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Effects of recombinant human endostatin and its synergy with cisplatin on circulating endothelial cells and tumor vascular normalization in A549 xenograft murine model

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Abstract

Purpose

Endostatin can normalize the tumor vasculature to some extent. However, exact length of its time window and corresponding markers for tumor vascular normalization are needed to be explored.

Methods

The A549 lung adenocarcinoma xenograft murine model was treated with recombinant human endostatin (rh-endostatin) for 14 days. Cisplatin was combined in different schedules. The effects of rh-endostatin on circulating endothelial cells (CECs) by flow cytometry, tumor vasculature and angiogenesis-related factors by confocal microscope and immunohistochemistry, and anti-tumor efficacy of cytotoxic drugs were observed.

Results

The activated CECs (aCECs) were increased on day 7 and decreased on day 10, and apoptotic CECs were increased on day 10. Tumor vasculature was transiently normalized with increased collagen coverage, decreased vessel permeability, intratumoral hypoxia, and microvascular density from day 7 to 10 after rh-endostatin administration. Extracellular matrix metalloproteinase inducer, vascular endothelial growth factor, matrix metalloproteinase (MMP)-2, and MMP-9 were transiently decreased by rh-endostatin from day 4 to 10, whereas the opposite effects were observed with tissue inhibitors of matrix metalloproteinase (TIMP)-1 and TIMP-2. The maximal anti-tumor effects of cisplatin were observed on administration from day 5 to 9 after rh-endostatin initial administration.

Conclusions

Rh-endostatin could transiently normalize tumor vasculature, probably via regulation of both pro- and anti-angiogenesis factors. The synergistic efficacy of anti-angiogenesis and chemotherapy was found during “the normalization window”. CEC could be a feasible blood biomarker for defining “vascular normalization window” and providing the evidence to make an optimizing combination therapeutic schedule in human tumor.

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Abbreviations

Rh-endostatin:

Recombinant human endostatin

NSCLC:

Non-small-cell lung cancer

VEGF:

Vascular endothelial growth factor

MMP:

Matrix metalloproteinase

TIMP:

Tissue inhibitors of matrix metalloproteinase

EMMPRIN:

Extracellular matrix metalloproteinase inducer

PB:

Peripheral blood

FC:

Flow cytometry

CECs:

Circulating endothelial cells

aCECs:

Activated circulating endothelial cells

HIF-1α:

Hypoxia-inducible factor-1α

MVD:

Microvascular density

IFP:

Interstitial fluid pressure

EPCs:

Endothelial precursor cells

IOD:

Integrated optical density

ECM:

Extracellular matrix

TAF:

Tumor angiogenesis factor

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Acknowledgments

This work was supported by grants from Tianjin Science & Technology Project (No. 09ZCZDSF04400) and CSCO (Y-X2011-001).

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Authors and Affiliations

  1. Department of Thoracic Oncology, Key Laboratory of Cancer Prevention and Therapy, Lung Cancer Center of Tianjin, Cancer Hospital of Tianjin Medical University, Tianjin, China

    Na Li, Xiyin Wei, Ziliang Jin, Cuicui Zhang & Kai Li

  2. Department of Oncology, The People’s Hospital of Rushan, Weihai, 264500, Shandong Province, China

    Na Li

  3. Department of Cardiology, The People’s Hospital of Rushan, Weihai, 264500, Shandong Province, China

    Dawei Zheng

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  1. Na Li
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  2. Dawei Zheng
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  3. Xiyin Wei
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  4. Ziliang Jin
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  5. Cuicui Zhang
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  6. Kai Li
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Correspondence to Kai Li.

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Li, N., Zheng, D., Wei, X. et al. Effects of recombinant human endostatin and its synergy with cisplatin on circulating endothelial cells and tumor vascular normalization in A549 xenograft murine model. J Cancer Res Clin Oncol 138, 1131–1144 (2012). https://doi.org/10.1007/s00432-012-1189-z

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  • DOI: https://doi.org/10.1007/s00432-012-1189-z

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