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

doi:10.1016/j.ccr.2014.04.021

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

Oncology

Research output: Contribution to journal › Article

779 Scopus citations

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	https://doi.org/10.1016/j.ccr.2014.04.021
State	Published - Jun 16 2014

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ASJC Scopus subject areas

Oncology
Cell Biology
Cancer Research

Cite this

Rhim, A. D., Oberstein, P. E., Thomas, D. H., Mirek, E. T., Palermo, C. F., Sastra, S. A., Dekleva, E. N., Saunders, T., Becerra, C. P., Tattersall, I. W., Westphalen, C. B., Kitajewski, J., Fernandez-Barrena, M. G., Fernandez-Zapico, M. E., Iacobuzio-Donahue, C., Olive, K. P., & 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 journal › Article

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, 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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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.",

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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.

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AU - Stanger, Ben Z.

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10.1016/j.ccr.2014.04.021