Learning from Jekyll to control Hyde: Hedgehog signaling in development and cancer

Abstract

The Hedgehog transduction cascade is a key part of the system that regulates how a single cell is transformed into a complex multicellular organism. This ubiquitous developmental pathway controls cell proliferation, differentiation, and patterning of tissues during embryogenesis but then, in many tissues, is suppressed in the adult. The Hedgehog pathway can become reactivated in cancer. With a single efficient switch, the cancer is able to activate cell-growth pathways, recruit a blood supply, and invade adjacent tissues. In this review, we focus on how and when the normal Hedgehog pathway is turned back on to aid the neoplastic process. Cancers can be catergorized based on the role Hh signaling plays in their growth. In the first category, abnormal Hh signaling initiates growth of the tumor. In the second category, Hh signaling is important for maintenance of the tumor. In the third, unclassified, category of tumors, Hh signaling has been implicated but its role is not yet defined.

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“…Analysis of upstream regulators using IPA revealed activation of STAT3 and the involvement of other transcription regulators like CTNNB1 (β-catenin) and SMARCA4 (Table 1). Interestingly, SMARCA4 (also known as BRG1) is a transcriptional regulator that can control the activity of Sonic hedgehog and GliA and their downstream targets, providing a driving force for tumor proliferation by activating mitogenic genes such as GLI1, CCND1 and MYC [16,17]. In addition, we analyzed the list of genes that were collectively up-regulated in all 4 conditions using DAVID bioinformatics analysis; a summary of the findings is presented with a functional annotation chart in Figure 2B.…”

Basal cell carcinomas in mice arise from hair follicle stem cells and multiple epithelial progenitor populations

“…Nearly all BCCs exhibit uncontrolled activation of the Hedgehog (Hh) signaling pathway, one of a handful of critical pathways that orchestrate embryonic patterning and development and can contribute to tumor formation when deregulated after birth (7). Whereas physiologic Hh signaling is spatially restricted, generally intermittent, and dependent on the presence of secreted Hh ligands (8), oncogenic Hh signaling in BCC is continuous and Hh ligand-independent (6).…”

“…Studies examining the normal functions of Hh signaling in different organs have provided clues as to where, and how, deregulated Hh signaling contributes to the development of cancer (7). In skin, physiologic Hh signaling is activated in growing hair follicles, where it is required for proliferation of hair follicle epithelium during morphogenesis (11)(12)(13).…”

Regulation of Sufu activity by p66β and Mycbp provides new insight into vertebrate Hedgehog signaling

“…Perturbation of Hh signaling is also associated with various types of human cancers Barakat et al 2010;Bijlsma and Roelink 2010). Elucidating the molecular mechanisms of Hh signaling is essential to our fundamental understanding of developmental processes and disease mechanisms.…”