Increased numbers of small circulating endothelial cells in renal cell cancer patients treated with sunitinib

Abstract

Mature circulating endothelial cell (CEC) as well as endothelial progenitor populations may reflect the activity of anti-angiogenic agents on tumor neovasculature or even constitute a target for anti-angiogenic therapy. We investigated the behavior of CECs in parallel with hematopoietic progenitor cells (HPCs) in the blood of renal cell cancer patients during sunitinib treatment. We analyzed the kinetics of a specific population of small VEGFR2-expressing CECs (CD45 neg /CD34 bright ), HPCs (CD45 dim / CD34 bright ), and monocytes in the blood of 24 renal cell cancer (RCC) patients receiving 50 mg/day of the multitargeted VEGF inhibitor sunitinib, on a 4-week-on/2-weekoff schedule. Blood was taken before treatment (C1D1), on C1D14, C1D28, and on C2D1 before the start of cycle 2. Also plasma VEGF and erythropoietin (EPO) were determined. Remarkably, while CD34 bright HPCs and monocytes decreased during treatment, CD34bright CECs increased from 69 cells/ml (C1D1) to 180 cells/ml (C1D14; P = 0.001) and remained high on C1D28. All cell populations recovered to near pre-treatment levels on C2D1. Plasma VEGF and EPO levels were increased on C1D14 and partly normalized to pre-treatment levels on C2D1. In conclusion, opposite kinetics of two circulating CD34 bright cell populations, HPCs and small CECs, were observed in sunitinib-treated RCC patients. The increase in CECs is likely caused by sunitinib targeting of immature tumor vessels.

CD133+ circulating haematopoietic progenitor cells predict for response to sorafenib plus erlotinib in non-small cell lung cancer patients

“…Regarding the explanations for the lack of correlation between pre-treatment values or increases in CECs and response one can only speculate. Our finding of an increase in CECs in SO/ER or BV/ER, but not monotherapy erlotinib-treated patients is consistent with our earlier finding of a similar increase in renal cell cancer patients treated with the VEGFR -TKI sunitinib (Vroling et al, 2009). Therefore, the increase of this cell population is likely to be a pharmacodynamic marker for VEGF/VEGFR signalling-inhibitor therapy.…”

“…The cutoff value for CD133 positivity in HPCs was determined based on isotype control and was adjusted for every individual sample. CECs are CD34 bright , which are almost uniformly positive for VEGFR2, but lack both markers CD45 and CD133 as previously defined (Vroling et al, 2007(Vroling et al, , 2009 (Figure 1). …”

“…As described previously for renal cell cancer patients (Vroling et al, 2009), two distinct CD34 þ cell populations, which differ in the expression of the leucocyte marker CD45 and progenitor marker CD133, were identified in NSCLC patients. HPCs are the CD45 dim /CD34 bright cells, which are largely CD133 pos .…”

“…Blood from SO/ER-treated patients was collected in EDTA tubes and the circulating HPCs and CECs were measured using a fullblood flow cytometric method as previously described (Vroling et al, 2007(Vroling et al, , 2009. (CD133 þ ) HPCs were defined as CD34 bright / CD45 dim (and CD133 þ ) and CECs were defined as CD34 bright / CD45 neg and largely positive for VEGFR2.…”

Sunitinib‐induced changes in circulating endothelial cell‐related proteins in patients with metastatic renal cell cancer

“…Each patient signed a protocol-specific informed consent. Collection of data was part of three protocols, [16][17][18][19] which were approved by the medical ethics review boards of the institutes.…”