TY - JOUR
T1 - BMP7 signaling in TGFBR2-deficient stromal cells provokes epithelial carcinogenesis
AU - Eikesdal, Hans Petter
AU - Becker, Lisa M.
AU - Teng, Yingqi
AU - Kizu, Akane
AU - Carstens, Julienne Leigh
AU - Kanasaki, Keizo
AU - Sugimoto, Hikaru
AU - LeBleu, Valerie
AU - Kalluri, Raghu
N1 - Funding Information:
This work was primarily supported by funds from the Department of Medicine for the Division of Matrix Biology at Beth Israel Deaconess Medical Center and support from the NIH (CA125550) and the Cancer Prevention and Research Institute of Texas to R. Kalluri. Research in the V.S. LeBleu laboratory is supported by the University of Texas MD Anderson Cancer Center Khalifa Bin Zayed Al Nahya Foundation. H.P. Eikesdal was supported by grants from the University of Bergen, Norway; the Fulbright Association; and Helse Vest, Norway. H. Sugimoto was in part supported by the Stop and Shop Pediatric Brain Tumor Foundation.
Publisher Copyright:
© 2018 American Association for Cancer Research.
PY - 2018/10
Y1 - 2018/10
N2 - Deregulated transforming growth factor-β (TGFβ) signaling is a common feature of many epithelial cancers. Deletion of TGFβ receptor type 2 (TGFBR2) in fibroblast specific protein-1 (FSP1)-positive stromal cells induces squamous cell carcinoma in the murine forestomach, implicating fibroblast-derived hepatocyte growth factor (HGF) as the major driver of the epithelium carcinogenesis. Prior to cancer development, hyperproliferative FSP1+ fibroblasts lacking TGFBR2 accumulate in the forestomach, disrupting the regulatory signaling cross-talk with the forestomach epithelium. Here, concurrent loss in TGFBR2 and SMAD4 completely abrogates the development of forestomach cancer. Bone morphogenic protein-7 (BMP7) was highly upregulated in forestomach cancer tissue, activating Smad1/5/8 signaling, cell proliferation, and HGF production in TGFBR2-deficient FSP1+ fibroblasts. This stimulation by BMP7 was lost in the combined TGFBR2 and SMAD4 double knockout fibroblasts, which included a profound decrease in HGF expression. Thus, Smad4-mediated signaling is required to initiate epithelial carcinogenesis subsequent to TGFBR2 deletion in FSP1+ fibroblasts. Implications: These findings reveal a complex cross-talk between epithelial cells and the stroma, wherein Smad4 is required to elicit squamous cell carcinomas in the forestomach of mice with TGFBR2-deficient stromal cells.
AB - Deregulated transforming growth factor-β (TGFβ) signaling is a common feature of many epithelial cancers. Deletion of TGFβ receptor type 2 (TGFBR2) in fibroblast specific protein-1 (FSP1)-positive stromal cells induces squamous cell carcinoma in the murine forestomach, implicating fibroblast-derived hepatocyte growth factor (HGF) as the major driver of the epithelium carcinogenesis. Prior to cancer development, hyperproliferative FSP1+ fibroblasts lacking TGFBR2 accumulate in the forestomach, disrupting the regulatory signaling cross-talk with the forestomach epithelium. Here, concurrent loss in TGFBR2 and SMAD4 completely abrogates the development of forestomach cancer. Bone morphogenic protein-7 (BMP7) was highly upregulated in forestomach cancer tissue, activating Smad1/5/8 signaling, cell proliferation, and HGF production in TGFBR2-deficient FSP1+ fibroblasts. This stimulation by BMP7 was lost in the combined TGFBR2 and SMAD4 double knockout fibroblasts, which included a profound decrease in HGF expression. Thus, Smad4-mediated signaling is required to initiate epithelial carcinogenesis subsequent to TGFBR2 deletion in FSP1+ fibroblasts. Implications: These findings reveal a complex cross-talk between epithelial cells and the stroma, wherein Smad4 is required to elicit squamous cell carcinomas in the forestomach of mice with TGFBR2-deficient stromal cells.
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U2 - 10.1158/1541-7786.MCR-18-0120
DO - 10.1158/1541-7786.MCR-18-0120
M3 - Article
C2 - 29934328
AN - SCOPUS:85054328353
SN - 1541-7786
VL - 16
SP - 1568
EP - 1578
JO - Molecular Cancer Research
JF - Molecular Cancer Research
IS - 10
ER -