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Year : 2019  |  Volume : 32  |  Issue : 3  |  Page : 770-776

Role of circulating endothelial progenitor cells in patients with breast cancer

1 Department of Clinical Pathology, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Department of General Surgery, Faculty of Medicine, Menoufia University, Menoufia, Egypt
3 Department of Clinical Pathology, Ministry of Health, Birkit El-Saba, Menoufia, Egypt

Date of Submission24-Oct-2017
Date of Acceptance13-Dec-2017
Date of Web Publication17-Oct-2019

Correspondence Address:
Asmaa S Abo El-Yazeed
Department of Clinical Pathology, Ministry of Health, Birkit El-Saba, Menoufia 32651
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/mmj.mmj_727_17

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The aim was to assess the role of the circulating endothelial progenitor cells (CEPCs) in stages of breast cancer (BC) in patients.
Materials and Methods
We reviewed papers on the relation between CEPCs and stages of BC from Medline databases (PubMed, Medscape, Science Direct, and EMF-Portal) and all materials available on the internet from 1994 to 2016. The initial search presented 100 articles, of which, 30 met the inclusion criteria. The articles studied the relation between endothelial progenitor cells and stages of BC. If the studies did not fulfill the inclusion criteria, they were excluded. Study quality assessment included whether ethical approval was gained, eligibility criteria specified, appropriate controls, adequate information, and defined assessment measures. Comparisons were made by structured review with the results tabulated.
Endothelial progenitor cells counts were significantly higher in advanced stages of BC compared with those with early stages and controls in almost all the studied publications.
Our review concludes CEPCs elevation in the blood of patients is a useful marker of tumor angiogenesis and progression and early predictor of metastasis in patients with BC.

Keywords: breast neoplasms, endothelial progenitor cells, neovascularization

How to cite this article:
Montaser LM, Sonbol AA, EL-Gammal AS, Abo El-Yazeed AS. Role of circulating endothelial progenitor cells in patients with breast cancer. Menoufia Med J 2019;32:770-6

How to cite this URL:
Montaser LM, Sonbol AA, EL-Gammal AS, Abo El-Yazeed AS. Role of circulating endothelial progenitor cells in patients with breast cancer. Menoufia Med J [serial online] 2019 [cited 2020 May 27];32:770-6. Available from: http://www.mmj.eg.net/text.asp?2019/32/3/770/268838

  Introduction Top

Cancer is a group of diseases that change cells in the body and grow out of control. Most types of cancer cells form a lump or mass called a tumor [1].

Breast cancer (BC) is considered the leading cause of death related to cancers among females. Many factors affect the behavior of tumor cells and their response to the treatment, so prognosis of BC becomes a serious problem [2].

Cancer is defined as abnormal cell growth and spread and that depend on neoangiogenesis (the formation of new blood vessels from pre-existing vasculature), which measured by circulating endothelial progenitor cells (CEPCs). Their counts reflect the progression of the tumor [3].

Endothelial progenitor cells (EPCs) in peripheral blood samples of patients with BC could correlate to extent of the disease [4].

Two sources of endothelial cells are migration and co-option of pre-existing vascular walls or recruitment of EPCs from the bone marrow [5].

EPCs could be identified by specific cell-surface markers, which include CD133, CD14, and vascular endothelial growth factor receptor 2 (VEGFR2) by flow cytometry [6].

Metastasis is defined as the spread of a cancer from one organ to another without being directly connected with it and caused by angiogenesis. When tumor cells metastasize, the new tumor is called a secondary or metastatic tumor, and its cells are similar to those in the original or primary tumor [7].

BC has been associated with an increase in the number of circulating EPCs. Tumors produce growth factors that modulate angiogenesis such as VEGF that recruits EPCs from bone marrow or activates tumor-resident EPCs [8].

Poor BC prognosis has been related to increased microvascular density or production of proangiogenic factors, some of which have been used as therapeutic goals [9].

A large number of studies have been performed over the past 2 decades to assess the role of CEPCs in patients with BC. These studies found that there is a strong relation between CEPCs counts and stage of BC [10].

So this present review aims to focus on observations that levels of EPCs correlate with the extent of disease in patients with BC and that circulating levels of peripheral blood EPCs may serve as an indicator of tumor progression.

It also aims to collect and critically review the most recent results from laboratory studies on the effects of CEPCs on BC to provide information relevant for angiogenesis and advice for using CEPCs as target for therapy.

