Enhanced hepatocyte growth factor signaling by type II transforming growth factor-beta receptor knockout fibroblasts promotes mammary tumorigenesis.
Transforming growth factor-beta (TGF-beta) plays complex dual roles as an inhibitor and promoter of tumor progression. Although the influence of the stromal microenvironment on tumor progression is well recognized, little is known about the functions of TGF-beta signaling in the stroma during tumor progression. Using cre-lox technology, expression of the type II TGF-beta receptor was selectively knocked out in fibroblasts (Tgfbr2(FspKO)). In a co-xenograft model, we show that Tgfbr2(FspKO) fibroblasts enhance mammary carcinoma growth and metastasis in mice while increasing hepatocyte growth factor (HGF) expression and c-Met signaling downstream pathways including signal transducers and activators of transcription 3 (Stat3) and p42/44 mitogen-activated protein kinase (MAPK). Treatment of tumor-bearing mice with a pharmacologic inhibitor (EXEL-7592) of c-Met blocks tumor progression and reduces levels of phospho-Stat3 and phospho-p42/44 MAPK. Similarly, small interfering RNA knockdown of c-Met expression in mammary tumor cells reduces metastasis and c-Met signaling caused by Tgfbr2(FspKO) fibroblasts. The results show that TGF-beta signaling in fibroblasts suppresses tumor metastasis by antagonizing HGF/c-Met signaling within tumor epithelial cells. Furthermore, this co-xenograft model represents a unique context to study stromal TGF-beta and HGF signaling in mammary tumorigenesis.
Cheng
Nikki
N
Department of Cancer Biology, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
Chytil
Anna
A
Shyr
Yu
Y
Joly
Alison
A
Moses
Harold L
HL
D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D017228:Hepatocyte Growth Factor / Q000378:metabolism*; D008325:Mammary Neoplasms, Experimental / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008819:Mice, Nude; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology
D034741:RNA, Small Interfering; D018125:Receptors, Transforming Growth Factor beta; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met; D017346:Protein Serine-Threonine Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D000077294:Receptor, Transforming Growth Factor-beta Type II