Cancer Cell
Volume 25, Issue 6, 16 June 2014, Pages 735-747
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Article
Stromal Elements Act to Restrain, Rather Than Support, Pancreatic Ductal Adenocarcinoma

https://doi.org/10.1016/j.ccr.2014.04.021Get rights and content
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Highlights

  • Shh-deficient tumors lacked stroma but were more aggressive and highly vascular

  • Differentiation status is plastic and may be dependent in part upon Hh signaling

  • Unlike differentiated tumors, undifferentiated PDAC is highly vascular

  • Undifferentiated pancreas tumors may be susceptible to VEGFR inhibition

Summary

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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