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Recombinant human endostatin improves anti-tumor efficacy of paclitaxel by normalizing tumor vasculature in Lewis lung carcinoma

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Abstract

Purpose

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.

Methods

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).

Results

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.

Conclusion

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.

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Abbreviations

Rh-endostatin:

Recombinant human endostatin

NSCLC:

Non-small cell lung cancer

VEGF-A:

Vascular endothelial growth factor-A

TSP-1:

Thrombospondin-1

MVD:

Microvascular density

RT–PCR:

Reverse transcription polymerase chain reaction

Rgs5:

Regulator of G-protein signaling 5

PECAM-1:

Platelet/endothelial cell adhesion molecule-1

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Acknowledgments

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.

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Authors and Affiliations

  1. Medical Oncology Department of Jinling Hospital, Medical School of Nanjing University, 305 ZhongShan Eastern Road, Nanjing, 210002, People’s Republic of China

    Guichun Huang & Longbang Chen

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  1. Guichun Huang
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  2. Longbang Chen
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Correspondence to Longbang Chen.

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432_2010_770_MOESM1_ESM.tif

Masson’s trichrome staining of subcutaneous interstitial space. Collagen and red blood cells were indicated by white and black arrows, respectively. Scale bar, 50 µm

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Huang, G., Chen, L. Recombinant human endostatin improves anti-tumor efficacy of paclitaxel by normalizing tumor vasculature in Lewis lung carcinoma. J Cancer Res Clin Oncol 136, 1201–1211 (2010). https://doi.org/10.1007/s00432-010-0770-6

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  • DOI: https://doi.org/10.1007/s00432-010-0770-6

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