Cancer Res. 2016 Dec 1;76(23):6851-6863.

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

Ireland L1, Santos A1, Ahmed MS1, Rainer C1, Nielsen SR1, Quaranta V1, Weyer-Czernilofsky U2, Engle DD3,4, Perez-Mancera PA1, Coupland SE1, Taktak A5, Bogenrieder T6,7, Tuveson DA3,4,8, Campbell F1, Schmid MC1, Mielgo A9.

1 Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, United Kingdom.
2 Pharmacology and Translational Research, Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria.
3 Cold Spring Harbor Laboratory, Cold Spring Harbor, New York.
4 Lustgarten Pancreatic Cancer Research Laboratory, Cold Spring Harbor, New York.
5 Department of Medical Physics and Clinical Engineering, Royal Liverpool University Hospital, Liverpool, United Kingdom.
6 Medicine and Translational Research, Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria.
7 Department of Urology, University Hospital Grosshadern, Ludwig-Maximilians-University, Munich, Germany.
8 Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York.
9 Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, United Kingdom. amielgo@liverpool.ac.uk.

 

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 (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. ©2016 AACR.

PMID: 27742686

 

Supplement 

Pancreatic cancer is one of the deadliest cancer types for which more effective therapies are urgently needed. The standard treatment for pancreatic cancer is chemotherapy, but unfortunately chemotherapy is not very effective and pancreatic cancer has one of the worse survival rates. A characteristic of pancreatic cancer is that it is surrounded by a variety of non-cancerous cells known as stromal cells which support pancreatic cancer progression in many different ways, including tumour growth, metastasis and resistance to therapies. However, the precise mechanisms by which stromal cells contribute to pancreatic cancer progression and resistance to chemotherapy is not completely understood. Tumor associated macrophages (TAM) and fibroblasts are the two most abundant stromal cells found in pancreatic tumors, thus in this study we aimed to gain a better understanding of how tumor associated macrophages and fibroblasts support resistance of pancreatic tumors to chemotherapy. 

We found that TAMs and fibroblasts directly support chemotherapy resistance of pancreatic cancer cells by secreting insulin-like growth factors 1 and 2 (IGF1 and IGF2). Stromal secreted IGF1 and IGF2 bind to IGF receptor 1 and Insulin receptor expressed on the membrane of pancreatic cancer cells and activate the AKT survival signalling pathway on pancreatic cancer cells making them resistant to chemotherapy. 

Analysis of biopsies from pancreatic cancer patients revealed that Insulin and IGF1 receptors are activated in 72% of the patients and this correlates with increase macrophage infiltration, suggesting that these patients could benefit from a combination treatment of IGF inhibitor and chemotherapy. Blockade of IGFs with two different IGF blocking antibodies, increased the response of pancreatic tumors to chemotherapy in pre-clinical pancreatic cancer models. 

In conclusion, our findings suggest that stroma-derived IGF1 and IGF2 can blunt the response to chemotherapy via an IGF-Insulin/IGF1R paracrine signaling axis, and provide the rationale for further evaluating the combination of chemotherapy with IGF inhibitors in pancreatic cancer treatment.

This study was supported by research groups from the University of Liverpool, Cold Spring Harbor Laboratory and Boehringer Ingelheim.

The study was funded by the Wellcome Trust, the Royal Society and North West Cancer Research.

 

 

Figure 1: Schematics depicting the role of stroma-derived IGFs in chemoresistance of pancreatic tumors.  Tumor associated macrophages and fibroblasts are the main sources of IGF1 and IGF2 in pancreatic tumors. IGF1 and IGF2 bind to and activate Insulin and IGF1 receptors expressed on pancreatic cancer cells, leading to chemoresistance of pancreatic cancer cells. Blockade of IGFs increases the response of pancreatic tumors to chemotherapy.