Abstract

Background: The profile of CEC can potentially be a biomarker of angiogenesis. As angiogenesis is increased in patients with MM, we studied the CEC and their relationships to angiogenesis-related factors in the blood and disease activity.

Methods: We prospectively quantitated (CD45-/CD146+/CD31+) and characterized (apoptotic [annexin stain], activated [CD106]) the CEC in the whole blood of 20 patients with MM (7 untreated [4 newly diagnosed, 3 smoldering], 9 receiving therapy, and 4 treated previously) using four-color flow cytometry and compared the findings to those from 20 normal volunteers. In addition, we determined the associations between CEC and disease activity and the plasma levels of several angiogenesis-related factors (vascular endothelial growth factor [VEGF], fibroblast growth factor-2 [FGF-2], hepatocyte growth factor [HGF], and thrombospondin-1 [TSP-1]) pertinent to MM.

Results: The median level of CEC was higher (P<0.001) in MM patients (124.8 cells/mL [range, 15–572] versus 21.9 cells/mL [range, 4–66]). However, only 6 (30%) MM patients had levels that were greater than 3 standard deviations from the mean of normal. In general, more apoptotic CEC were present in MM patients (41.5% [range, 0–100] vs 25.9% [range, 0–57.1]; P=0.028), while activated CEC were similar in both groups. There were no significant associations between CEC levels and disease stage, disease status (progressive versus stable/responding), or serum monoclonal protein levels. MM patients had higher levels of HGF (1159 pg/mL [range, 628–5401] vs 524.5 pg/mL [range, 260–938]; P<0.001) but lower levels of TSP-1 (43.9 mcg/mL [range, 3.9–134.1] vs 66.5 mcg/mL [range, 6.4–214.4]; P=0.021), and FGF-2 (20 pg/mL [range, 0–52] vs 34.5 pg/mL [range, 8–82]; P=0.018) in the plasma. In the subgroup of MM patients with elevated CEC, VEGF level was significantly higher than control (211 pg/mL [range, 13–1156] vs 61 pg/mL [0–401]; P=0.012).

Conclusions: Increased levels of CEC can be detected in some patients with MM. In these patients, measurement of CEC may be useful as a biomarker of angiogenesis. As we did not find a significant association between CEC and disease activity, additional studies are necessary to determine the clinical significance of increased CEC in MM.

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