Non-cell-autonomous signaling by Shh in tumors: challenges and opportunities for therapeutic targets

Abstract

Importance of the field: The Hedgehog (Hh) pathway is required during many developmental events; in adults the Hedgehog pathway is involved in the maintenance of several stem cell niches. It is therefore not surprising that aberrantly regulated Hh pathway activity can cause birth defects in the developing organism, as well as neoplastic disease later in life.

Areas covered in this review: As a consequence of the involvement in pathogenesis, the Hh pathway components are subject to an intense scrutiny as potential targets for therapeutic agents. We aim to provide an overview of the biology of the Hh proteins and the cellular response, in conjunction with potential therapeutic interventions.

What the reader will gain: Specifically, we focus on the recently discovered non-cell-autonomous Shh signaling used by tumors and the implications of this for the design of treatment strategies. This should provide the reader with up-to-date knowledge on the role of the Hh pathway in tumor progression and the options to treat these malignancies.

Take home message: An important concept that we advocate in this review is the need to recognize the need to target both the stromal and the tumor compartment in malignancies that rely on paracrine Shh signaling.

Figure 1.. Hedgehog production, transport and signaling.

Following translation, the full length Hh protein autocatalytically cleaves and a cholesterol moiety is added in the process. A palmitoyl group is added by a dedicated acyl transferase. Secretion into the extracellular space in the form of multimers is mediated by the action of Disp1. In the absence of Hh ligand, or when Hh is sequestered by an inhibitory protein like Hhip, Ptch1 represses Smo and the downstream pathway is inactive. In the presence of Hh that is free to bind to Ptch1, the repression of Ptch1 on Smo is released and Smo activates downstream pathway components through G-proteins.

Figure 2.. Hedgehog secretion and endocytosis.

Fully processed Shh is trafficked from the Golgi into acidified vesicles where they are complexed into multimers by the proton driven pump activity of Disp1. The complexes are subsequently released in the extracellular space, and subsequently bound and internalized by the action of Ptch1 in adjacent cells. Trafficking of the complex to late endosomes exposes Ptch1 to a lower pH, which is required for the activation of the downstream pathway components.