Neoadjuvant Treatment of Colorectal Cancer with Bevacizumab: The Perioperative Angiogenic Balance Is Sensitive to Systemic Thrombospondin-1 Levels

Abstract

Purpose: Colorectal cancer patients receiving neoadjuvant treatment with bevacizumab, a monoclonal antibody neutralizing vascular endothelial growth factor (VEGF), may suffer from wound healing complications after surgery as the antibody persists in patient blood. We characterized the systemic angiogenic balance in the perioperative period to evaluate its effect on physiologic angiogenesis. Experimental Design: Nineteen patients receiving combination chemotherapy and bevacizumab for six neoadjuvant cycles were compared with 14 patients receiving chemotherapy without bevacizumab. Plasma from perioperative days −1, +1, +7, and +21 was analyzed for VEGF, thrombospondin-1 (TSP-1), and PD-ECGF concentrations. The angiogenic capacity was further tested in an in vitro assay of endothelial cell proliferation and migration. Results: On day +1, the onset of wound healing was reflected in a change of balance, i.e., an increase of proangiogenic factors VEGF and platelet-derived endothelial cell growth factor compared with low TSP-1 inhibitor levels in both treatment groups. Patients with bevacizumab therapy showed significantly higher blood levels of total VEGF throughout the evaluation period. However, most VEGF molecules were inactive, i.e., complexed with antibody. Nevertheless, the capacity to stimulate endothelial growth was higher for these plasma samples and was reflected in low TSP-1 levels and an altered TSP-1 sensitivity. When purified TSP-1 protein was added, plasma samples of the bevacizumab but not the chemotherapy group showed reduced endothelial growth. Conclusions: Feedback mechanisms of bevacizumab therapy are not restricted to VEGF expression but seem to involve additional factors, such as TSP-1, which influences the systemic angiogenic balance and permits endothelial growth.

Intracellular bevacizumab reduces phagocytotic uptake in RPE cells

“…The reduction of proliferation cannot be translated into wound healing, as we do not see any significant differences between either VEGF antagonisttreated and untreated cells. In a scratch wound-healing assay with endothelial cells treated with the serum of bevacizumab treated patients, no inhibition of wound healing could be seen, either, corresponding well to our findings [22]. RPE cells are reported to close wounds in vitro rather by single cell migration of elongated RPE cells [23,24] than by proliferation, which would be a logical explanation as to why the impairment of proliferation is of no consequence for wound healing.…”

Predictive model of thrombospondin-1 and vascular endothelial growth factor in breast tumor tissue

“…The model provides a quantitative and mechanistic description as to how this pro-angiogenic state occurs. Specifically, the predictions provide insight into why the absolute concentration of TSP1 can be significantly greater than VEGF, either in plasma or tumor tissue, 9 but may not be sufficient to inhibit angiogenesis.…”

“…9 Therefore, another means of increasing the efficacy of anti-angiogenic treatment may be to mimic the action of inhibitors of angiogenesis, while simultaneously inhibiting the promoters. For example, in a preclinical model of pancreatic cancer, altering the balance between pro- and anti-angiogenic factors was shown to modulate tumor growth.…”

Neoadjuvant bevacizumab persistently inactivates VEGF at the time of surgery despite preoperative cessation

“…Platelet-poor plasma was prepared as previously described (Brostjan et al , 2008; Starlinger et al , 2010b, 2011). Briefly, blood (10 ml) was drawn into prechilled CTAD tubes containing sodium citrate, theophylline, adenosine, and dipyridamole, was kept on ice and further processed within 30 min.…”