Transcription profiling of mouse E18.5 intestinal mesenchyme treated with Sonic or Indian hedgehog ligand to identify targets regulated by Hedgehog signaling
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ABSTRACT:
ORGANISM(S): Mus musculus
SUBMITTER: William Zacharias
PROVIDER: E-GEOD-17840 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:Canonical Hedgehog (Hh) signaling regulates the expression of genes that are critical to the patterning and development of a variety of organ systems. In adult, both ligand-dependent and ligand-independent Hh pathway activation are known to promote tumorigenesis. Recent studies have shown that in tumors promoted by Hh ligand, activation occurs within the stromal microenvironment (Yauch et al., 2009). In situ hybridization of the pathway target gene, Ptch1, shows that signaling is located at stromal perivascular fibroblast-like cells in xenograft tumor sections derived from Hh-expressing colorectal cancer cell lines. To study the downstream genes regulated by Hh signaling, we treated a primary human colon myofibroblast, CCD-18Co, with SHH (1 ug/ml) or no treatment (control) in serum-free medium supplemented with 0.1% BSA for 72 hrs and performed microarray analysis (Affymetrix U133P) on these samples. Three biological replicates of SHH stimulated and three replicates of unstimulated primary colon myofibroblast cells CCD-18Co were used in the experiment to analyze their gene expression.
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Project description:Aberrant activation of the Hedgehog (Hh) signaling pathway is implicated in the pathogenesis of many cancers, including medulloblastoma and basal cell carcinoma (BCC). In this study, using neonatally irradiated Ptch1+/- mice as a model of Hh-dependent tumors, we investigated the in vivo effects of MK-4101, a novel SMO antagonist, for treatment of medulloblastoma and BCC. Results clearly demonstrate a robust antitumor activity of MK-4101, achieved through the inhibition of proliferation and induction of extensive apoptosis in tumor cells. Of note, beside antitumor activity on transplanted tumors, MK-4101 was highly efficacious against primary medulloblastoma and BCC developing in the cerebellum and skin of Ptch1+/- mice. By identifying the changes induced by MK-4101 in gene expression profiles in tumors, we also elucidate the mechanism of action of this novel, orally administrable compound. MK-4101 targets the Hh pathway in the tumor cells, showing the maximum inhibitory effect on Gli1 activity. MK-4101 also induced deregulation of cell cycle and block of DNA replication in tumors. Members of the IGF and Wnt signaling pathways , were among the most highly deregulated genes by MK-4101, suggesting that the interplay among Hh, IGF and Wnt is crucial in Hh-dependent tumorigenesis. Altogether, the results of this preclinical study support a therapeutic opportunity for MK-4101 in the treatment of Hh-driven cancers, also providing useful information for combination therapy with drugs targeting pathways cooperating with Hh oncogenic activity. Gene expression data was generated (in replicates) from Medulloblastoma allografts collected at various time points and following low (40mpk) or high (80 mpk) or vehicle single dose (QD) or mutiple dose (BID) treatment with a SHH pathway inhibitor.
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