[HTML][HTML] Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma

AD Rhim, PE Oberstein, DH Thomas, ET Mirek… - Cancer cell, 2014 - cell.com
AD Rhim, PE Oberstein, DH Thomas, ET Mirek, CF Palermo, SA Sastra, EN Dekleva…
Cancer cell, 2014cell.com
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 …
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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