Abstract
BackgroundAngiopoietin-Tie2 and nitric oxide pathway is crucial in tumor angiogenesis and closely correlates with tumor development, growth, and metastasis. This study aimed to investigate the angiopoietin-Tie2 and nitric oxide signaling of the erythrocyte membrane in response to surgical trauma in head and neck cancer.MethodsWe prospectively enrolled the patients with histology-proven head and neck squamous cell carcinoma undergoing surgical resection of primary tumors at the medical center between August and November 2019. We measured the preoperative and postoperative levels of angiopoietin-1, angiopoietin-2 in plasma using enzyme-linked immunosorbent assays, nitric oxide in plasma using nitrate/nitrite colorimetric assays, and Tie2 phosphorylation in erythrocyte membrane using Western blotting.ResultsThe plasma angiopoietin-1 was downregulated from the median 971.3 pg/mL (interquartile range [IQR] 532.1–1569.3) to 417.9 (IQR 270.5–597.3) after tumor resection (p = 0.0020). Conversely, the plasma angiopoietin-2 was enhanced from 1173.6 pg/mL (IQR 977.7–1450.2) to 2353.7 (IQR 1352.4–2954.3) after surgery (p = 0.0021), with a concomitant increase in plasma nitric oxide level from 7.73 μM (IQR 5.39–10.06) to 10.50 (IQR 7.65–14.18) after surgical resection (p = 0.0093). Subgroup analyses further showed the angiopoietin-Tie2 and nitric oxide signaling was significant only in stage III and IV cancer.ConclusionsThe dynamic change of angiopoietin-Tie2 signaling in the erythrocyte membrane along with the enhanced nitric oxide in plasma after tumor resection suggests erythrocytes play a significant role in modulating surgery-induced angiogenesis, which may provide a novel marker for cancer surveillance and control.
Highlights
Angiopoietin-Tie2 and nitric oxide pathway is crucial in tumor angiogenesis and closely correlates with tumor development, growth, and metastasis
In head and neck squamous cell carcinoma (HNSCC), carcinogenesis is a two-step process featured by an initial precancerous lesion and the malignant transformation characterized by an angiogenic switch with an increase in neovascularization [2]
In this study, we found that surgical resection of the HNSCC tumors downregulated the plasma angiopoietin1 level and upregulated the plasma angiopoietin-2 in conjunction with an increase in plasma Nitric oxide (NO) level and reduced phosphorylation level of Tie2 in the erythrocyte membrane
Summary
Angiopoietin-Tie and nitric oxide pathway is crucial in tumor angiogenesis and closely correlates with tumor development, growth, and metastasis. This study aimed to investigate the angiopoietin-Tie and nitric oxide signaling of the erythrocyte membrane in response to surgical trauma in head and neck cancer. The angiopoietin-Tie signaling pathway is crucial in regulating tumor angiogenesis and closely linked to the development, progression, and metastasis of cancer cells [4,5,6]. Previous studies have showed that expression of angiopoietin-2 was significantly associated with angiogenesis and vessel maturation in oral squamous cell carcinoma (SCC) [6]. An experimental study demonstrated the distinct expressions of angiopoietin-1 and angiopoietin-2 in tumor samples of human oral SCC [9]. The dynamic changes of these angiogenic factors in the setting of tumor resection remains unclear
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