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

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Abstract

Background

Circulating tumour cells (CTCs) in blood associate with overall survival (OS) of cancer patients, but they are detected in extremely low numbers. Large tumour-derived extracellular vesicles (tdEVs) in castration-resistant prostate cancer (CRPC) patients are present at around 20 times higher frequencies than CTCs and have equivalent prognostic power. In this study, we explored the presence of tdEVs in other cancers and their association with OS.

Methods

The open-source ACCEPT software was used to automatically enumerate tdEVs in digitally stored CellSearch® images obtained from previously reported CTC studies evaluating OS in 190 CRPC, 450 metastatic colorectal cancer (mCRC), 179 metastatic breast cancer (MBC) and 137 non-small cell lung cancer (NSCLC) patients before the initiation of a new treatment.

Results

Presence of unfavourable CTCs and tdEVs is predictive of OS, with respective hazard ratios (HRs) of 2.4 and 2.2 in CRPC, 2.7 and 2.2 in MBC, 2.3 and 1.9 in mCRC and 2.0 and 2.4 in NSCLC, respectively.

Conclusions

tdEVs have equivalent prognostic value as CTCs in the investigated metastatic cancers. CRPC, mCRC, and MBC (but not NSCLC) patients with favourable CTC counts can be further prognostically stratified using tdEVs. Our data suggest that tdEVs could be used in clinical decision-making.

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Most cited references 41

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Tumor cells circulate in the peripheral blood of all major carcinomas but not in healthy subjects or patients with nonmalignant diseases.

W Jeffrey Allard, Jeri Matera, M. Craig Miller … (2004)

The purpose of this study was to determine the accuracy, precision, and linearity of the CellSearch system and evaluate the number of circulating tumor cells (CTCs) per 7.5 mL of blood in healthy subjects, patients with nonmalignant diseases, and patients with a variety of metastatic carcinomas. The CellSearch system was used to enumerate CTCs in 7.5 mL of blood. Blood samples spiked with cells from tumor cell lines were used to establish analytical accuracy, reproducibility, and linearity. Prevalence of CTCs was determined in blood from 199 patients with nonmalignant diseases, 964 patients with metastatic carcinomas, and 145 healthy donors. Enumeration of spiked tumor cells was linear over the range of 5 to 1,142 cells, with an average recovery of >/=85% at each spike level. Only 1 of the 344 (0.3%) healthy and nonmalignant disease subjects had >/=2 CTCs per 7.5 mL of blood. In 2,183 blood samples from 964 metastatic carcinoma patients, CTCs ranged from 0 to 23,618 CTCs per 7.5 mL (mean, 60 +/- 693 CTCs per 7.5 mL), and 36% (781 of 2,183) of the specimens had >/=2 CTCs. Detection of >/=2 CTCs occurred at the following rates: 57% (107 of 188) of prostate cancers, 37% (489 of 1,316) of breast cancers, 37% (20 of 53) of ovarian cancers, 30% (99 of 333) of colorectal cancers, 20% (34 of 168) of lung cancers, and 26% (32 of 125) of other cancers. The CellSearch system can be standardized across multiple laboratories and may be used to determine the clinical utility of CTCs. CTCs are extremely rare in healthy subjects and patients with nonmalignant diseases but present in various metastatic carcinomas with a wide range of frequencies.

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Circulating tumor cells predict survival benefit from treatment in metastatic castration-resistant prostate cancer.

Johann de Bono, Howard Scher, R. Montgomery … (2008)

A method for enumerating circulating tumor cells (CTC) has received regulatory clearance. The primary objective of this prospective study was to establish the relationship between posttreatment CTC count and overall survival (OS) in castration-resistant prostate cancer (CRPC). Secondary objectives included determining the prognostic utility of CTC measurement before initiating therapy, and the relationship of CTC to prostate-specific antigen (PSA) changes and OS at these and other time points. Blood was drawn from CRPC patients with progressive disease starting a new line of chemotherapy before treatment and monthly thereafter. Patients were stratified into predetermined Favorable or Unfavorable groups ( or =5 CTC/7.5mL). Two hundred thirty-one of 276 enrolled patients (84%) were evaluable. Patients with Unfavorable pretreatment CTC (57%) had shorter OS (median OS, 11.5 versus 21.7 months; Cox hazard ratio, 3.3; P 26 to 9.3 months). CTC are the most accurate and independent predictor of OS in CRPC. These data led to Food and Drug Administration clearance of this assay for the evaluation of CRPC.

