1. Blocking Hedgehog release from pancreatic cancer cells increases paracrine signaling potency.
- Author
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Damhofer H, Veenstra VL, Tol JA, van Laarhoven HW, Medema JP, and Bijlsma MF
- Subjects
- ADAM Proteins genetics, ADAM Proteins metabolism, Animals, Cell Line, Tumor, HEK293 Cells, Hedgehog Proteins genetics, Humans, Mice, Neoplasm Proteins genetics, Pancreatic Neoplasms genetics, Pancreatic Neoplasms pathology, Hedgehog Proteins metabolism, Neoplasm Proteins metabolism, Pancreatic Neoplasms metabolism, Paracrine Communication, Signal Transduction
- Abstract
Members of the Hedgehog (Hh) family of morphogens play crucial roles in development but are also involved in the progression of certain types of cancer. Despite being synthesized as hydrophobic dually lipid-modified molecules, and thus being strongly membrane-associated, Hh ligands are able to spread through tissues and act on target cells several cell diameters away. Various mechanisms that mediate Hh release have been discussed in recent years; however, little is known about dispersion of this ligand from cancer cells. Using co-culture models in conjunction with a newly developed reporter system, we were able to show that different members of the ADAM family of metalloproteinases strongly contribute to the release of endogenous bioactive Hh from pancreatic cancer cells, but that this solubilization decreases the potency of cancer cells to signal to adjacent stromal cells in direct co-culture models. These findings imply that under certain conditions, cancer-cell-tethered Hh molecules are the more potent signaling activators and that retaining Hh on the surface of cancer cells can unexpectedly increase the effective signaling range of this ligand, depending on tissue context., (© 2015. Published by The Company of Biologists Ltd.)
- Published
- 2015
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