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BMP7 Signaling in TGFBR2-Deficient Stromal Cells Provokes Epithelial Carcinogenesis

Hans Petter Eikesdal1,2, Lisa M Becker1, Yingqi Teng2

  • 1Department of Cancer Biology, Metastasis Research Center, University of Texas, MD Anderson Cancer Center, Houston, Texas.

Molecular Cancer Research : MCR
|June 24, 2018
PubMed

Insights

Loss of TGFβ receptor type 2 (TGFBR2) in stromal cells drives forestomach cancer via HGF. Smad4 is essential for this process, as its concurrent loss with TGFBR2 abrogates cancer development.

Area of Science:

  • Oncology
  • Cancer Biology
  • Molecular Biology

Background:

  • Deregulated transforming growth factor-β (TGFβ) signaling is prevalent in epithelial cancers.
  • Loss of TGFβ receptor type 2 (TGFBR2) in fibroblast specific protein-1 (FSP1)-positive stromal cells induces forestomach squamous cell carcinoma.

Purpose of the Study:

  • To investigate the role of Smad4 in TGFβ signaling-driven forestomach carcinogenesis.
  • To elucidate the cross-talk between stromal and epithelial cells in cancer development.

Main Methods:

  • Utilized genetic mouse models with specific gene deletions (TGFBR2, SMAD4) in FSP1+ fibroblasts.
  • Analyzed forestomach tissue for histological changes, cell proliferation, and gene expression (HGF, BMP7).

Main Results:

  • TGFBR2 deletion in FSP1+ fibroblasts led to hyperproliferation and HGF production, driving carcinogenesis.
  • Concurrent loss of TGFBR2 and SMAD4 completely prevented forestomach cancer development.
  • Bone morphogenic protein-7 (BMP7) upregulated Smad1/5/8 signaling and HGF production in TGFBR2-deficient fibroblasts, an effect abolished by SMAD4 loss.

Conclusions:

  • Smad4-mediated signaling is critical for initiating epithelial carcinogenesis subsequent to TGFBR2 deletion in FSP1+ fibroblasts.
  • Stromal Smad4 is required for the development of squamous cell carcinomas driven by TGFBR2-deficient stromal cells.

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