Recombinant Human Endostatin Normalizes Tumor Vasculature and Enhances Radiation Response in Xenografted Human Nasopharyngeal Carcinoma Models

Abstract

BackgroundHypoxic 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 FindingsTransient 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.ConclusionsEndostar 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.

Elevated expression of CD93 promotes angiogenesis and tumor growth in nasopharyngeal carcinoma

“…Xianlu Zhuo et al assessed Microvessel density (MVD) in 65 cases of clinical paraffin-embedded NPC tissues, and found that MVD was closely related to NPC progression as reflected by distant metastasis (P < 0.05) [8]. Fang Peng et al have found that anti-angiogenesis could normalize NPC vasculature and enhance radiation response [27]. Therefore, some mechanistic insights into angiogenesis are emerging.…”

MiR-200c Increases the Radiosensitivity of Non-Small-Cell Lung Cancer Cell Line A549 by Targeting VEGF-VEGFR2 Pathway

“…The paracrine/autocrine role of vascular endothelial growth factor (VEGF) by binding to its receptors is one important component of tumor microenvironment and its self regulation. Suppression of VEGF gene expression could enhance the radiosensitivity of cancer cells [4], [5]. And VEGFR2 is usually considered to mediate the main function attributed to VEGF.…”

Endostar enhances the antitumor effects of radiation by affecting energy metabolism and alleviating the tumor microenvironment in a Lewis lung carcinoma mouse model

“…During vascular normalization, treatment with paclitaxel was identified to exhibit a maximal effect on tumor growth inhibition (38). In addition, Endostar was demonstrated to normalize tumor vasculature, which alleviated hypoxia and significantly sensitized the antitumor function of radiation in human nasopharyngeal cancer (39). Based on energy metabolism, the present study investigated the underlying mechanism through which Endostar exhibits a radiosensitization effect.…”