Polarization of tumor-associated macrophage is associated with tumor vascular normalization by endostatin.

Abstract

Vascular normalization is an emerging concept in cancer treatment, but its precise mechanisms are not completely understood. The polarization of tumor-associated macrophages (TAMs) is important in tumor angiogenesis and metastasis. However, little is known about the effect of anti-angiogenic agents on the polarization of tumor-associated macrophages. Therefore, we explore the changes of TAMs polarization in the development of tumor vascular normalization induced by endostatin. A murine xenograft model of lung cancer was treated with endostatin for 10 days. The morphology and function of tumor vasculature was examined using various techniques. Flow cytometry was carried out to assess the TAMs, and immunofluorescence was used to examine Tie-2-expressing monocytes (TEMs) in tumors. Levels of the histidine-rich glycoprotein (HRG) in tumors were measured by immunohistochemistry and Western blot. Tumor vessels became more normal and mature on day six in the endostatin-treated mice. During vascular normalization, the number of M2-like TAMs and TEMs in the tumors was significantly reduced, whereas the number of M1-like TAMs showed an increase on day six after endostatin treatment, although the latter was not statistically significant. The HRG in the tumors accumulated at an early stage after endostatin administration. The polarization of TAMs is associated with tumor vascular normalization induced by endostatin. These observations may be useful in the exploration of new strategies for anti-angiogenic treatment.