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Circulating small-sized endothelial microparticles as predictors of clinical outcome after chemotherapy for breast cancer: an exploratory analysis

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Abstract

Purpose

Therapeutic exploitation of angiogenesis in breast cancer has been limited by the lack of reliable biomarkers. Circulating small-sized endothelial microparticles (sEMP) are likely to play a significant role as messengers of angiogenesis. Higher levels of EMP have been observed in cancer patients, but their prognostic value in breast cancer is unknown. Our aim was to determine the value of circulating sEMP as a marker of response to chemotherapy in breast cancer.

Methods

We included patients with breast cancer treated with neoadjuvant or first-line chemotherapy. Baseline and post-treatment circulating sEMP (CD144+) were quantified using a flow cytometer approach specifically designed for analysis of small-sized particles (0.1–0.5 μm). Small-sized EMP response was defined as a post-treatment decrease of sEMP larger than the median decrease of sEMP after chemotherapy. Baseline and post-chemotherapy VEGFA levels were determined with ELISA.

Results

Forty-four breast cancer patients were included (19 with metastatic and 25 with locally advanced disease). Median levels of sEMP decreased after chemotherapy (P = 0.005). Response to chemotherapy showed a non-significant trend to associate with sEMP response (P = 0.056). A sEMP response was observed in 51% of patients and was associated with better overall survival (HR 0.18; 95% CI 0.04–0.87; P = 0.02) and progression free survival (HR 0.30; 95% CI 0.09–0.99; P = 0.04) in the group of women with metastatic disease. Post-chemotherapy decrease of VEGFA levels was not associated with breast cancer prognosis.

Conclusions

Our results did not support sEMP as a marker of response to chemotherapy. However, our exploratory analysis suggests that in patients with metastatic breast cancer, the decrease of sEMP levels after chemotherapy is associated with better overall and disease free survival and might be superior to VEGFA levels as an angiogenesis-related prognostic marker.

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Abbreviations

BC:

Breast cancer

CT:

Chemotherapy

HR:

Hormonal receptors

LABC:

Locally advanced breast cancer

MBC:

Metastatic breast cancer

MP:

Microparticles

MV:

Extracellular microvesicles

sEMP:

Small-sized endothelial microparticles

TNBC:

Triple negative breast cancer

VEGFA:

Vascular and endothelial growth factor A

References

  1. Miles DW, Diéras V, Cortés J et al (2013) First-line bevacizumab in combination with chemotherapy for HER2-negative metastatic breast cancer: pooled and subgroup analyses of data from 2447 patients. Ann Oncol 24:2773–2780

    Article  CAS  PubMed  Google Scholar 

  2. Ghosh S, Sullivan CAW, Zerkowski MP et al (2008) High levels of vascular endothelial growth factor and its receptors (VEGFR-1, VEGFR-2, neuropilin-1) are associated with worse outcome in breast cancer. Hum Pathol 39:1835–1843

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Berns EMJJ, Klijn JGM, Look MP et al (2003) Combined vascular endothelial growth factor and TP53 status predicts poor response to tamoxifen therapy in estrogen receptor-positive advanced breast cancer. Clin Cancer Res 9:1253–1258

    CAS  PubMed  Google Scholar 

  4. Foekens JA, Peters HA, Grebenchtchikov N et al (2001) High tumor levels of vascular endothelial growth factor predict poor response to systemic therapy in advanced breast cancer. Cancer Res 61:5407–5414

    CAS  PubMed  Google Scholar 

  5. Lissoni P, Rovelli F, Malugani F et al (2003) Changes in circulating VEGF levels in relation to clinical response during chemotherapy for metastatic cancer. Int J Biol Markers 18:152–155

    Article  CAS  PubMed  Google Scholar 

  6. dos Santos LV, Cruz MR, de Lopes G, Lima JP (2015) VEGF-A levels in bevacizumab-treated breast cancer patients: a systematic review and meta-analysis. Breast Cancer Res Treat 151:481–489

    Article  PubMed  Google Scholar 

  7. Al-Nedawi K, Rak J, D’Asti E et al (2011) Microvesicles as mediators of intercellular communication in cancer—the emerging science of cellular “debris”. Semin Immunopathol 33:455–467

    Article  PubMed  Google Scholar 

  8. Lozito TP, Tuan RS (2014) Endothelial and cancer cells interact with mesenchymal stem cells via both microparticles and secreted factors. J Cell Mol Med 18:2372–2384

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Piccin A, Murphy WG, Smith OP (2007) Circulating microparticles: pathophysiology and clinical implications. Blood Rev 21:157–171

