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.
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.
Analysis of tumor-infiltrating lymphocytes (TIL) in primary human colorectal cancer (CRC) by in situ immunohistochemical staining supports the hypothesis that the adaptive immune response influences the course of human CRC. Specifically, high densities of TILs in the primary tumor are associated with good prognosis independent of other prognostic markers. However, the prognostic role of TILs in metastatic CRC lesions is unknown, as is their role in response or resistance to conventional chemotherapy. We analyzed the association of TIL densities at the invasive margin of CRC liver metastases with response to chemotherapy and progression-free survival in a set of 101 large section samples. High-resolution automated microscopy on complete tissue sections was used to objectively generate cell densities for CD3, CD8, granzyme B, or FOXP3 positive immune cells. A predictive scoring system using TIL densities was developed in a training set and tested successfully in an independent validation set. TIL densities at the invasive margin of liver metastases allowed the prediction of response to chemotherapy with a sensitivity of 79% and specificity of 100%. The association of high density values with longer progression-free survival under chemotherapy was statistically significant. Overall, these findings extend the impact of the local immune response on the clinical course from the primary tumor also to metastatic lesions. Because detailed quantification of TILs in metastatic lesions revealed a strong association with chemotherapy efficacy and prognosis, we suggest that the developed scoring system may be used as a predictive tool for response to chemotherapy in metastatic CRC. Cancer Res; 71(17); 5670-7. Ó2011 AACR.
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