title: Blocking Hedgehog release from pancreatic cancer cells increases paracrine signaling potency.
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.
authors.affiliation: Laboratory for Experimental Oncology and Radiobiology, Center for Experimental Molecular Medicine, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands.
authors.forename: Helene
authors.initials: H
authors.lastname: Damhofer
authors.affiliation: Laboratory for Experimental Oncology and Radiobiology, Center for Experimental Molecular Medicine, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands.
authors.forename: Veronique L
authors.initials: VL
authors.lastname: Veenstra
authors.affiliation: Department of Surgery, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands.
authors.forename: Johanna A M G
authors.initials: JA
authors.lastname: Tol
authors.affiliation: Laboratory for Experimental Oncology and Radiobiology, Center for Experimental Molecular Medicine, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands Department of Medical Oncology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands.
authors.forename: Hanneke W M
authors.initials: HW
authors.lastname: van Laarhoven
authors.affiliation: Laboratory for Experimental Oncology and Radiobiology, Center for Experimental Molecular Medicine, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands.
authors.forename: Jan Paul
authors.initials: JP
authors.lastname: Medema
authors.affiliation: Laboratory for Experimental Oncology and Radiobiology, Center for Experimental Molecular Medicine, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands m.f.bijlsma@amc.uva.nl.
authors.forename: Maarten F
authors.initials: MF
authors.lastname: Bijlsma
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D057809:HEK293 Cells; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019899:Paracrine Communication; D015398:Signal Transduction
chemical_list: D053823:Hedgehog Proteins; D009363:Neoplasm Proteins; D051722:ADAM Proteins
keywords: ADAM; Pancreatic cancer; Shedding; Sonic Hedgehog