Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2014 Dec 1;2(3):e975606.
doi: 10.4161/23723556.2014.975606. eCollection 2015 Jul-Sep.

Stromal TGFβR2 signaling: a gateway to progression for pancreatic cancer

Moriah M Hagopian  1 , Rolf A Brekken  1
Affiliations

Stromal TGFβR2 signaling: a gateway to progression for pancreatic cancer

Moriah M Hagopian et al. Mol Cell Oncol. .

Abstract

The function of transforming growth factor β (TGFβ) in the progression of pancreatic ductal adenocarcinoma (PDA) is complex and therapeutic targeting of this pathway is challenging. We showed that antibody-mediated inhibition of stromal Tgfβr2 prevented or reversed epithelial plasticity resulting in a potent reduction of metastasis in xenograft models of PDA.

Keywords: TGF-β; epithelial to mesenchymal transition; metastasis; pancreatic cancer; tumor–stroma interactions.

PubMed Disclaimer

Figures

Figure 1.
Figure 1.
Transforming growth factor β receptor 2 (Tgfβr2) blockade promotes an epithelial phenotype in murine tumors in vivo. A-E, LSL-KrasG12D; Cdkn2alox/lox; p48-Cre (KIC) mice establish tumors and precursor pancreatic intraepithelial neoplasia (PanIN) lesions by 4 weeks of age. At this time point the mice were randomized to receive saline (Control), gemcitabine (Gem), 2G8, or 2G8 + Gem for 4 weeks. (A) Analysis of tumor architecture by hematoxylin and eosin (H&E) staining (scale bar, 100 μm). 2G8-treated tumors had significantly more PanIN and epithelial lesions than mice treated with Gem or Control. (B) This was confirmed with Periodic Acid-Schiff (PAS)-Alcian Blue staining, which marks mucin-secreting PanIN lesions but not invasive lesions (PAS-Alcian Blue, purple; scale bar, 100 μm). Additionally, 2G8 tumors had significantly increased expression of epithelial cadherin (E-cadherin or ECAD) (C) and decreased expression of vimentin (D) by immunohistochemistry. (E) Representative images of these tumors demonstrate the predominant epithelial phenotype of 2G8-treated tumors (ECAD, red; vimentin, green; scale bar, 50 μm). (F, G) 2G8 induces a similar epithelial phenotype in murine pancreatic Pan02 tumors. Immunohistochemical analysis of β-catenin (F) and ECAD (G) in Pan02 tumors treated with control, Gem, 2G8, or 2G8+Gem. Bar graphs represent mean+/−SEM. **, P < 0.01; #, P < 0.0001 vs. control; ^^, P < 0.001; ^^^, P < 0.0001 vs. Gem. Reproduced with permission from Ostapoff et al.
See this image and copyright information in PMC

References

    1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin 2012; 62:10-29; PMID:22237781; http://dx.doi.org/ 10.3322/caac.20138 - DOI - PubMed
    1. Jones S, Zhang X, Parsons DW, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Kamiyama H, Jimeno A, et al. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science 2008; 321:1801-6; PMID:18772397; http://dx.doi.org/ 10.1126/science.1164368 - DOI - PMC - PubMed
    1. Yang L, Pang Y, Moses HL. TGF-beta and immune cells: an important regulatory axis in the tumor microenvironment and progression. Trends Immunol 2010; 31:220-7; PMID:20538542; http://dx.doi.org/ 10.1016/j.it.2010.04.002 - DOI - PMC - PubMed
    1. Ostapoff KT, Cenik BK, Wang M, Ye R, Xu X, Nugent D, Hagopian MM, Topalovski M, Rivera LB, Carroll KD, et al. Neutralizing murine TGFβR2 promotes a differentiated tumor cell phenotype and inhibits pancreatic cancer metastasis. Cancer Res 2014; 74:4996-5007; PMID:25060520; http://dx.doi.org/ 10.1158/0008-5472.CAN-13-1807 - DOI - PMC - PubMed
    1. Qian BZ, Pollard JW. Macrophage diversity enhances tumor progression and metastasis. Cell 2010; 141:39-51; PMID:20371344; http://dx.doi.org/ 10.1016/j.cell.2010.03.014 - DOI - PMC - PubMed

LinkOut - more resources