Summary
Exosomes are lipid bilayer-enclosed extracellular vesicles (EVs) that
contain proteins and nucleic acids. They are secreted by all cells and circulate
in the blood. Specific detection and isolation of cancer cell-derived exosomes
in circulation is currently lacking. Using mass spectrometry analyses, we
identified a cell surface proteoglycan, glypican-1 (GPC1), specifically enriched
on cancer cell-derived exosomes. GPC1+ circulating exosomes
(crExos) were monitored and isolated using flow cytometry from the serum of
cancer patients and mice with cancer. GPC1+ crExos were
detected in the serum of patients with pancreas cancer with absolute specificity
and sensitivity, distinguishing healthy subjects and patients with a benign
pancreas disease from patients with early and late stage pancreas cancer. Levels
of GPC1+ crExos correlate with tumor burden and survival in
patients pre- and post-surgical tumor resection. GPC1+ crExos
from patients and from mice with spontaneous pancreas tumors driven by oncogenic
KRAS contained RNA with specific KRAS mutation, and it emerges as a reliable
biomarker for the detection of PanIN lesions despite negative signal by MRI in
mice. GPC1+ crExos may serve as a potential non-invasive
diagnostic and screening tool to detect early stages of pancreas cancer to
facilitate possible curative surgical therapy.
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.
Background: Exosomes are small vesicles in the tumor microenvironment containing nucleic acids and proteins with the capacity to influence cell behavior. Results: Exosomes contain double-stranded genomic DNA. Conclusion: Exosomes have the capacity to carry and transport genomic DNA spanning all chromosomes with KRAS and p53 mutations. Significance: Exosomes can aid in identifying genomic mutations in patients with pancreatic cancer.
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