Chemoresistance in Pancreatic Cancer Is Driven by Stroma-Derived Insulin-Like Growth Factors

Tumor-associated macrophages (TAM) and myofibroblasts are key drivers in cancer that are associated with drug resistance in many cancers, including pancreatic ductal adenocarcinoma (PDAC). However, our understanding of the molecular mechanisms by which TAM and fibroblasts contribute to chemoresistan...

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Published inCancer research (Chicago, Ill.) Vol. 76; no. 23; pp. 6851 - 6863
Main Authors Ireland, Lucy, Santos, Almudena, Ahmed, Muhammad S, Rainer, Carolyn, Nielsen, Sebastian R, Quaranta, Valeria, Weyer-Czernilofsky, Ulrike, Engle, Danielle D, Perez-Mancera, Pedro A, Coupland, Sarah E, Taktak, Azzam, Bogenrieder, Thomas, Tuveson, David A, Campbell, Fiona, Schmid, Michael C, Mielgo, Ainhoa
Format Journal Article
LanguageEnglish
Published United States 01.12.2016
Subjects
Animals
Cell Line, Tumor
Cell Proliferation
Humans
Mice
Pancreatic Neoplasms - genetics
Pancreatic Neoplasms - pathology
Signal Transduction
Somatomedins - genetics
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Summary:Tumor-associated macrophages (TAM) and myofibroblasts are key drivers in cancer that are associated with drug resistance in many cancers, including pancreatic ductal adenocarcinoma (PDAC). However, our understanding of the molecular mechanisms by which TAM and fibroblasts contribute to chemoresistance is unclear. In this study, we found that TAM and myofibroblasts directly support chemoresistance of pancreatic cancer cells by secreting insulin-like growth factors (IGF) 1 and 2, which activate insulin/IGF receptors on pancreatic cancer cells. Immunohistochemical analysis of biopsies from patients with pancreatic cancer revealed that 72% of the patients expressed activated insulin/IGF receptors on tumor cells, and this positively correlates with increased CD163 TAM infiltration. In vivo, we found that TAM and myofibroblasts were the main sources of IGF production, and pharmacologic blockade of IGF sensitized pancreatic tumors to gemcitabine. These findings suggest that inhibition of IGF in combination with chemotherapy could benefit patients with PDAC, and that insulin/IGF1R activation may be used as a biomarker to identify patients for such therapeutic intervention. Cancer Res; 76(23); 6851-63. ©2016 AACR.
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ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.can-16-1201