Late release of circulating endothelial cells and endothelial progenitor cells after chemotherapy predicts response and survival in cancer patients

Abstract

We and others have previously demonstrated that the acute release of progenitor cells in response to chemotherapy actually reduces the efficacy of the chemotherapy. Here, we take these data further and investigate the clinical relevance of circulating endothelial (progenitor) cells (CE(P)Cs) and modulatory cytokines in patients after chemotherapy with relation to progression-free and overall survival (PFS/OS). Patients treated with various chemotherapeutics were included. Blood sampling was performed at baseline, 4 hours, and 7 and 21 days after chemotherapy. The mononuclear cell fraction was analyzed for CE(P)C by FACS analysis. Plasma was analyzed for cytokines by ELISA or Luminex technique. CE(P)Cs were correlated with response and PFS/OS using Cox proportional hazard regression analysis. We measured CE(P)Cs and cytokines in 71 patients. Only patients treated with paclitaxel showed an immediate increase in endothelial progenitor cell 4 hours after start of treatment. These immediate changes did not correlate with response or survival. After 7 and 21 days of chemotherapy, a large and consistent increase in CE(P)C was found (P < .01), independent of the type of chemotherapy. Changes in CE(P)C levels at day 7 correlated with an increase in tumor volume after three cycles of chemotherapy and predicted PFS/OS, regardless of the tumor type or chemotherapy. These findings indicate that the late release of CE(P)C is a common phenomenon after chemotherapeutic treatment. The correlation with a clinical response and survival provides further support for the biologic relevance of these cells in patients' prognosis and stresses their possible use as a therapeutic target.

Figure 1

Kinetics of CECs, EPCs, and growth factors during the first cycle of chemotherapy. Overall, a significant increase was seen in CECs (A), EPCs (B), G-CSF (C), and SDF-1α (D) (n = 71, P < .01). The increase in CECs (E) and EPCs (F) seems also present in patients treated with adjuvant chemotherapy (n = 9, P = .08 and P = .18).

Figure 2

Significant correlation between the changes in CECs (A) and EPCs (B) 7 days after chemotherapy and the percent tumor shrinkage according to RECIST. n = 53, Pearson R = 0.5 and 0.4, respectively (P < .01). CEC levels, but not EPC levels, after 7 and 21 days discriminated between patients with PD (n = 5) and SD/PR (P <.05) (C and D).

Figure 3

PFS (upper panels) and OS (lower panels) of 33 patients by CECs (A) and EPCs (B) levels 7 days after chemotherapy individually and combined into three groups (C): (1) low CEC and low EPC levels, (2) either low CEC or low EPC levels, and (3) both high CEC and EPC levels.