Depletion of Carcinoma-Associated Fibroblasts and Fibrosis Induces Immunosuppression and Accelerates Pancreas Cancer with Diminished Survival
By B. Özdemir, Tsvetelina Pentcheva-Hoang, Julienne L. Carstens, Xiaofeng Zheng, Chin-Chia Wu, T. Simpson, Hanane Laklai, H. Sugimoto, Christoph Kahlert, Sergey Novitskiy and 11 more. Cancer Cell, 2014
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Summary Pancreatic ductal adenocarcinoma (PDAC) is associated with marked fibrosis and stromal myofibroblasts but their functional contribution remains unknown. Transgenic mice with ability to delete αSMA+ myofibroblasts in pancreatic cancer were generated. Depletion starting at either non-invasive precursor (PanIN) 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, lower myofibroblasts in their tumors also correlated with reduced survival. Suppressed immune surveillance with increased CD4+Foxp3+ Tregs was observed in myofibroblasts depleted mouse tumors. While myofibroblasts 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.
View Paper: https://www.semanticscholar.org/paper/06a7c5569b9a10d5ec5e62ecaa9799069893fb50
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In Oncology
Citations in the corpus
- Fibroblast heterogeneity in the cancer wound (2014, result): “Similar results were obtained in another study, where depletion of cancer-associated myofibroblasts in a pancreatic cancer model led to more aggressive and less differentiated tumors (Özdemir et al., 2014).”
- Role of Extracellular Matrix in Development and Cancer Progression (2018, background): “Interestingly, however, depletion of fibrillar collagens I and III can also promote malignant behaviour, indicating that biomechanical forces produced by collagen deposition can have both beneficial and deleterious effects on tumour progression [136,137].”
- ANTIANGIOGENESIS STRATEGIES REVISITED: FROM STARVING TUMORS TO ALLEVIATING HYPOXIA (2014, neutral): “For example, a recent study utilized the genetic ablation of SMA+ cells to deplete stroma in desmoplastic pancreatic tumors (Özdemir et al., 2014).”