Tumour-derived extracellular vesicles in blood of metastatic cancer patients associate with overall survival

Nanou, Afroditi; Miller, Michael Craig; Zeune, Leonie L.; Wit, Sanne de; Punt, Cornelis J.A.; Groen, Harry J.M.; Hayes, Daniel F.; Bono, Johann S. de; Terstappen, Leon W.M.M.

doi:10.1038/s41416-019-0726-9

Cited by 61 publications

(74 citation statements)

References 65 publications

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“…As noted previously, B7-H3 may be a useful prognostic marker for MB patients [ 17 , 74 ]. Interestingly, various cancer models have shown that increased microvesicle and exosome shedding correlates with more aggressive neoplasms [ 75 , 76 , 77 , 78 ]. Since B7-H3 appears to increase exosomal production in D283 cells, further investigation into this relationship may lead to improved understanding of how valuable B7-H3 may be as a prognostic marker.…”

Section: Discussionmentioning

confidence: 99%

B7-H3 in Medulloblastoma-Derived Exosomes; A Novel Tumorigenic Role

Purvis

Velpula

Guda

et al. 2020

IJMS

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(1) Aim: Medulloblastoma is the most common aggressive pediatric cancer of the central nervous system. Improved therapies are necessary to improve life outcomes for medulloblastoma patients. Exosomes are a subset of extracellular vesicles that are excreted outside of the cell, and can transport nucleic acids and proteins from donor cells to nearby recipient cells of the same or dissimilar tissues. Few publications exist exploring the role that exosomes play in medulloblastoma pathogenesis. In this study, we found B7-H3, an immunosuppressive immune checkpoint, present in D283 cell-derived exosomes. (2) Methods: Utilizing mass spectrometry and immunoblotting, the presence of B7-H3 in D283 control and B7-H3 overexpressing exosomes was confirmed. Exosomes were isolated by Systems Biosciences from cultured cells as well as with an isolation kit that included ultracentrifugation steps. Overlay experiments were performed to determine mechanistic impact of exosomes on recipient cells by incubating isolated exosomes in serum-free media with target cells. Impact of D283 exosome incubation on endothelial and UW228 medulloblastoma cells was assessed by immunoblotting. Immunocytochemistry was employed to visualize exosome fusion with recipient cells. (3) Results: Overexpressing B7-H3 in D283 cells increases exosomal production and size distribution. Mass spectrometry revealed a host of novel, pathogenic molecules associated with B7-H3 in these exosomes including STAT3, CCL5, MMP9, and PI3K pathway molecules. Additionally, endothelial and UW228 cells incubated with D283-derived B7-H3-overexpressing exosomes induced B7-H3 expression while pSTAT1 levels decreased in UW228 cells. (4) Conclusions: In total, our results reveal a novel role in exosome production and packaging for B7-H3 that may contribute to medulloblastoma progression.

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Section: Discussionmentioning

confidence: 99%

B7-H3 in Medulloblastoma-Derived Exosomes; A Novel Tumorigenic Role

Purvis

Velpula

Guda

et al. 2020

IJMS

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“…Values are derived from the literature (5,7,11). The frequency of the large tumor-derived extracellular vesicles (ltdEVs, light green circle) determined in the Cancer-ID program and the small tdEVs (stdEVs, light green square) estimated using the frequency of ltdEVs (8)(9)(10).…”

Section: Cancer-id Specific Methods and Operating Principlementioning

confidence: 99%

“…By the use of affinity-based techniques using antibodies directed to antigens expressed on tumor cells but not on blood cells, we demonstrated the enrichment of large (>1 µm) EpCAM + tdEVs from blood from metastatic cancer patients (8,9). EVs from different origin were eliminated in the enriched sample.…”

Section: Cancer-id Insightsmentioning

confidence: 97%

“…Moreover, the concentration of larger lipoproteins, such as chylomicrons, depends on food intake, thereby emphasizing the need to discriminate EVs from other such particles. To illustrate this challenge, we determined that 1 ml of human blood of metastatic castration-resistant prostate cancer patients contains about 10 large (>1 µm) tdEVs (8,9), and we extrapolated this to encompass the small tdEVs to arrive at an estimated 10 4 tdEVs per 1 ml. Furthermore, the blood contains up to 10 16 lipoproteins, up to 10 9 platelets, and up to 10 11 other EVs (5,7,(10)(11)(12), see Figure 1.…”

