatic melanoma and other cancers in mouse models and human cell lines.

Similar Datasets

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