| First Author | Eikesdal HP | Year | 2018 |
| Journal | Mol Cancer Res | Volume | 16 |
| Issue | 10 | Pages | 1568-1578 |
| PubMed ID | 29934328 | Mgi Jnum | J:265986 |
| Mgi Id | MGI:6201817 | Doi | 10.1158/1541-7786.MCR-18-0120 |
| Citation | Eikesdal HP, et al. (2018) BMP7 Signaling in TGFBR2-Deficient Stromal Cells Provokes Epithelial Carcinogenesis. Mol Cancer Res 16(10):1568-1578 |
| abstractText | Deregulated transforming growth factor-beta (TGFbeta) signaling is a common feature of many epithelial cancers. Deletion of TGFbeta 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. Mol Cancer Res; 16(10); 1568-78. (c)2018 AACR. |
