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


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
University of California Berkeley, Department of Molecular and Cell Biology, Berkeley, CA 94720-3204, USA.
Maarten F
MF
Bijlsma
Henk
H
Roelink
D000215:Acylation / Q000187:drug effects; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D004705:Endocytosis / Q000187:drug effects; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology; D008024:Ligands; D009369:Neoplasms / Q000188:drug therapy* / Q000503:physiopathology*; D019899:Paracrine Communication / Q000187:drug effects / Q000502:physiology; D011499:Protein Processing, Post-Translational; D055571:Secretory Pathway / Q000187:drug effects; D055153:Stem Cell Niche / Q000187:drug effects / Q000503:physiopathology; D017154:Stromal Cells / Q000187:drug effects / Q000502:physiology
D000970:Antineoplastic Agents; D053823:Hedgehog Proteins; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; C509239:SHH protein, human