A novel 3-dimensional culture system uncovers growth stimulatory actions by TGFβ in pancreatic cancer cells

Lorenzo F. Sempere, Jason R. Gunn, Murray Korc

Research output: Contribution to journalArticlepeer-review

39 Scopus citations

Abstract

Transforming Growth Factor-β (TGFβ) exerts cell type-specific and context-dependent effects. Understanding the intrinsic actions of TGFβ on cancer cells in pancreatic ductal adenocarcinoma (PDAC) is a prerequisite for rationalizing clinical implementation of TGFβ targeted therapies. Since the tumor microenvironment can affect how cancer cells respond to TGFβ, we employed a novel 3-dimensional (3D) culturing system to recapitulate stromal and extracellular matrix interactions. We show here that TGFβ stimulates the growth of several human and murine pancreatic cancer cell lines (PCCs) when embedded in a 3% collagen IV/laminin-rich gelatinous medium (Matrigel™) over a solidified layer of soft agar. Moreover, in this novel 3D model, concomitant treatment with TGFβ1 and epidermal growth factor (EGF) enhanced PCC growth to a greater extent than either growth factor alone and conferred increased chemoresistance to cytotoxic compounds. These cooperative growth-stimulatory effects were blocked by pharmacological inhibition of either the TGFβ type I receptor with SB431542 or the EGF receptor with erlotinib. Co-incubation with SB431542 and erlotinib enhanced the efficacy of gemcitabine and cisplatin in PCCs and in primary cell cultures established from pancreata of genetically-engineered mouse models of PDAC. These findings suggest that concomitant inhibition of TGFβ and EGF signaling may represent an effective therapeutic strategy in PDAC, and that this 3D culturing system could be utilized to test ex vivo the therapeutic response of pancreatic tumor biopsies from PDAC patients, thereby providing a functional assay to facilitate personalized targeted therapies.

Original languageEnglish (US)
Pages (from-to)198-207
Number of pages10
JournalCancer Biology and Therapy
Volume12
Issue number3
DOIs
StatePublished - Aug 1 2011

Keywords

  • Epidermal growth factor (EGF)
  • Extracellular matrix
  • Matrigel™
  • Pancreatic adenocarcinoma (PDAC)
  • Soft agar
  • Transforming growth factor-β (TGFβ)
  • Tumor microenvironment

ASJC Scopus subject areas

  • Molecular Medicine
  • Oncology
  • Pharmacology
  • Cancer Research

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