Circulating endothelial cells and angiogenic serum factors during neoadjuvant chemotherapy of primary breast cancer

Abstract

Circulating endothelial cells (CECs) as well as bone-marrow-derived endothelial precursor cells (EPC) play an important role in neovascularisation and tumour growth. To study the impact of neoadjuvant chemotherapy on the amounts of CEC and their precursor cells, mature CEC and their progenitors were quantified by flow cytometry in peripheral blood of breast cancer patients during anthracycline and/or taxane based neoadjuvant chemotherapy and subsequent surgery in comparison to age-matched healthy controls. Cell numbers were tested for correlation with serum levels of angiopoietin-2, erythropoietin, endostatin, endoglin, VEGF and sVCAM-1 as well as clinical and pathological features of breast cancer disease. Circulating endothelial cells were significantly elevated in breast cancer patients and decreased during chemotherapy, whereas EPC (CD34 þ /VEGFR-2 þ ) as well as their progenitor cell population CD133 þ /CD34 þ and the population of CD34 þ stem cells increased. Concomitantly with the increase of progenitor cells an increase of VEGF, erythropoietin and angiopoietin-2 was observed. These data suggest that chemotherapy can only reduce the amounts of mature CEC, probably reflecting detached cells from tumour vessels, whereas the EPC and their progenitors are mobilised by chemotherapy. Since this mobilisation of EPC may contribute to tumour neovascularisation an early antiangiogenic therapy in combination with chemotherapy could be beneficial for the success of cancer therapy.

Endothelial Progenitor Cells Significantly Contribute to Vasculatures in Human and Mouse Breast Tumors

“…Several other investigators have shown that exogenous G-CSF administration increases the levels of circulating EPCs, ECs, and angiogenesis in adult, tumor-free human subjects and mice [7,33,62], as well as the growth of fibrosarcoma, colon and lung cancers in animal models [63][64][65][66]. Similar to our results, Beerepoot et al [43] and Fürstenberger and coinvestigators [67] have also shown that the levels of circulating endothelial cells (CECs) are higher in breast cancer patients when compared to healthy subjects. Additionally, Beerpoot et al found that the levels of CECs in breast and other cancer patients with progressive disease correlated with levels of therapeutic G-CSF and chemotherapy, but not with the plasma levels of VEGF, SCF, or other cytokines and growth factors frequently reported to mobilize EPCs [4,7,41].…”

The relationship of the neo-angiogenic marker, endoglin, with response to neoadjuvant chemotherapy in breast cancer

“…For example, elevated levels of soluble CD105 have been found in the plasma of breast cancer patients when compared with normal controls, and particularly high levels have been linked with metastatic disease (Li et al, 2000a, b). Furstenberger et al (2006) recently looked at changes in serum levels of soluble angiogenesis-related factors in breast cancer patients receiving anthracycline or taxane-based neoadjuvant chemotherapy. Although there were no differences in baseline levels of soluble CD105 between patients and controls, they found that patients demonstrated significant decrease in circulating levels of soluble CD105 after two cycles of chemotherapy (Po0.01).…”

Mechanisms of Resistance to Anti-Angiogenic Therapy and Development of Third-Generation Anti-Angiogenic Drug Candidates

“…68 Consistent with their role in tissue regeneration, EPCs are also recruited when the tumor vasculature is destroyed by chemo/radiation therapy, both in preclinical models as well as in clinical studies. [69][70][71] 74 and why EPC levels rebound in glioblastoma patients during drugfree intervals of a pan-VEGF inhibitor. 25 In breast cancer patients during drug-free intervals after chemotherapy, EPCs increase similarly, concomitant with a rise of plasma VEGF and other pro-angiogenic cytokines.…”