  Materials and Methods Top

Search strategy

Papers on the effect of CEPCs and its role in staging of BC in patients were reviewed from Medline databases (PubMed, Medscape, and Science Direct) and also materials available in the internet. The searching items were CEPCs, BC, and angiogenesis. In addition, we examined references from the specialist databases EMF-Portal (http://www.emf-portal.de) and reference lists in relevant publications. The search was performed in the electronic databases from 1994 to 2016.

Study selection

All the studies were independently assessed for inclusion. They were included if they fulfilled the following criteria:

  1. Published in English language
  2. Reports within national research programmer, letters/comments/editorials/news
  3. Published in peer-reviewed journals
  4. Focused on CEPCs in BC
  5. Discussed the relation among CEPCs, BC, and angiogenesis.

If a study had several publications on certain aspects, we used the latest publication giving the most relevant data.

Data extraction

If the studies did not fulfilled the aforementioned criteria, they were excluded, such as studies done on patients after surgery only or after chemotherapy only and not before and after, surveys included patients with secondary tumor in breast and not primary, and reports and studies not fulfilling the inclusion criteria.

Data from each eligible study were independently abstracted in duplicate using a data collection form to capture information on study characteristics, interventions, and quantitative results reported for each outcome of interest. Conclusion and comments on each study were made.

The analyzed publications were evaluated according to evidence-based medicine (EBM) criteria using the classification of the US Preventive Services Task Force and UK National Health Service protocol for EBM in addition to the evidence pyramid [Figure 1].
Figure 1: The pyramid of evidence-based medicine.

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US preventive services task force

The following is the classification of US Preventive Services Task Force:

  1. Level I: evidence obtained from at least one properly designed randomized controlled trial
  2. Level II-1: evidence obtained from well-designed controlled trials without randomization
  3. Level II-2: evidence obtained from well-designed cohort or case–control analytic studies, preferably from more than one center or research group
  4. Level II-3: evidence obtained from multiple time series with or without the intervention. Dramatic results in uncontrolled trials might also be regarded as this type of evidence
  5. Level III: pinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees.

UK national health service protocol

The UK national health service protocol is as follows:

  1. 1a: systematic reviews (with homogeneity) of randomized controlled trials
  2. 1b: individual randomized controlled trials (with narrow confidence interval)
  3. 1c: all or none randomized controlled trials
  4. 2a: systematic reviews (with homogeneity) of cohort studies
  5. 2b: individual cohort study or low-quality randomized controlled trials (e.g. <80% follow-up)
  6. 2c: 'outcomes' research; ecological studies
  7. 3a: systematic review (with homogeneity) of case–control studies
  8. 3b: individual case–control study
  9. 4: case series (and poor quality cohort and case–control studies)
  10. 5: expert opinion without explicit critical appraisal, or based on physiology, bench research or ' first principles'.

Quality assessment

The quality of all the studies was assessed. Important factors included study design, attainment of ethical approval, evidence of a power calculation, specified eligibility criteria, appropriate controls, adequate information, and specified assessment measures. It was expected that confounding factors would be reported and controlled for and appropriate data analysis made in addition to an explanation of missing data.

Data synthesis

A structured systematic review was performed with the results tabulated.

  Results Top

Study selection and characteristics

In total, 100 potentially relevant publications were identified, 70 articles were excluded as they did not meet our inclusion criteria. A total of 30 studies were included in the review as they were deemed eligible by fulfilling the inclusion criteria. All these studies were human, case–control studies and detected the role of CEPCs in different stages of BC. They were reviewed from Medline databases (PubMed, Medscape, and Science Direct). The studies were analyzed with respect to the study design using the classification of the US Preventive Services Task Force and UK National Health Service protocol for EBM. A structured systematic review was performed [Figure 2].
Figure 2: Flow chart of study selection.

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All of the included studies showed higher levels of CEPCs counts in different stages of BC [Table 1].
Table 1: Summary of studies showing the role of circulating endothelial progenitor cells in different stages of breast cancer in patients

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A total of 59 patients with invasive BC were included in a cohort study with level II-2 (level A) EBM criteria by Senchukova et al. [1] which showed that there was a strong relation between angiogenesis and CEPCs in different types of BC.