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Extracellular vesicles in cancer: exosomes, microvesicles and the emerging role of large oncosomes.

Valentina R. Minciacchi, Michael R. Freeman, Dolores Di Vizio (2015)

Since their first description, extracellular vesicles (EVs) have been the topic of avid study in a variety of physiologic contexts and are now thought to play an important role in cancer. The state of knowledge on biogenesis, molecular content and horizontal communication of diverse types of cancer EVs has expanded considerably in recent years. As a consequence, a plethora of information about EV composition and molecular function has emerged, along with the notion that cancer cells rely on these particles to invade tissues and propagate oncogenic signals at distance. The number of in vivo studies, designed to achieve a deeper understanding of the extent to which EV biology can be applied to clinically relevant settings, is rapidly growing. This review summarizes recent studies on cancer-derived EV functions, with an overview about biogenesis and molecular cargo of exosomes, microvesicles and large oncosomes. We also discuss current challenges and emerging technologies that might improve EV detection in various biological systems. Further studies on the functional role of EVs in specific steps of cancer formation and progression will expand our understanding of the diversity of paracrine signaling mechanisms in malignant growth.

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Author and article information

Contributors

Afroditi Nanou: a.nanou@utwente.nl

Leon W. M. M. Terstappen: l.w.m.m.terstappen@utwente.nl

Journal

Journal ID (nlm-ta): Br J Cancer

Journal ID (iso-abbrev): Br. J. Cancer

Title: British Journal of Cancer

Publisher: Nature Publishing Group UK (London )

ISSN (Print): 0007-0920

ISSN (Electronic): 1532-1827

Publication date (Electronic): 15 January 2020

Publication date PMC-release: 15 January 2020

Publication date (Print): 17 March 2020

Volume: 122

Issue: 6

Pages: 801-811

Affiliations

[1 ]ISNI 0000 0004 0399 8953, GRID grid.6214.1, Department of Medical Cell BioPhysics, Faculty of Science and Technology, , University of Twente, ; Enschede, The Netherlands

[2 ]ClarifyDx Consulting, Quakertown, PA USA

[3 ]ISNI 0000000084992262, GRID grid.7177.6, Department of Medical Oncology, Academic Medical Center, , University of Amsterdam, ; Amsterdam, The Netherlands

[4 ]ISNI 0000 0000 9558 4598, GRID grid.4494.d, Department of Pulmonary Diseases, , University of Groningen and University Medical Centre of Groningen, ; Groningen, The Netherlands

[5 ]ISNI 0000000086837370, GRID grid.214458.e, Department of Internal Medicine, , University of Michigan Rogel Cancer Center, ; Ann Arbor, MI USA

[6 ]ISNI 0000 0001 0304 893X, GRID grid.5072.0, Prostate Cancer Targeted Therapy Group, , The Royal Marsden NHS Foundation Trust, ; London, UK

[7 ]ISNI 0000 0004 0417 0461, GRID grid.424926.f, Division of Clinical Studies, , The Institute of Cancer Research, Royal Marsden Hospital, ; London, UK

Article

Publisher ID: 726

DOI: 10.1038/s41416-019-0726-9

PMC ID: 7078322

PubMed ID: 31937922

SO-VID: 960c8f7d-86ef-4391-baf3-93fe4fe43267

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 19 September 2019

Date revision received : 17 December 2019

Date accepted : 19 December 2019

Funding

Funded by: NWO Applied and Engineering Science, Cancer ID project # 14190

Funded by: EUFP7 CTCTrap project #305341 and EU IMI CANCER-ID project #115749-1

Funded by: EMC funding, Movember

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ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: tumour biomarkers,fluorescence imaging,prognostic markers,metastasis

Data availability:

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: tumour biomarkers, fluorescence imaging, prognostic markers, metastasis

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

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Karger: Oncology

Most cited references 41

Tumor cells circulate in the peripheral blood of all major carcinomas but not in healthy subjects or patients with nonmalignant diseases.

Circulating tumor cells predict survival benefit from treatment in metastatic castration-resistant prostate cancer.

Extracellular vesicles in cancer: exosomes, microvesicles and the emerging role of large oncosomes.

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