Chemoresistance in pancreatic cancer is driven by stroma-derived insulin-like growth factors

Ireland, L., Santos, A., Ahmed, M. S., Rainer, C., Nielsen, S. R., Quaranta, V., Weyer-Czernilofsky, U., Engle, D. D., Perez-Mancera, P., Coupland, S. E., Taktak, A. F., Bogenrieder, T., Tuveson, D. A., Campbell, F., Schmid, M. C., Mielgo, A. (December 2016) Chemoresistance in pancreatic cancer is driven by stroma-derived insulin-like growth factors. Cancer Res, 76 (23). pp. 6851-6863. ISSN 1538-7445 (Electronic)0008-5472 (Linking)

URL: https://www.ncbi.nlm.nih.gov/pubmed/27742686
DOI: 10.1158/0008-5472.can-16-1201

Abstract

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 1 and 2 (IGF), which activate Insulin/IGF receptors on pancreatic cancer cells. Immunohistochemical analysis of biopsies from pancreatic cancer patients 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 pharmacological blockade of IGF sensitized pancreatic tumors to gemcitabine. These findings suggest that inhibition of IGF in combination with chemotherapy could benefit PDAC patients, and that insulin/IGF1R activation may be used to as a biomarker to identify patients for such therapeutic intervention.

Item Type: Paper
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > IGF
diseases & disorders > cancer > drugs and therapies > chemoresistance
diseases & disorders > cancer > drugs and therapies
diseases & disorders > cancer > cancer types > pancreatic cancer
CSHL Authors:
Communities: CSHL labs > Tuveson lab
Depositing User: Matt Covey
Date: 1 December 2016
Date Deposited: 27 Oct 2016 16:09
Last Modified: 21 Dec 2016 21:08
Related URLs:
URI: http://repository.cshl.edu/id/eprint/33821

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