Hepatocyte growth factor/scatter factor induces a variety of tissue-specific morphogenic programs in epithelial cells.
Hepatocyte growth factor/scatter factor (HGF/SF) is the mesenchymal ligand of the epithelial tyrosine kinase receptor c-Met. In vitro, HGF/SF has morphogenic properties, e.g., induces kidney epithelial cells to form branching ducts in collagen gels. Mutation of the HGF/SF gene in mice results in embryonic lethality due to severe liver and placenta defects. Here, we have evaluated the morphogenic activity of HGF/SF with a large variety of epithelial cells grown in three-dimensional collagen matrices. We found that HGF/SF induces SW 1222 colon carcinoma cells to form crypt-like structures. In these organoids, cells exhibit apical/basolateral polarity and build a well-developed brush border towards the lumen. Capan 2 pancreas carcinoma cells, upon addition of HGF/SF, develop large hollow spheroids lined with a tight layer of polarized cells. Collagen inside the cysts is digested and the cells show features of pancreatic ducts. HGF/SF induces EpH4 mammary epithelial cells to form long branches with end-buds that resemble developing mammary ducts. pRNS-1-1 prostate epithelial cells in the presence of HGF/SF develop long ducts with distal branching as found in the prostate. Finally, HGF/SF simulates alveolar differentiation in LX-1 lung carcinoma cells. Expression of transfected HGF/SF cDNA in LX-1 lung carcinoma and EpH4 mammary epithelial cells induce morphogenesis in an autocrine manner. In the cell lines tested, HGF/SF activated the Met receptor by phosphorylation of tyrosine residues. These data show that HGF/SF induces intrinsic, tissue-specific morphogenic activities in a wide variety of epithelial cells. Apparently, HGF/SF triggers respective endogenous programs and is thus an inductive, not an instructive, mesenchymal effector for epithelial morphogenesis.
Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.
V
V
Brinkmann
H
H
Foroutan
M
M
Sachs
K M
KM
Weidner
W
W
Birchmeier
D000230:Adenocarcinoma; D000818:Animals; D002277:Carcinoma; D048429:Cell Size / Q000502:physiology; D003110:Colonic Neoplasms; D004285:Dogs; D005314:Embryonic and Fetal Development / Q000502:physiology; D004847:Epithelial Cells; D004848:Epithelium / Q000502:physiology / Q000648:ultrastructure; D017228:Hepatocyte Growth Factor / Q000502:physiology*; D006801:Humans; D007668:Kidney / Q000166:cytology; D008099:Liver / Q000166:cytology* / Q000254:growth & development*; D008168:Lung / Q000166:cytology; D008297:Male; D051379:Mice; D008854:Microscopy, Electron; D009024:Morphogenesis / Q000502:physiology; D010179:Pancreas / Q000166:cytology; D010766:Phosphorylation; D011467:Prostate / Q000166:cytology; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000502:physiology / Q000648:ultrastructure
D011518:Proto-Oncogene Proteins; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met; D020794:Receptor Protein-Tyrosine Kinases