Enhanced hepatocyte growth factor signaling by type II transforming growth factor-β receptor knockout fibroblasts promotes mammary tumorigenesis

Nikki Cheng, Anna Chytil, Yu Shyr, Alison Joly, Harold L. Moses

Research output: Contribution to journalArticle

49 Citations (Scopus)

Abstract

Transforming growth factor-β (TGF-β) 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-β signaling in the stroma during tumor progression. Using cre-lox technology, expression of the type II TGF-β receptor was selectively knocked out in fibroblasts (Tgfbr2FspKO). In a co-xenograft model, we show that Tgfbr2EspKO 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 Tgfbr2FspKO fibroblasts. The results show that TGF-β 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-β and HGF signaling in mammary tumorigenesis.

Original languageEnglish
Pages (from-to)4869-4877
Number of pages9
JournalCancer Research
Volume67
Issue number10
DOIs
Publication statusPublished - 2007 May 15

Fingerprint

Hepatocyte Growth Factor
Growth Factor Receptors
Transforming Growth Factors
Carcinogenesis
Breast
Fibroblasts
STAT3 Transcription Factor
Mitogen-Activated Protein Kinase 1
Neoplasms
Neoplasm Metastasis
Heterografts
Breast Neoplasms
Tumor Microenvironment
Carcinogens
Small Interfering RNA
Epithelial Cells
Technology
Growth

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

@article{0e4f8792b0194887b6e2040abe68ddab,
title = "Enhanced hepatocyte growth factor signaling by type II transforming growth factor-β receptor knockout fibroblasts promotes mammary tumorigenesis",
abstract = "Transforming growth factor-β (TGF-β) 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-β signaling in the stroma during tumor progression. Using cre-lox technology, expression of the type II TGF-β receptor was selectively knocked out in fibroblasts (Tgfbr2FspKO). In a co-xenograft model, we show that Tgfbr2EspKO 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 Tgfbr2FspKO fibroblasts. The results show that TGF-β 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-β and HGF signaling in mammary tumorigenesis.",
author = "Nikki Cheng and Anna Chytil and Yu Shyr and Alison Joly and Moses, {Harold L.}",
year = "2007",
month = "5",
day = "15",
doi = "10.1158/0008-5472.CAN-06-3381",
language = "English",
volume = "67",
pages = "4869--4877",
journal = "Journal of Cancer Research",
issn = "0099-7013",
publisher = "American Association for Cancer Research Inc.",
number = "10",

}

Enhanced hepatocyte growth factor signaling by type II transforming growth factor-β receptor knockout fibroblasts promotes mammary tumorigenesis. / Cheng, Nikki; Chytil, Anna; Shyr, Yu; Joly, Alison; Moses, Harold L.

In: Cancer Research, Vol. 67, No. 10, 15.05.2007, p. 4869-4877.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Enhanced hepatocyte growth factor signaling by type II transforming growth factor-β receptor knockout fibroblasts promotes mammary tumorigenesis

AU - Cheng, Nikki

AU - Chytil, Anna

AU - Shyr, Yu

AU - Joly, Alison

AU - Moses, Harold L.

PY - 2007/5/15

Y1 - 2007/5/15

N2 - Transforming growth factor-β (TGF-β) 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-β signaling in the stroma during tumor progression. Using cre-lox technology, expression of the type II TGF-β receptor was selectively knocked out in fibroblasts (Tgfbr2FspKO). In a co-xenograft model, we show that Tgfbr2EspKO 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 Tgfbr2FspKO fibroblasts. The results show that TGF-β 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-β and HGF signaling in mammary tumorigenesis.

AB - Transforming growth factor-β (TGF-β) 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-β signaling in the stroma during tumor progression. Using cre-lox technology, expression of the type II TGF-β receptor was selectively knocked out in fibroblasts (Tgfbr2FspKO). In a co-xenograft model, we show that Tgfbr2EspKO 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 Tgfbr2FspKO fibroblasts. The results show that TGF-β 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-β and HGF signaling in mammary tumorigenesis.

UR - http://www.scopus.com/inward/record.url?scp=34250321214&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=34250321214&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-06-3381

DO - 10.1158/0008-5472.CAN-06-3381

M3 - Article

C2 - 17495323

AN - SCOPUS:34250321214

VL - 67

SP - 4869

EP - 4877

JO - Journal of Cancer Research

JF - Journal of Cancer Research

SN - 0099-7013

IS - 10

ER -