Tumor refractoriness to endostatin anti-angiogenesis is associated with the recruitment of CD11b+Gr1+ myeloid cells and inflammatory cytokines
Aims and background. A major challenge in developing antiangiogenic therapies is tumor intrinsic refractoriness and the emergence of treatment-induced resistance. Recently, such resistance is considered to be associated with inflammatory changes in the tumor microenvironment. However, no information has been acquired about the effect of endostatin on tumor microenvironment in this field. We established two tumor models refractory to endostatin treatment and sought to determine the role of inflammatory changes in the development of tumor refractoriness to antiangiogenic therapy. Methods. Three xenograft tumor murine models were treated with low-dose endostatin or high-dose endostatin for 10 days. The effect of endostatin on tumor growth was observed, and tumors refractory to endostatin treatment were defined. Flow cytometry were carried out to assess the presence of CD11b+Gr1+ myeloid cells in the peripheral blood and in the tumor. Inflammatory cytokine levels in peripheral blood were measured using the enzyme-linked immunosorbent assay. The expression of NF-κB, versican and hypoxia-inducible factor-1α in the tumor was evaluated using immunohistochemistry. Results. LLC and B16F1 tumors were defined as animal models of refractoriness to endostatin treatment. CD11b+Gr1+ myeloid cells were inherently recruited into the peripheral blood and the tumor microenvironment in the LLC tumor-bearing mice, and levels of serum G-CSF and TNF-α were increased along with the progression of tumor growth. In the B16F1 tumor-bearing mice, CD11b+Gr1+ myeloid cells were acquiredly recruited by endostatin into the peripheral blood and the tumor microenvironment. Additionally, high levels of G-CSF and TNF-α in serum and high expression of NF-κB, versican and hypoxia-inducible factor-1α in tumor tissue were found in B16F1 tumor-bearing mice after endostatin administration. Conclusions. A tumor can grow inherently or acquiredly with refractoriness to endostatin treatment in vivo. Recruitment of CD11b+Gr1+ myeloid cells and inflammatory cytokines may play an important role in the development of tumor refractoriness to endostatin anti-angiogenesis.
Tumori 2013; 99(6): 723 - 733
Article Type: ORIGINAL RESEARCH ARTICLE
Hui Zhang, Zi Wang, Qian Peng, Yan-Yang Liu, Wei Zhang, Lu Wu, Xia Wang, Feng Luo
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