Recombinant human endostatin improves anti-tumor efficacy of paclitaxel by normalizing tumor vasculature in Lewis lung carcinoma
- 417 Downloads
Normalization of the tumor vasculature and microenvironment by several angiogenesis inhibitors has been reported. Given that recombinant human endostatin (rh-endostatin) is also an endogenous angiogenesis inhibitor, a comprehensive evaluation of the effects of rh-endostatin on tumor vasculature and microenvironment and chemotherapy sensitivity would be favorable.
Multiple treatment schedules of the combination of rh-endostatin and paclitaxel were tested in Lewis lung carcinoma. Further, we monitored microvascular density, tumor hypoxic fraction, and collagen covered tumor vessels at three different time points following the treatment of rh-endostatin, as well as the transcription of angiogenesis related factors (vascular endothelial growth factor-A and thrombospondin-1) and vasculature markers (regulator of G-protein signaling 5 and platelet/endothelial cell adhesion molecule-1).
The anti-tumor efficacy of paclitaxel was significantly improved 7 days after the treatment of rh-endostatin. Tumor microvascular density was decreased by rh-endostatin, although it became even higher 7 days after termination of rh-endostatin. Non-necrotic hypoxic fraction was significantly reduced 7 days after treatment of rh-endostatin, accompanied with increased collagen covered tumor vessels and coverage of pericytes around endothelial cells. Rh-endostatin could transiently upregulate the transcription of thrombospondin-1 and modulate the imbalance between vascular endothelial growth factor-A and thrombospondin-1.
Rh-endostatin could normalize the tumor vasculature and microenvironment in Lewis lung carcinoma probably via modulation of the balance between vascular endothelial growth factor-A and thrombospondin-1. During the time of vascular normalization, paclitaxel treatment was found to have maximal effect on tumor growth delay.
KeywordsTumor microenvironment Vasculature normalization Recombinant human endostatin
Recombinant human endostatin
Non-small cell lung cancer
Vascular endothelial growth factor-A
Reverse transcription polymerase chain reaction
Regulator of G-protein signaling 5
Platelet/endothelial cell adhesion molecule-1
This work was supported by the National Natural Science Foundation of China (Grant No. 30872979). We are grateful to the technique support of immunohistochemistry of Pathology Department of Jinling Hospital.
Conflict of interest statement
- Sorensen AG, Batchelor TT, Zhang WT, Chen PJ, Yeo P, Wang M, Jennings D, Wen PY, Lahdenranta J, Ancukiewicz M, di Tomaso E, Duda DG, Jain RK (2009) A “vascular normalization index” as potential mechanistic biomarker to predict survival after a single dose of cediranib in recurrent glioblastoma patients. Cancer Res 69(13):5296–5300CrossRefPubMedGoogle Scholar
- Winkler F, Kozin SV, Tong RT, Chae SS, Booth MF, Garkavtsev I, Xu L, Hicklin DJ, Fukumura D, di Tomaso E, Munn LL, Jain RK (2004) Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: role of oxygenation, angiopoietin-1, and matrix metalloproteinases. Cancer Cell 6:553–563PubMedGoogle Scholar