CANCER-ASSOCIATED FIBROBLAST EXOSOMES REGULATE SURVIVAL AND PROLIFERATION OF PANCREATIC CANCER CELLS
By Katherine E. Richards, Ann E. Zeleniak, M. Fishel, Junmin Wu, Laurie E. Littlepage, R. Hill. Oncogene, 2016
641 citations recorded by the source corpus.
Cancer-associated fibroblasts (CAFs) comprise the majority of the tumor bulk of pancreatic ductal adenocarcinomas (PDACs). Current efforts to eradicate these tumors focus predominantly on targeting the proliferation of rapidly growing cancer epithelial cells. We know that this is largely ineffective with resistance arising in most tumors following exposure to chemotherapy. Despite the long-standing recognition of the prominence of CAFs in PDAC, the effect of chemotherapy on CAFs and how they may contribute to drug resistance in neighboring cancer cells is not well characterized. Here, we show that CAFs exposed to chemotherapy have an active role in regulating the survival and proliferation of cancer cells. We found that CAFs are intrinsically resistant to gemcitabine, the chemotherapeutic standard of care for PDAC. Further, CAFs exposed to gemcitabine significantly increase the release of extracellular vesicles called exosomes. These exosomes increased chemoresistance-inducing factor, Snail, in recipient epithelial cells and promote proliferation and drug resistance. Finally, treatment of gemcitabine-exposed CAFs with an inhibitor of exosome release, GW4869, significantly reduces survival in co-cultured epithelial cells, signifying an important role of CAF exosomes in chemotherapeutic drug resistance. Collectively, these findings show the potential for exosome inhibitors as treatment options alongside chemotherapy for overcoming PDAC chemoresistance.
Subfields: Cancer Research, Molecular Biology, Oncology
View Paper: https://www.semanticscholar.org/paper/69cf948ed0e28a6576b412550b4d9c0761a27932
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- Exosome-Based Cell-Cell Communication in the Tumor Microenvironment (2018, positive): “EMT is also modulated by CAF-derived exosomes containing miRs-21, −278e, and−143, influencing breast cancer cell phenotype and aggressiveness (Donnarumma et al., 2017).”
- Signaling pathways in cancer-associated fibroblasts and targeted therapy for cancer (2021, positive): “Cells can be directly cocultured and indirectly cocultured in Transwell chambers or conditioned medium (CM).(69,70) Indeed, we extended the two-dimensional (2D) culture of fibroblasts from oral precancerous lesions with the addition of Candida.”