Discrimination between Circulating Endothelial Cells and Blood Cell Populations with Overlapping Phenotype Reveals Distinct Regulation and Predictive Potential in Cancer Therapy

Abstract

Flow cytometric CEC analysis based on CD45, CD31, and CD146 requires careful discrimination between blood cell populations with overlapping phenotype showing hallmarks of activated T cells and large platelets. However, these three cell populations show distinct regulation during cancer therapy, and their concomitant analysis may offer extended prognostic and predictive information.

Circulating endothelial cells and tumor blood volume as predictors in lung cancer

“…Apart from a possible deviation caused by the limited number of cases, this is probably due to the fact that effective antiangiogenic therapy also increases aCEC through “vasculature normalization” separately from decreasing aCEC by suppression of EPC mobilization and induction of aCEC apoptosis, which renders aCEC to be kept stable or slightly increased in the SD and PR patients. However, the “window” of vasculature normalization is only 1–2 weeks after antiangiogenic therapy, after which it turns into vascular insufficiency induced by suppression of tumor angiogenesis . These two effects of antiangiogenesis could alternate during therapy leading to CEC fluctuation and a gradual decline along with tumor shrinkage and decreasing circulating TAF after effective prolonged therapy, resulting in the inverse correlation between ∆aCEC and either PFS or BV in the present study, which also suggests a need for multiple inspections of CEC during therapy.…”

“…(41) Because endothelial cells in tumoral vasculature are more vulnerable to damage by antiangiogenic agents and are easy to shed, both endothelial retraction ⁄ apoptosis and tumor vasculature shrinkage might simultaneously induce endothelial cells to shed from the blood vessel walls, allowing for easier penetration by chemotherapeutic agents. (34) In the present study, to eliminate possible disturbance from transient elevation of aCECs caused by chemotherapeutic or antiangiogenic drugs, (38,42) the blood samples were obtained after completion of the previous therapeutic cycle and prior to the beginning of next therapeutic cycle until completion of therapy (other than three blood samples drawn in another trial (17) ) in order to obtain the 'dynamic tendency' and confirmed terminal data of aCECs during therapy. The results showed aCEC increased on tumor progression, especially in the single NP arm, but did not increase or slightly increased in SD and PR, which showed a tumor response.…”

Flow cytometric analysis of circulating endothelial cells and endothelial progenitors for clinical purposes in oncology: A critical evaluation

“…Since CECs are rare events, their precise quantification in peripheral blood (PB) samples requires a technically rigorous analytical approach, which should take many factors into consideration (8). Several pre-analytical and analytical steps significantly affect not only the quantification of CECs, but can also result in a change in the definition of these cells, leading to problems in the interpretation of the results (Table I) and in their potential association with clinical endpoints (Table II) (16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34).…”

“…In many previous studies, CECs are identified as those positive for a nuclear binding fluorochrome, negative for the leukocyte marker, cluster of differentiation (CD)45, and positive for CD31 and CD146 (25,28,(30)(31)(32)(33)(34). Previously, the expression of CD109, a cell surface glycoprotein which has been shown to be overexpressed in tumor endothelial cells, has been utilized to identify a specific subpopulation of CECs potentially useful as a prognostic marker in specific tumor types (35).…”

The association of blood angioregulatory microRNA levels with circulating endothelial cells and angiogenic proteins in patients receiving dacarbazine and interferon

“…Several clinical trials have associated changes in CEC with outcome to anti-angiogenic treatments. Increases in CEC were associated with clinical benefit in studies in renal [2], pancreatic [3], and breast cancers [4] and gastrointestinal stromal tumor [5]. In patients with solid tumors randomized to anti-angiogenic drug combinations, CEC were lower in patients without clinical benefit; of note, levels of VEGF did not differ in these patients [6].…”