    Article  CAS  PubMed  Google Scholar 

  10. Orozco AF, Lewis DE (2010) Flow cytometric analysis of circulating microparticles in plasma. Cytometry A 77:502–514

    Article  PubMed  PubMed Central  Google Scholar 

  11. Melo SA, Luecke LB, Kahlert C et al (2015) Glypican-1 identifies cancer exosomes and detects early pancreatic cancer. Nature 523:177–182

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Valenti R, Huber V, Iero M et al (2007) Tumor-released microvesicles as vehicles of immunosuppression. Cancer Res 67:2912–2915

    Article  CAS  PubMed  Google Scholar 

  13. Martinez MC, Andriantsitohaina R (2011) Microparticles in Angiogenesis: therapeutic Potential. Circ Res 109:110–119

    Article  CAS  PubMed  Google Scholar 

  14. Ribeiro MF, Zhu H, Millard RW, Fan G-C (2013) Exosomes function in pro- and anti-angiogenesis. Curr Angiogenes 2:54–59

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Taraboletti G, D’Ascenzo S, Borsotti P et al (2002) Shedding of the matrix metalloproteinases MMP-2, MMP-9, and MT1-MMP as membrane vesicle-associated components by endothelial cells. Am J Pathol 160:673–680

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Janowska-Wieczorek A, Marquez-Curtis LA, Wysoczynski M, Ratajczak MZ (2006) Enhancing effect of platelet-derived microvesicles on the invasive potential of breast cancer cells. Transfusion 46:1199–1209

    Article  PubMed  Google Scholar 

  17. Millimaggi D, Mari M, D’Ascenzo S et al (2007) Tumor vesicle-associated CD147 modulates the angiogenic capability of endothelial cells. Neoplasia 9:349–357

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Hoyer FF, Nickenig G, Werner N (2010) Microparticles–messengers of biological information. J Cell Mol Med 14:2250–2256

    Article  PubMed  PubMed Central  Google Scholar 

  19. Sheremata WA, Jy W, Delgado S et al (2006) Interferon-beta1a reduces plasma CD31 + endothelial microparticles (CD31 + EMP) in multiple sclerosis. J Neuroinflammation 3:23

    Article  PubMed  PubMed Central  Google Scholar 

  20. Montoro-García S, Shantsila E, Tapp LD et al (2013) Small-size circulating microparticles in acute coronary syndromes: relevance to fibrinolytic status, reparative markers and outcomes. Atherosclerosis 227:313–322

    Article  PubMed  Google Scholar 

  21. Tseng C-C, Wang C-C, Chang H-C et al (2013) Levels of circulating microparticles in lung cancer patients and possible prognostic value. Dis Markers 35:301–310

    Article  PubMed  PubMed Central  Google Scholar 

  22. Laresche C, Pelletier F, Garnache-Ottou F et al (2013) Increased levels of circulating microparticles are associated with increased procoagulant activity in patients with cutaneous malignant melanoma. J Invest Dermatol 134:176–182

    Article  PubMed  Google Scholar 

  23. Wang C-C, Tseng C-C, Hsiao C-C et al (2014) Circulating endothelial-derived activated microparticle: a useful biomarker for predicting 1-year mortality in patients with advanced non-small cell lung cancer. Biomed Res Int 2014:173401

    PubMed  PubMed Central  Google Scholar 

  24. Campello E, Spiezia L, Radu CM et al (2011) Endothelial, platelet, and tissue factor-bearing microparticles in cancer patients with and without venous thromboembolism. Thromb Res 127:473–477

    Article  CAS  PubMed  Google Scholar 

  25. Toth B, Nieuwland R, Liebhardt S et al (2008) Circulating microparticles in breast cancer patients: a comparative analysis with established biomarkers. Anticancer Res 28:1107–1112

    CAS  PubMed  Google Scholar 

  26. Eisenhauer EA, Therasse P, Bogaerts J et al (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45:228–247

    Article  CAS  PubMed  Google Scholar 

  27. McShane LM, Altman DG, Sauerbrei W et al (2006) REporting recommendations for tumor MARKer prognostic studies (REMARK). Breast Cancer Res Treat 100:229–235

    Article  PubMed  Google Scholar 

  28. Montoro-García S, Shantsila E, Orenes-Piñero E et al (2012) An innovative flow cytometric approach for small-size platelet microparticles: influence of calcium. Thromb Haemost 108:373–383

    Article  PubMed  Google Scholar 

  29. Aharon A, Sabbah A, Ben-shaul S et al (2017) Chemotherapy administration to breast cancer patients affects extracellular vesicles thrombogenicity and function. Oncotarget 8:63265–63280

    Article  PubMed  PubMed Central  Google Scholar 

  30. Shantsila E, Montoro-García S, Gallego P, Lip GYH (2014) Circulating microparticles: challenges and perspectives of flow cytometric assessment. Thromb Haemost 111:1009–1014

