Hedgehog Signaling and Cancer

Contributed by Allison A. Curley, PhD

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The Hedgehog (Hh) signaling pathway is very active during early embryonic development, where it is essential for tissue patterning and organogenesis, but is largely silent during adulthood. Mammals have three secreted Hh ligands: sonic (Shh), indian (Ihh), and desert Hh (Dhh). Additional downstream components of the pathway include the transmembrane receptors, Patched (Ptch) and Smoothened (Smo), which eventually culminate in the activation of glioma-associated oncogene (GLI) transcription factors.1

 Dysregulation of the Hh pathway has been linked to several types of cancer. Somatic mutations in Ptch are present in over 90% of sporadic basal cell carcinoma cases and in about a fifth of medulloblastoma brain tumors.2,3 In addition, large-scale, whole-genome and whole-exome studies have linked extremely rare Ptch mutations with many other cancers. Mutations leading to increased activity of Smo and GLI are also implicated in carcinogenesis.4 In contrast to these ligand-independent mechanisms of tumor formation, the Hh molecule itself is also thought to play a role. One hypothesized mechanism involves tumor cell secretion of Hh into the local environment, which in turn stimulates further tumor growth.1 Another ligand-dependent mechanism is thought to involve Hh’s maintenance and differentiation of cancer stem cells.5

 Blocking Hh signaling for therapeutic purposes has been the subject of a great deal of research. Drugs that inhibit the function of SMO, affect the binding between Hh and Ptch, or repress GLI have all been tested, with varied results. One such SMO inhibitor, vismodegib, is now approved for the treatment of basal cell carcinoma.6 However, many SMO inhibitor trials in other types of cancer have been negative, underscoring the need for future research on Hh signaling.4

 

Detection of human TRIP1(SUG1) in FFPE metastatic lymph node from lung carcinoma by IHC

Detection of human TRIP1(SUG1) in FFPE metastatic lymph node from lung carcinoma by IHC. Antibody: Rabbit anti-TRIP1(SUG1) (A300-791A). Secondary: HRP-conjugated goat anti-rabbit IgG (A120-501P). Substrate: DAB.

Detection of human p300 in FFPE lung carcinoma by IHC

Detection of human p300 in FFPE lung carcinoma by IHC. Antibody: Rabbit anti-p300 (A300-358A). Secondary: HRP-conjugated goat anti-rabbit IgG (A120-501P). Substrate: DAB.

Detection of human CDK8 by WB of immunoprecipitates from HeLa lysate

Detection of human CDK8 by WB of immunoprecipitates from HeLa lysate. Antibodies: Rabbit anti-CDK8 (A302-500A). Secondary: ReliaBLOT® reagents (WB120).

 

Below is the entire list of targets involved in hedgehog signaling. Can’t find what you are looking for? Bethyl offers a custom antibody service.

 

References

1. Scales SJ, de Sauvage 2009. Mechanisms of Hedgehog pathway activation in cancer and implications for therapy. Trends Pharmacol Sci. Jun;30(6):303-312.

2. Gailani MR, Ståhle-Bäckdahl M, Leffell DJ, Glynn M, Zaphiropoulos PG, Pressman C, Undén AB, Dean M, Brash DE, Bale AE, Toftgård. 1996. The role of the human homologue of Drosophila patched in sporadic basal cell carcinomas. Nat Genet. Sept;14(1):78-81.

3. Raffel C, Jenkins RB, Frederick L, Hebrink D, Alderete B, Fults DW, James CD. 1997. Sporadic medulloblastomas contain PTCH mutations. Cancer Res. Mar 1;57(5):842-845.

4. Amakye D, Jagani Z, Dorsch M. 2013. Unraveling the therapeutic potential of the Hedgehog pathway in cancer. Nat Med. Nov;19(11):1410-1422.

5. Merchant AA, Matsui 2010. Targeting Hedgehog--a cancer stem cell pathway. Clin Cancer Res. Jun 15;16(12):3130-3140.

6. Proctor AE, Thompson LA, O'Bryant CL. 2014. Vismodegib: an inhibitor of the hedgehog signaling pathway in the treatment of basal cell carcinoma. Ann Pharmacother. Jan;48(1):99-106.