[PDF][PDF] Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival

BC Özdemir, T Pentcheva-Hoang, JL Carstens… - Cancer cell, 2014 - cell.com
BC Özdemir, T Pentcheva-Hoang, JL Carstens, X Zheng, CC Wu, TR Simpson, H Laklai…
Cancer cell, 2014cell.com
Pancreatic ductal adenocarcinoma (PDAC) is associated with marked fibrosis and stromal
myofibroblasts, but their functional contribution remains unknown. Transgenic mice with the
ability to delete αSMA+ myofibroblasts in pancreatic cancer were generated. Depletion
starting at either noninvasive precursor (pancreatic intraepithelial neoplasia) or the PDAC
stage led to invasive, undifferentiated tumors with enhanced hypoxia, epithelial-to-
mesenchymal transition, and cancer stem cells, with diminished animal survival. In PDAC …
Summary
Pancreatic ductal adenocarcinoma (PDAC) is associated with marked fibrosis and stromal myofibroblasts, but their functional contribution remains unknown. Transgenic mice with the ability to delete αSMA+ myofibroblasts in pancreatic cancer were generated. Depletion starting at either noninvasive precursor (pancreatic intraepithelial neoplasia) or the PDAC stage led to invasive, undifferentiated tumors with enhanced hypoxia, epithelial-to-mesenchymal transition, and cancer stem cells, with diminished animal survival. In PDAC patients, fewer myofibroblasts in their tumors also correlated with reduced survival. Suppressed immune surveillance with increased CD4+Foxp3+ Tregs was observed in myofibroblast-depleted mouse tumors. Although myofibroblast-depleted tumors did not respond to gemcitabine, anti-CTLA4 immunotherapy reversed disease acceleration and prolonged animal survival. This study underscores the need for caution in targeting carcinoma-associated fibroblasts in PDAC.
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