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

Cancer Biol Ther. 2011 Aug 1;12(3):198-207. doi: 10.4161/cbt.12.3.15979. Epub 2011 Aug 1.

Abstract

Transforming Growth Factor-β (TGF-β) exerts cell type-specific and context-dependent effects. Understanding the intrinsic effects of TGF-β on cancer cells in pancreatic ductal adenocarcinoma (PDAC) is a prerequisite for rationalized clinical implementation of TGF-β targeting therapies. Since the tumor microenvironment can affect how cancer cell respond to TGF-β, we employed a novel three-dimensional (3D) culturing system to recapitulate stromal and extracellular matrix interactions. We show here that TGF-β stimulates growth of 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 TGF-β1 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 TGF-β 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 TGF-β 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzamides / pharmacology
  • Carcinoma, Pancreatic Ductal / drug therapy
  • Carcinoma, Pancreatic Ductal / metabolism*
  • Carcinoma, Pancreatic Ductal / pathology*
  • Cell Culture Techniques / methods*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cisplatin / pharmacology
  • Culture Media
  • Deoxycytidine / analogs & derivatives
  • Deoxycytidine / pharmacology
  • Dioxoles / pharmacology
  • Drug Resistance, Neoplasm
  • Epidermal Growth Factor / pharmacology
  • ErbB Receptors / antagonists & inhibitors
  • Erlotinib Hydrochloride
  • Extracellular Matrix / metabolism
  • Humans
  • Mice
  • Mice, Transgenic
  • Pancreatic Neoplasms / drug therapy
  • Pancreatic Neoplasms / metabolism*
  • Pancreatic Neoplasms / pathology*
  • Quinazolines / pharmacology
  • Receptors, Transforming Growth Factor beta / antagonists & inhibitors
  • Transforming Growth Factor beta / metabolism*
  • Transforming Growth Factor beta1 / pharmacology
  • Tumor Microenvironment

Substances

  • 4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide
  • Benzamides
  • Culture Media
  • Dioxoles
  • Quinazolines
  • Receptors, Transforming Growth Factor beta
  • Transforming Growth Factor beta
  • Transforming Growth Factor beta1
  • Deoxycytidine
  • Epidermal Growth Factor
  • gemcitabine
  • Erlotinib Hydrochloride
  • ErbB Receptors
  • Cisplatin