Circulating Endothelial Cells and Circulating Progenitor Cells in Breast Cancer: Relationship to Endothelial Damage/Dysfunction/ Apoptosis, Clinicopathologic Factors, and the Nottingham Prognostic Index

Abstract

BACKGROUND AND METHODS: Abnormal circulating endothelial cell (CEC) and circulating progenitor cell (CPC) numbers are present in cancer, but their relationship with angiogenesis, apoptosis, vascular biology, and prognosis is unclear. We prospectively studied 160 patients with breast cancer and 63 age-matched controls free of breast cancer, measuring CECs (CD45−/CD146+/CD34+) and CPCs (CD45−/CD133+/CD34+) by flow cytometry and plasma markers of endothelial damage/dysfunction (von Willebrand factor), apoptosis (Fas/Fas-L) and angiogenesis (vascular endothelial growth factor [VEGF], angiogenin) by ELISA. These were compared with clinicopathophysiologic features and the Nottingham Prognostic Index (NPI). An additional blood sample was taken 6 to 8 weeks after surgery from 15 women to test the effect of tumor removal. RESULTS: CECs were significantly higher in the NPI poor prognostic group compared with moderate and good prognostic groups, and the cancer-free controls, whereas CPCs were lower in the poor prognosis group (both P < .05). Levels of von Willebrand factor, VEGF, angiogenin, and Fas-L (but not soluble Fas) were abnormal in breast cancer compared with controls (P < .05), with no relationship to prognosis groups. VEGF (P = .04) and angiogenin (P = .001) were markedly different after surgery. In multivariate analysis, vascular invasion (P < .05) and tumor size (P < .001) were independently associated with CECs. CPCs did not significantly associate with NPI in a linear regression model; age (P < .05) was a negative predictor, whereas Her-2 status (P < .05) positively predicted CPCs. After adjustment, no variable independently predicted CPC levels. CONCLUSIONS: CECs and CPCs demonstrate a strong relationship with NPI groups, but only CECs positively predict higher NPI scores and correlate with tumor invasiveness and size, possibly reflecting total tumor vascular volume.