A total of 46 consecutive patients with histologically confirmed breast tumors were analyzed in a case–control study, which comes in Level II-2 (level B) of EBM criteria, by Brugger et al. [3], and the results showed increased detection rate of CEPCs in patients, with the highest probability being documented in patients with stage IV BC.

Peichev et al. [6] reported in a well-designed cohort study with level II-2 (level A) EBM criteria that the percentage of CEPCs may be modulated by pathophysiologic processes, such as tumor neoangiogenesis, especially in BC.

A randomized controlled trial, which comes in level I (level A), was conducted by Naik et al. [11] on 25 women with pathologically confirmed invasive BC, from whom a peripheral blood sample was taken for assaying counts of CEPCs before surgery. Results showed the median circulating EPC level in patients with stages III and IV BC was significantly higher than that those with stages I and II.

Additionally, Beerepoot et al. [12] quantified viable CEPCs from patients with cancer (95 patients) and healthy participants (46 patients) in a case–control study, which comes in level II-2 (level B) of EBM criteria, where whole blood positive staining for specific endothelial cell markers (i.e. von Willebrand factor, CD31, and VEGFR2) was used to confirm the endothelial phenotype. Results showed increased counts of CEPCs in patients with cancer with progressive disease. Patients with stable disease had CEPCs numbers similar to those of controls.

An additional evidence of increased EPCs in metastatic BC was given by Mancuso et al. [13] in a well-designed cohort study with level II-2 (level A) EBM criteria, which included healthy participants (n = 37) and patients with cancer (n = 78). CEPCs were higher in patients with cancer than healthy participants.

Goon et al. [14] studied 160 patients with BC and 63 age-matched controls free of BC in a case–control study with level II-2 EBM criteria measuring CEPCs (CD45/CD133+/CD34+) by flow cytometry. CEPCs were significantly higher in poor prognostic group compared with moderate and good prognostic groups and the cancer-free controls.

Mancuso et al. [15] conducted a study on 20 healthy controls and 76 newly diagnosed patients with cancer by means of flow cytometry in a case–control study with level II-2 EBM criteria, in which CEPCs were increased by five-fold in patients with cancer versus controls.

Patients (n = 41) with localized or metastatic BC who were not currently receiving treatment were eligible for a cohort study by Goodale et al. [16] with level II-2 (level A) EBM criteria. Peripheral blood was collected and analyzed by flow cytometry for CEPCs. Patients with metastatic BC demonstrated higher levels of CEPCs relative to patients with localized BC and normal donors, and levels of cells increased with disease stage.

Of seven case–control studies with level II-2 or (level B) EBM criteria, five studies [17],[18],[19],[20],[21] reported that there was increased level of CEPCs in patients with BC versus controls, whereas the other two studies [22],[23] reported the effect of chemotherapy on level of CEPCs in patients with BC.

The relation between CEPCs with different parameters in BC was discussed in seven human studies [Table 2]. The first three are case–control studies with level II-2 or (level B) EBM criteria. Gill et al. [5] found that CEPCs recruitment and mobilization was positively correlated with increased levels of angiogenic growth factors such as VEGF. Positive correlation between CEPCs and alkaline phosphatase in patients with BC was reported by Giuliano et al. [24]. Cheung et al. [7] found that the level of CEPCs had positive correlation with tumor markers between patients with BC and controls. Furstenberger et al. [25] showed that the level of CEPCs was significantly correlated with the size of the primary breast tissue tumor in a cohort study with level II-2 (level A) EBM criteria.
Table 2: The relation between circulating endothelial progenitor cells with different parameters in breast cancer

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However, two cohort studies with level II-2 or (level A) EBM criteria [26],[27] found no significant correlation among CEPCs level, stages of cancer, alkaline phosphatase, tumor markers, and the size of the primary breast.

Eight studies discussed CEPCs level in vascular insult in general included BC [Table 3]. Four cohort studies with level II-2 or (level A) EBM criteria and four cases–control study with level III EBM criteria. Four of these studies found that the highest CEPCs level was in BC [8],[9],[10],[28],[29]. Mallat et al. [2] found the highest level was in acute coronary syndrome. Gill et al. [5],[30] found that any vascular trauma induced mobilization of CEPCs.
Table 3: The relation of circulating endothelial progenitor cells level in vascular insult in general included breast cancer

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  Discussion Top

BC is a varied group of neoplasm that is characterized by irregular proliferation and growth of cells that appear malignant and related to breast tissue [28].

