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

Ireland, L, Santos, A, Ahmed, MS ORCID: 0000-0001-6163-8102, Rainer, C, Nielsen, SR, Quaranta, V, Weyer-Czernilofsky, U, Engle, DD, Perez-Mancera, P, Coupland, SE ORCID: 0000-0002-1464-2069
et al (show 6 more authors) (2016) Chemoresistance in Pancreatic Cancer Is Driven by Stroma-Derived Insulin-Like Growth Factors. Cancer Research, 76 (23). pp. 6851-6863.

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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: Article
Uncontrolled Keywords: Cell Line, Tumor, Animals, Humans, Mice, Pancreatic Neoplasms, Somatomedins, Signal Transduction, Cell Proliferation
Depositing User: Symplectic Admin
Date Deposited: 09 Nov 2016 09:02
Last Modified: 19 Jan 2023 07:25
DOI: 10.1158/0008-5472.CAN-16-1201
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