FGF-10 disrupts lung morphogenesis and causes pulmonary adenomas in vivo.
Transgenic mice in which fibroblast growth factor (FGF)-10 was expressed in the lungs of fetal and postnatal mice were generated with a doxycycline-inducible system controlled by surfactant protein (SP) C or Clara cell secretory protein (CCSP) promoter elements. Expression of FGF-10 mRNA in the fetal lung caused adenomatous malformations, perturbed branching morphogenesis, and caused respiratory failure at birth. When expressed after birth, FGF-10 caused multifocal pulmonary tumors. FGF-10-induced tumors were highly differentiated papillary and lepidic pulmonary adenomas. Epithelial cells lining the tumors stained intensely for thyroid transcription factor (TTF)-1 and SP-C but not CCSP, indicating that FGF-10 enhanced differentiation of cells to a peripheral alveolar type II cell phenotype. Withdrawal from doxycycline caused rapid regression of the tumors associated with rapid loss of the differentiation markers TTF-1, SP-B, and proSP-C. FGF-10 disrupted lung morphogenesis and induced multifocal pulmonary tumors in vivo and caused reversible type II cell differentiation of the respiratory epithelium.
Clark
J C
JC
Division of Pulmonary Biology, Children's Hospital Medical Center, 3333 Burnet Ave., Cincinnati, OH 45229-3039, USA.
Tichelaar
J W
JW
Wert
S E
SE
Itoh
N
N
Perl
A K
AK
Stahlman
M T
MT
Whitsett
J A
JA
D000236:Adenoma / Q000139:chemically induced* / Q000648:ultrastructure; D000818:Animals; D000831:Animals, Newborn / Q000254:growth & development*; D004318:Doxycycline; D005314:Embryonic and Fetal Development / Q000187:drug effects; D005333:Fetus / Q000502:physiology*; D051526:Fibroblast Growth Factor 10; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000494:pharmacology*; D036341:Intercellular Signaling Peptides and Proteins; D008168:Lung / Q000187:drug effects / Q000196:embryology* / Q000254:growth & development* / Q000378:metabolism; D008175:Lung Neoplasms / Q000139:chemically induced* / Q000648:ultrastructure; D051379:Mice; D008822:Mice, Transgenic / Q000235:genetics; D009687:Nuclear Proteins / Q000378:metabolism; D010455:Peptides / Q000378:metabolism; D011498:Protein Precursors / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000494:pharmacology; D011510:Proteolipids / Q000378:metabolism; D037721:Pulmonary Surfactant-Associated Protein C; D011663:Pulmonary Surfactants / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors / Q000378:metabolism; D014598:Uteroglobin
C496464:Fgf10 protein, mouse; D051526:Fibroblast Growth Factor 10; D036341:Intercellular Signaling Peptides and Proteins; C000614414:Nkx2-1 protein, mouse; D009687:Nuclear Proteins; D010455:Peptides; D011498:Protein Precursors; D011506:Proteins; D011510:Proteolipids; D037721:Pulmonary Surfactant-Associated Protein C; D011663:Pulmonary Surfactants; D012333:RNA, Messenger; C556390:Scgb1a1 protein, mouse; C489680:Sftpc protein, mouse; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors; C105511:surfactant protein B propeptide; D005346:Fibroblast Growth Factors; D014598:Uteroglobin; D004318:Doxycycline