Recombinant human endostatin normalizes tumor vasculature and enhances radiation response in xenografted human nasopharyngeal carcinoma models

PLoS One. 2012;7(4):e34646. doi: 10.1371/journal.pone.0034646. Epub 2012 Apr 9.


Background: Hypoxic tumor cells can reduce the efficacy of radiation. Antiangiogenic therapy may transiently "normalize" the tumor vasculature to make it more efficient for oxygen delivery. The aim of this study is to investigate whether the recombinant human endostatin (endostar) can create a "vascular normalization window" to alleviate hypoxia and enhance the inhibitory effects of radiation therapy in human nasopharyngeal carcinoma (NPC) in mice.

Methodology/principal findings: Transient changes in morphology of tumor vasculature and hypoxic tumor cell fraction in response to endostar were detected in mice bearing CNE-2 and 5-8F human NPC xenografts. Various treatment schedules were tested to assess the influence of endostar on the effect of radiation therapy. Several important factors relevant to the angiogenesis were identified through immunohistochemical staining. During endostar treatment, tumor vascularity decreased, while the basement membrane and pericyte coverage associated with endothelial cells increased, which supported the idea of vessel normalization. Hypoxic tumor cell fraction also decreased after the treatment. The transient modulation of tumor physiology caused by endostar improved the effect of radiation treatment compared with other treatment schedules. The expressions of vascular endothelial growth factor (VEGF), matrix metalloproteinase-2 (MMP-2), MMP-9, and MMP-14 decreased, while the level of pigment epithelium-derived factor (PEDF) increased.

Conclusions: Endostar normalized tumor vasculature, which alleviated hypoxia and significantly sensitized the function of radiation in anti-tumor in human NPC. The results provide an important experimental basis for combining endostar with radiation therapy in human NPC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenesis Inhibitors / therapeutic use*
  • Animals
  • Basement Membrane / metabolism
  • Carcinoma
  • Cell Line, Tumor
  • Endostatins / therapeutic use*
  • Eye Proteins / biosynthesis
  • Humans
  • Immunohistochemistry
  • Male
  • Matrix Metalloproteinase 14 / biosynthesis
  • Matrix Metalloproteinase 2 / biosynthesis
  • Mice
  • Mice, Nude
  • Nasopharyngeal Carcinoma
  • Nasopharyngeal Neoplasms / blood supply*
  • Nasopharyngeal Neoplasms / radiotherapy
  • Neovascularization, Pathologic / drug therapy*
  • Nerve Growth Factors / biosynthesis
  • Pericytes / metabolism
  • Radiation Tolerance*
  • Radiotherapy, Adjuvant
  • Recombinant Proteins
  • Serpins / biosynthesis
  • Vascular Endothelial Growth Factor A / biosynthesis
  • Xenograft Model Antitumor Assays


  • Angiogenesis Inhibitors
  • Endostatins
  • Eye Proteins
  • Nerve Growth Factors
  • Recombinant Proteins
  • Serpins
  • Vascular Endothelial Growth Factor A
  • pigment epithelium-derived factor
  • MMP2 protein, human
  • Matrix Metalloproteinase 2
  • MMP14 protein, human
  • Matrix Metalloproteinase 14
  • endostar protein