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

Andrew D. Rhim, Paul E. Oberstein, Dafydd H. Thomas, Emily T. Mirek, Carmine F. Palermo, Stephen A. Sastra, Erin N. Dekleva, Tyler Saunders, Claudia P. Becerra, Ian W. Tattersall, C. Benedikt Westphalen, Jan Kitajewski, Maite G. Fernandez-Barrena, Martin E Fernandez-Zapico, Christine Iacobuzio-Donahue, Kenneth P. Olive, Ben Z. Stanger

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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 languageEnglish (US)
Pages (from-to)735-747
Number of pages13
JournalCancer Cell
Volume25
Issue number6
DOIs
StatePublished - Jun 16 2014

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Hedgehogs
Adenocarcinoma
Neoplasms
Blocking Antibodies
Growth
Histology
Fibroblasts
Ligands

ASJC Scopus subject areas

  • Cancer Research
  • Cell Biology
  • Oncology

Cite this

Rhim, A. D., Oberstein, P. E., Thomas, D. H., Mirek, E. T., Palermo, C. F., Sastra, S. A., ... Stanger, B. Z. (2014). Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma. Cancer Cell, 25(6), 735-747. https://doi.org/10.1016/j.ccr.2014.04.021

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 journalArticle

Rhim, AD, Oberstein, PE, Thomas, DH, Mirek, ET, Palermo, CF, Sastra, SA, Dekleva, EN, Saunders, T, Becerra, CP, Tattersall, IW, Westphalen, CB, Kitajewski, J, Fernandez-Barrena, MG, Fernandez-Zapico, ME, Iacobuzio-Donahue, C, Olive, KP & Stanger, BZ 2014, 'Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma', Cancer Cell, vol. 25, no. 6, pp. 735-747. https://doi.org/10.1016/j.ccr.2014.04.021
Rhim AD, Oberstein PE, Thomas DH, Mirek ET, Palermo CF, Sastra SA et al. Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma. Cancer Cell. 2014 Jun 16;25(6):735-747. https://doi.org/10.1016/j.ccr.2014.04.021
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. / Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma. In: Cancer Cell. 2014 ; Vol. 25, No. 6. pp. 735-747.
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