Loss of TGF-beta type II receptor in fibroblasts promotes mammary carcinoma growth and invasion through upregulation of TGF-alpha-, MSP- and HGF-mediated signaling networks.
Stromal fibroblasts regulate epithelial cell behavior through direct and indirect cell-cell interactions. To clarify the role of TGF-beta signaling in stromal fibroblasts during mammary development and tumorigenesis, we conditionally knocked out the TGF-beta type II receptor gene in mouse mammary fibroblasts (Tgfbr2(fspKO)). Tgfbr2(fspKO) mice exhibit defective mammary ductal development, characterized in part by increased ductal epithelial cell turnover associated with an increase in stromal fibroblast abundance. Tgfbr2(fspKO) mammary fibroblasts transplanted with mammary carcinoma cells promote growth and invasion, which is associated with increased activating phosphorylation of the receptors: erbB1, erbB2, RON, and c-Met. Furthermore, the increased receptor phosphorylation correlates with increased secretion of the cognate ligands by Tgfbr2(fspKO) fibroblasts. Treatment of tumor cells with fibroblast-conditioned medium leads to increased tumor cell proliferation and motility, which are blocked by addition of pharmacologic inhibitors of TGF-alpha signaling or neutralizing antibodies to macrophage-stimulating protein (MSP), HGF, or c-Met. These studies characterize a significant role for stromal TGF-beta signaling in mammary tissue homeostasis and mammary tumor progression via regulation of TGF-alpha, MSP, and HGF signaling pathways.
Cheng
Nikki
N
Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN 37232-6838, USA.
Bhowmick
Neil A
NA
Chytil
Anna
A
Gorksa
Agnieszka E
AE
Brown
Kimberly A
KA
Muraoka
Rebecca
R
Arteaga
Carlos L
CL
Neilson
Eric G
EG
Hayward
Simon W
SW
Moses
Harold L
HL
D000818:Animals; D002455:Cell Division; D005260:Female; D017353:Gene Deletion; D020868:Gene Silencing; D017930:Genes, Reporter; D017228:Hepatocyte Growth Factor / Q000502:physiology*; D006720:Homozygote; D015674:Mammary Neoplasms, Animal / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008819:Mice, Nude; D009077:Mucins / Q000502:physiology*; D009124:Muscle Proteins / Q000502:physiology*; D009361:Neoplasm Invasiveness; D010455:Peptides / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000172:deficiency* / Q000235:genetics*; D016211:Transforming Growth Factor alpha / Q000502:physiology*; D000071164:Trefoil Factor-2
D009077:Mucins; D009124:Muscle Proteins; D010455:Peptides; D018125:Receptors, Transforming Growth Factor beta; C481546:TFF2 protein, mouse; D016211:Transforming Growth Factor alpha; D000071164:Trefoil Factor-2; D017228:Hepatocyte Growth Factor; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II