Abstract
Sonic hedgehog (Shh), a soluble ligand overexpressed by neoplastic cells in pancreatic ductal adenocarcinoma (PDAC), drives formation of a fibroblast-rich desmoplastic stroma. To better understand its role in malignant progression, we deleted Shh in a well-defined mouse model of PDAC. As predicted, Shh-deficient tumors had reduced stromal content. Surprisingly, such tumors were more aggressive and exhibited undifferentiated histology, increased vascularity, and heightened proliferation-features that were fully recapitulated in control mice treated with a Smoothened inhibitor. Furthermore, administration of VEGFR blocking antibody selectively improved survival of Shh-deficient tumors, indicating that Hedgehog-driven stroma suppresses tumor growth in part by restraining tumor angiogenesis. Together, these data demonstrate that some components of the tumor stroma can act to restrain tumor growth.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 735-747 |
| Number of pages | 13 |
| Journal | Cancer Cell |
| Volume | 25 |
| Issue number | 6 |
| DOIs | |
| State | Published - Jun 16 2014 |
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ASJC Scopus subject areas
- Cancer Research
- Cell Biology
- Oncology
Cite this
Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma. / Rhim, Andrew D.; Oberstein, Paul E.; Thomas, Dafydd H.; Mirek, Emily T.; Palermo, Carmine F.; Sastra, Stephen A.; Dekleva, Erin N.; Saunders, Tyler; Becerra, Claudia P.; Tattersall, Ian W.; Westphalen, C. Benedikt; Kitajewski, Jan; Fernandez-Barrena, Maite G.; Fernandez-Zapico, Martin E; Iacobuzio-Donahue, Christine; Olive, Kenneth P.; Stanger, Ben Z.
In: Cancer Cell, Vol. 25, No. 6, 16.06.2014, p. 735-747.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma
AU - Rhim, Andrew D.
AU - Oberstein, Paul E.
AU - Thomas, Dafydd H.
AU - Mirek, Emily T.
AU - Palermo, Carmine F.
AU - Sastra, Stephen A.
AU - Dekleva, Erin N.
AU - Saunders, Tyler
AU - Becerra, Claudia P.
AU - Tattersall, Ian W.
AU - Westphalen, C. Benedikt
AU - Kitajewski, Jan
AU - Fernandez-Barrena, Maite G.
AU - Fernandez-Zapico, Martin E
AU - Iacobuzio-Donahue, Christine
AU - Olive, Kenneth P.
AU - Stanger, Ben Z.
PY - 2014/6/16
Y1 - 2014/6/16
N2 - Sonic hedgehog (Shh), a soluble ligand overexpressed by neoplastic cells in pancreatic ductal adenocarcinoma (PDAC), drives formation of a fibroblast-rich desmoplastic stroma. To better understand its role in malignant progression, we deleted Shh in a well-defined mouse model of PDAC. As predicted, Shh-deficient tumors had reduced stromal content. Surprisingly, such tumors were more aggressive and exhibited undifferentiated histology, increased vascularity, and heightened proliferation-features that were fully recapitulated in control mice treated with a Smoothened inhibitor. Furthermore, administration of VEGFR blocking antibody selectively improved survival of Shh-deficient tumors, indicating that Hedgehog-driven stroma suppresses tumor growth in part by restraining tumor angiogenesis. Together, these data demonstrate that some components of the tumor stroma can act to restrain tumor growth.
AB - Sonic hedgehog (Shh), a soluble ligand overexpressed by neoplastic cells in pancreatic ductal adenocarcinoma (PDAC), drives formation of a fibroblast-rich desmoplastic stroma. To better understand its role in malignant progression, we deleted Shh in a well-defined mouse model of PDAC. As predicted, Shh-deficient tumors had reduced stromal content. Surprisingly, such tumors were more aggressive and exhibited undifferentiated histology, increased vascularity, and heightened proliferation-features that were fully recapitulated in control mice treated with a Smoothened inhibitor. Furthermore, administration of VEGFR blocking antibody selectively improved survival of Shh-deficient tumors, indicating that Hedgehog-driven stroma suppresses tumor growth in part by restraining tumor angiogenesis. Together, these data demonstrate that some components of the tumor stroma can act to restrain tumor growth.
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UR - http://www.scopus.com/inward/citedby.url?scp=84902435628&partnerID=8YFLogxK
U2 - 10.1016/j.ccr.2014.04.021
DO - 10.1016/j.ccr.2014.04.021
M3 - Article
C2 - 24856585
AN - SCOPUS:84902435628
VL - 25
SP - 735
EP - 747
JO - Cancer Cell
JF - Cancer Cell
SN - 1535-6108
IS - 6
ER -