Early detection of BC micrometastasis can reduce its morbidity and mortality at the time of primary diagnosis. Because undetected micrometastasis can denote failure of primary treatment, their identification may have a considerable effect on prognosis and treatment choice for these patients. Thus, improved identification of these occult metastases in blood offers opportunity to enhance management of patients with BC [29].

Endothelial cell proliferation in the tumor vasculature has been studied to show evidence that the endothelial compartment is involved in tumor growth [17].

The aim of this review is the comparison between CEPCs level in stages of BC in patients, and this may provide evidence about the potential role of CEPCs in tumor progression.

To increase the CEPCs prognostic results, some literature studies have also done modifications. Giuliano et al. [24] measured CEPCs count before beginning a new line of systemic therapy in patients with advanced BC with metastatic site dissemination. Results showed that baseline CEPCs counts can be used as an early predictor of metastatic potential in patients with BC with limited metastatic spreading.

A study by Dong et al. [18] collected blood samples from patients with BC, who received 56 courses of systemic chemotherapy, and measured the CEPCs by flow cytometry within the 7 days before chemotherapy, twice a week during the first and second cycles of chemotherapy, and then once a week during the subsequent cycles. They found that the CEPCs counts changed dynamically during each course of chemotherapy and after the chemotherapy cycles, providing background data for any future study planning to use CEPCs as surrogate marker of angiogenesis in antiangiogenesis treatments combined with chemotherapy.

Additionally, the result of Botelho and Alves [19] showed a significant increase of CEPCs in the peripheral blood of patients with BC, and they attributed this to the recruitment of CEPCs by the tumor during cancer progression.

Circulating EPCs cannot be successfully defined with a single surface antigen, instead requiring the use of several markers (including VEGFR2, CD14, and CD133) for their detection in peripheral blood [30].

Most studies concerning the correlation of circulating EPCs with BC have used double-positive flow cytometry analysis (e.g. CD133/VEGFR2) [20].

Circulating EPCs (CD133/VEGFR2) were shown to be significantly more numerous in advanced BC than in early-stage disease [11].

The level of CEPCs was significantly higher in patients with BC when compared with controls. This is because of the production of CEPCs by BC tissue, which are then secreted in the blood. This result was supported by Dome et al. [21] and Goodale et al. [16], as they found that CEPCs were significantly higher in patients with BC than controls.

Moreover, CEPCs recruitment and mobilization had been positively correlated with increased levels of angiogenic growth factors such as VEGF [5]. Positive correlation between CEPCs and alkaline phosphatase in patients with BC was reported by Giuliano et al. [24]. Cheung et al. [7] found that the level of CEPCs had positive correlation with tumor markers between patients with BC and controls. Furstenberger et al. [25] showed that the level of CEPCs was significantly correlated with the size of the primary breast tissue tumor.

Recent studies suggest that account of circulating EPCs in patients may be useful in expecting the outcome of therapy or disease course. Studies in mice indicate that the amount of circulating EPCs is affected by systemic exposure to angiogenic regulators such as VEGF and can decrease in response to antiangiogenic therapy such as anti-VEGFR2 antibody therapy [22]. Chemotherapeutic drug response can be measured in part by the level of EPCs in circulation. Thus, measurement of circulating EPCs may provide a useful assessment of disease response to therapies [23].

However, Su et al. [26] claimed a questionable role for CEPCs in cancer for detection angiogenesis, progression, and treatment response, demanding more evidence to verify its efficacy. They found that high circulating EPCs correlated with poor overall survival regardless of the staging of cancer, and EPCs levels rapidly declined after excision of the tumor.

Additionally, Werner et al. [27] claimed that EPCs are markers of repair not damage, as the number and function of EPCs associated inversely with cardiovascular risk factors.

  Conclusion Top

CEPCs appeared to be effective in the staging, prognosis, and angiogenesis of patients with BC and can be used as a useful marker for prognosis. Further research on CEPCs may provide a vital source of information in the understanding of tumor biology. More studies are required concerning the phenotype and enumeration of these cells to better define their exact role in clinical oncology. The study recommends that studying the biology of CEPCs is essential and ultimately will lead to the development and utilization of CEPCs as a powerful diagnostic, therapeutic, and prognostic tool in a wide variety of diseases.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

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  [Figure 1], [Figure 2]

  [Table 1], [Table 2], [Table 3]


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