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Research ArticleExperimental Studies

Antitumor Activity of TGF-β, Inhibitor is Dependent on the Microenvironment

SATYANARAYANA MEDICHERLA, LINGYUN LI, JING YING MA, ANN M. KAPOUN, NICHOLAS J. GASPAR, YU-WANG LIU, RUBAN MANGADU, GILBERT O'YOUNG, ANDREW A. PROTTER, GEORGE F. SCHREINER, DARREN H. WONG and LINDA S. HIGGINS
Anticancer Research November 2007, 27 (6B) 4149-4157;
SATYANARAYANA MEDICHERLA
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  • For correspondence: satya.medicherla@spcorp.com
LINGYUN LI
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JING YING MA
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ANN M. KAPOUN
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NICHOLAS J. GASPAR
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YU-WANG LIU
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RUBAN MANGADU
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GILBERT O'YOUNG
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ANDREW A. PROTTER
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GEORGE F. SCHREINER
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DARREN H. WONG
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LINDA S. HIGGINS
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Abstract

Pancreatic cancer is one of the deadliest forms of cancer and effective treatment remains a clinical challenge. Transforming growth factor-beta (TGF-β) has important roles in primary tumor progression and in promoting metastasis, and has become an attractive target for therapy. Previously, we reported that treatment of pancreatic cancer cells in vitro with SD-208, a small molecule inhibitor of the TGF-β receptor I kinase (TGF-βRI), inhibited expression of genes associated with tumor progression and inhibited invasiveness in a cell-based assay. In a demonstration of efficacy of TGF-β signaling inhibition in an in vivo model of pancreatic cancer, we showed significantly reduced primary tumor weight and decreased incidence of metastasis in the Panc-1 orthotopic xenograft model of established pancreatic cancer. In this report, we extend these in vivo findings to examine the mechanistic consequences of TGF-βRI inhibition on Panc-1 primary tumors and their microenvironment in situ. In a longitudinal study of TGF-βRI inhibition in the Panc-1 orthotopic model, we show that SD-208 treatment significantly reduced tumor growth measured as bioluminescence intensity throughout the study. Histological evaluation revealed that SD-208 treatment reduced proliferation and induced apoptosis in the primary tumors, and reduced fibrosis in the tumor microenvironment. An immune contribution (greater B-cell infiltration in SD-208-treated tumors) was also suggested by the histological analyses. SD-208 not only blocked direct TGF-β signaling in Panc-1 primary tumors (reduced phospho SMAD2/3), but also down-regulated the expression of TGF-β-regulated genes (PAI-1 and COL7A1). Taken together, our results indicate that a TGF-βRI kinase inhibitor has a potential therapeutic benefit for pancreatic cancer patients.

  • SD-208
  • gemcitabine
  • Smad
  • pancreatic cancer
  • primary tumor
  • metastasis

Footnotes

  • ↵* Both authors contributed equally to this work.

  • Received March 5, 2007.
  • Revision received August 20, 2007.
  • Accepted October 4, 2007.
  • Copyright© 2007 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
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Anticancer Research: 27 (6B)
Anticancer Research
Vol. 27, Issue 6B
November-December 2007
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Antitumor Activity of TGF-β, Inhibitor is Dependent on the Microenvironment
SATYANARAYANA MEDICHERLA, LINGYUN LI, JING YING MA, ANN M. KAPOUN, NICHOLAS J. GASPAR, YU-WANG LIU, RUBAN MANGADU, GILBERT O'YOUNG, ANDREW A. PROTTER, GEORGE F. SCHREINER, DARREN H. WONG, LINDA S. HIGGINS
Anticancer Research Nov 2007, 27 (6B) 4149-4157;

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Antitumor Activity of TGF-β, Inhibitor is Dependent on the Microenvironment
SATYANARAYANA MEDICHERLA, LINGYUN LI, JING YING MA, ANN M. KAPOUN, NICHOLAS J. GASPAR, YU-WANG LIU, RUBAN MANGADU, GILBERT O'YOUNG, ANDREW A. PROTTER, GEORGE F. SCHREINER, DARREN H. WONG, LINDA S. HIGGINS
Anticancer Research Nov 2007, 27 (6B) 4149-4157;
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