    Article  CAS  PubMed  Google Scholar 

  31. Sabatier F, Camoin-Jau L, Anfosso F et al (2009) Circulating endothelial cells, microparticles and progenitors: key players towards the definition of vascular competence. J Cell Mol Med 13:454–471

    Article  CAS  PubMed  Google Scholar 

  32. Lechner D, Kollars M, Gleiss A et al (2007) Chemotherapy-induced thrombin generation via procoagulant endothelial microparticles is independent of tissue factor activity. J Thromb Haemost 5:2445–2452

    Article  CAS  PubMed  Google Scholar 

  33. Bovy N, Blomme B, Frères P et al (2015) Endothelial exosomes contribute to the antitumor response during breast cancer neoadjuvant chemotherapy via microRNA transfer. Oncotarget 6:10253–10266

    Article  PubMed  PubMed Central  Google Scholar 

  34. Andre N, Cointe S, Barlogis V, Arnaud L et al (2015) Maintenance chemotherapy in children with aLL exerts metronomic-like thrombospondin-1 associated anti-endothelial effect. Oncotarget 6:23008–23014

    Article  PubMed  PubMed Central  Google Scholar 

  35. Tang J-H, Zhao J-H, Lu J-W et al (2011) Circulating levels of angiogenic cytokines in advanced breast cancer patients with system chemotherapy and their potential value in monitoring disease course. J Cancer Res Clin Oncol 137:55–63

    Article  PubMed  Google Scholar 

  36. Munster M, Fremder E, Miller V et al (2014) Anti-VEGF-A affects the angiogenic properties of tumor-derived microparticles. PLoS ONE 9:e95983. https://doi.org/10.1371/journal.pone.0095983

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We acknowledge technical assistance by José A. López Oliva (Clinical Research Unit, Department of Hematology and Medical Oncology, Hospital Universitario Morales Meseguer) and Alberto Martínez (Biobancmur, Nodo 3, Hospital Universitario Morales Meseguer, IMIB Arrixaca). This work was partially funded by “Calasparra se mueve,” a research-funding initiative inspired by women from Calasparra (Murcia), Spain. SMG was supported by the People Program (Marie Curie Actions) of the European Union’s Seventh Framework Program (FP7/2007-2013) under REA Grant Agreement No. 608765.

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Authors and Affiliations

  1. Servicio de Hematología y Oncología Médica, Hospital Universitario Morales Meseguer, Avda. Marqués de los Velez, s/n, 30008, Murcia, Spain

    Elisa García Garre, Ginés Luengo Gil, Enrique Gonzalez Billalabeitia, Marta Zafra Poves, Elena García Martinez, Vanessa Roldán Schilling, Esther Navarro Manzano, Alejandra Ivars Rubio & Francisco Ayala de la Peña

  2. Instituto Murciano de Investigación Biosanitaria (IMIB-Arrixaca), Murcia, Spain

    Elisa García Garre, Ginés Luengo Gil, Enrique Gonzalez Billalabeitia, Marta Zafra Poves, Elena García Martinez, Vanessa Roldán Schilling, Esther Navarro Manzano, Alejandra Ivars Rubio & Francisco Ayala de la Peña

  3. Universidad de Murcia, Murcia, Spain

    Ginés Luengo Gil, Vanessa Roldán Schilling, Esther Navarro Manzano & Francisco Ayala de la Peña

  4. Universidad Católica San Antonio de Murcia, Guadalupe, Murcia, Spain

    Silvia Montoro García, Enrique Gonzalez Billalabeitia & Elena García Martinez

  5. Institute of Cardiovascular Sciences, University of Birmingham, Birmingham, UK

    Silvia Montoro García & Gregory Y. H. Lip

Authors
  1. Elisa García Garre
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  2. Ginés Luengo Gil
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  3. Silvia Montoro García
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  4. Enrique Gonzalez Billalabeitia
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  5. Marta Zafra Poves
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  6. Elena García Martinez
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  7. Vanessa Roldán Schilling
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  8. Esther Navarro Manzano
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  10. Gregory Y. H. Lip
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  11. Francisco Ayala de la Peña
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Corresponding author

Correspondence to Francisco Ayala de la Peña.

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The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in this study were in accordance with the ethical standards of the institution and with the 1964 Helsinki declaration and its later amendments.

Informed consent

Informed consent was obtained from all individual participants included in the study and the Institutional Review Board of Hospital Morales Meseguer approved the study.

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García Garre, E., Luengo Gil, G., Montoro García, S. et al. Circulating small-sized endothelial microparticles as predictors of clinical outcome after chemotherapy for breast cancer: an exploratory analysis. Breast Cancer Res Treat 169, 83–92 (2018). https://doi.org/10.1007/s10549-017-4656-z

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  • DOI: https://doi.org/10.1007/s10549-017-4656-z

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