Section: Introductionmentioning

confidence: 99%

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Cancer-ID: Toward Identification of Cancer by Tumor-Derived Extracellular Vesicles in Blood

et al. 2020

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Extracellular vesicles (EVs) have great potential as biomarkers since their composition and concentration in biofluids are disease state dependent and their cargo can contain disease-related information. Large tumor-derived EVs (tdEVs, >1 µm) in blood from cancer patients are associated with poor outcome, and changes in their number can be used to monitor therapy effectiveness. Whereas, small tumor-derived EVs (<1 µm) are likely to outnumber their larger counterparts, thereby offering better statistical significance, identification and quantification of small tdEVs are more challenging. In the blood of cancer patients, a subpopulation of EVs originate from tumor cells, but these EVs are outnumbered by non-EV particles and EVs from other origin. In the Dutch NWO Perspectief Cancer-ID program, we developed and evaluated detection and characterization techniques to distinguish EVs from non-EV particles and other EVs. Despite low signal amplitudes, we identified characteristics of these small tdEVs that may enable the enumeration of small tdEVs and extract relevant information. The insights obtained from Cancer-ID can help to explore the full potential of tdEVs in the clinic.

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“…Large tumor-derived extracellular vesicles (tdEVs) are co-isolated with CTCs and are present in an order of magnitude higher frequencies than CTCs [7,8]; thus, they can increase the number of "readable" patient samples for the assessment of therapeutic targets.…”

Section: Introductionmentioning

confidence: 99%

HER2 expression on tumor-derived extracellular vesicles and circulating tumor cells in metastatic breast cancer

et al. 2020

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Background: Tumor-derived extracellular vesicles (tdEVs) and circulating tumor cells (CTCs) in the blood of metastatic cancer patients associate with poor outcomes. In this study, we explored the human epidermal growth factor receptor 2 (HER2) expression on CTCs and tdEVs of metastatic breast cancer patients. Methods: Blood samples from 98 patients (CLCC-IC-2006-04 study) were originally processed with the CellSearch® system using the CTC kit and anti-HER2 as an additional marker in the staining cocktail. CTCs and tdEVs were automatically enumerated from the generated CellSearch images using the open-source ACCEPT software. Results: CTCs and tdEVs were subdivided based on their cytokeratin (CK) and HER2 phenotype into CK+HER2 −, CK−HER2+, and CK+HER2+. The inclusion of anti-HER2 increased the percentage of informative samples with ≥ 1 detectable CTC from 89 to 95%. CK− CTCs and tdEVs correlated equally well with the clinical outcome as CK+ CTCs and tdEVs. Inter-and intra-patient heterogeneity was found for the CTC/tdEV phenotypes, and the presence of 2 or 3 classes of CTCs/tdEVs was associated with worse prognosis compared to a uniform CTC/tdEV phenotype present (1 class). The use of ≥ 7% HER2+CK+ tdEVs can predict HER2 expression of the tissue with 74% sensitivity and specificity using the HER2 amplification status of the primary tumor as a classification variable. Conclusions: HER2 can be detected on CTCs and tdEVs not expressing CK, and these CK− CTCs/tdEVs have similar clinical relevance to CTCs and tdEVs expressing CK. tdEVs perform better than CTCs in predicting the HER2 status of the primary tissue. CTC and tdEV heterogeneity in the blood of patients is inversely associated with overall survival.

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Tumour-derived extracellular vesicles in blood of metastatic cancer patients associate with overall survival

Cited by 61 publications

References 65 publications

B7-H3 in Medulloblastoma-Derived Exosomes; A Novel Tumorigenic Role

B7-H3 in Medulloblastoma-Derived Exosomes; A Novel Tumorigenic Role

Cancer-ID: Toward Identification of Cancer by Tumor-Derived Extracellular Vesicles in Blood

HER2 expression on tumor-derived extracellular vesicles and circulating tumor cells in metastatic breast cancer

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