Stromal Elements Act to Restrain, Rather Than Support, Pancreatic Ductal Adenocarcinoma

被引：1610

作者：

Rhim, Andrew D. ^{[1
,2
,3
,4
]}

Oberstein, Paul E. ^{[5
]}

Thomas, Dafydd H. ^{[6
,7
]}

Mirek, Emily T. ^{[3
,4
]}

Palermo, Carmine F. ^{[6
,7
]}

Sastra, Stephen A. ^{[6
,7
]}

Dekleva, Erin N. ^{[3
,4
]}

Saunders, Tyler ^{[8
,9
]}

Becerra, Claudia P. ^{[7
]}

Tattersa, Ian W. ^{[7
]}

Westphalen, C. Benedikt ^{[6
]}

Kitajewski, Jan ^{[7
]}

Fernandez-Barrena, Maite G. ^{[10
]}

Fernandez-Zapico, Martin E. ^{[10
]}

Iacobuzio-Donahue, Christine ^{[8
,9
]}

Olive, Kenneth P. ^{[6
,7
]}

Stanger, Ben Z. ^{[3
,4
]}

机构：

[1] Univ Michigan, Sch Med, Dept Internal Med, Div Gastroenterol, Ann Arbor, MI 48109 USA

[2] Univ Michigan, Sch Med, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA

[3] Univ Penn, Dept Med, Gastroenterol Div, Philadelphia, PA 19104 USA

[4] Univ Penn, Perelman Sch Med, Abramson Family Canc Res Inst, Philadelphia, PA 19104 USA

[5] Columbia Univ, Med Ctr, Div Hematol & Oncol, New York, NY 10032 USA

[6] Columbia Univ, Med Ctr, Dept Med, Div Digest & Liver Dis, New York, NY 10032 USA

[7] Columbia Univ, Med Ctr, Herbert Irving Comprehens Canc Ctr, Dept Pathol & Cell Biol, New York, NY 10032 USA

[8] Johns Hopkins Univ, Sol Goldman Pancreat Canc Res Ctr, Baltimore, MD 21287 USA

[9] Johns Hopkins Univ, Dept Pathol, Baltimore, MD 21287 USA

[10] Mayo Clin, Schulze Ctr Novel Therapeut, Rochester, MN 55905 USA

来源：

CANCER CELL | 2014年 / 25卷 / 06期

关键词：

STELLATE CELLS; MOUSE MODEL; STEM-CELLS; HEDGEHOG; CANCER; INHIBITION; PROMOTE; CARCINOMA; SURVIVAL; PATHWAY;

D O I：

10.1016/j.ccr.2014.04.021

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：735 / 747

页数：13

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