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

Lucy Ireland1, Almudena Santos1, Muhammad S Ahmed1

  • 1Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, United Kingdom.

Cancer Research
|October 16, 2016
PubMed

Insights

Tumor-associated macrophages and myofibroblasts promote pancreatic cancer chemoresistance by secreting insulin-like growth factors (IGF). Blocking IGF sensitizes tumors to chemotherapy, suggesting IGF inhibition as a potential therapeutic strategy.

Area of Science:

  • Oncology
  • Cancer Biology
  • Molecular Medicine

Background:

  • Tumor-associated macrophages (TAM) and cancer-associated fibroblasts (CAF) are crucial in cancer progression and drug resistance.
  • Mechanisms linking TAM and CAF to chemoresistance in pancreatic ductal adenocarcinoma (PDAC) remain incompletely understood.

Purpose of the Study:

  • To elucidate the molecular mechanisms by which TAM and myofibroblasts mediate chemoresistance in pancreatic cancer.
  • To investigate the role of insulin-like growth factors (IGF) in this process.
  • To evaluate IGF blockade as a therapeutic strategy for PDAC.

Main Methods:

  • Immunohistochemical analysis of patient biopsies.
  • In vivo studies using mouse models.
  • Pharmacologic blockade of IGF signaling.

Main Results:

  • TAM and myofibroblasts secrete IGF-1 and IGF-2, activating insulin/IGF receptors on pancreatic cancer cells, thereby supporting chemoresistance.
  • Activated insulin/IGF receptors were found in 72% of PDAC patient tumors, correlating with CD163+ TAM infiltration.
  • Pharmacologic inhibition of IGF sensitized pancreatic tumors to gemcitabine chemotherapy in vivo.

Conclusions:

  • IGF secreted by TAM and myofibroblasts is a key mediator of chemoresistance in PDAC.
  • Combined inhibition of IGF and chemotherapy shows promise for PDAC treatment.
  • Insulin/IGF1R activation may serve as a predictive biomarker for patient selection in IGF-targeted therapies.

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