The accumulation of macrophages attenuates the effect of recombinant human endostatin on lung cancer

Abstract

BackgroundAlthough anti-angiogenic therapy is widely applied clinically, its efficacy has been less than expected. Screening for regulatory factors and sensitive indicators to define the effectiveness of these drugs is required. Through a retrospective study of clinical data, we found that patients with a higher peripheral monocyte-to-lymphocyte ratio (MLR) obtained less benefit from recombinant human endostatin (rhES, Endostar®), an anti-angiogenic drug, in lung cancer. Because MLR is positively correlated with macrophage count in tumors, this result suggests that macrophages may influence the effectiveness of rhES therapy in lung cancer.MethodsClinical data from 72 lung cancer patients treated with rhES were collected. Animal study, flow cytometry, immunofluorescence, enzyme-linked immunosorbent assay, Western blot analysis, and transwell migration assays were carried on Lewis lung carcinoma (LLC) cells, bone marrow-derived macrophages, macrophage cell line RAW264.7, and ANA-1 cells.ResultsClinical data showed that compared with the baseline MLR before rhES treatment, patients with progressive disease had higher MLRs than those of patients with partial response. Experimental results showed that more macrophages were recruited in the LLC tumors after rhES treatment and the majority of them displayed an M2-like phenotype. rhES aggravated hypoxia and the inflammatory response in the tumor microenvironment. Hypoxia promoted the expression of CCL2 by endothelial and fibroblast cells, which could induce macrophages recruitment, and increased levels of inflammatory cytokines (interleukin-4 [IL-4], IL-6, and IL-10) skewed macrophage polarization toward the M2-like phenotype. Hypoxia or inflammation cytokine-treated macrophages enhanced the progression of LLC in vitro and in vivo.ConclusionWe found rhES could aggravate hypoxia and the inflammatory response in the tumor microenvironment. These changes were favorable for macrophage accumulation, and skewed their polarization toward the M2-like phenotype which could help LLC to escape from the anti-angiogenic therapy. Thus, these data indicate the accumulation of macrophages in the tumor microenvironment may adversely affect the efficacy of rhES on lung cancer.

The targeting of endoglin on vascular endothelial cells affects the infiltration of M2 macrophages into the breast cancer microenvironment by modulating the interleukin-6 (IL-6) level

“…In Eng-IKO e mice, the phenomenon of initial inhibition followed by rebound of tumour growth was observed. The present study indicated that increased infiltration of CD206-positive M2 macrophages and that this increased infiltration might lead to failure of antiangiogenic therapy (33). Moreover, we found that the increased number of infiltrated M2 macrophages might be due to activation of the IL-6/JAK2/STAT3 signalling pathway in the tumour microenvironment.…”

New Angiogenic Regulators Produced by TAMs: Perspective for Targeting Tumor Angiogenesis

“…In LLC xenograft mice, endostatin inhibited tumor angiogenesis by reducing the number of CD31+ cells and VEGF expression, aggravated hypoxia, and increased levels of inflammatory cytokines (IL-4, IL-6, IL-10) in tumor and CCL2 expression in endothelial cells and fibroblasts [224]. Contradictory to above listed examples, the percentage of F4/80+ macrophages was increased significantly after the treatment with recombinant human endostatin [224].…”

“…In LLC xenograft mice, endostatin inhibited tumor angiogenesis by reducing the number of CD31+ cells and VEGF expression, aggravated hypoxia, and increased levels of inflammatory cytokines (IL-4, IL-6, IL-10) in tumor and CCL2 expression in endothelial cells and fibroblasts [224]. Contradictory to above listed examples, the percentage of F4/80+ macrophages was increased significantly after the treatment with recombinant human endostatin [224]. In patients with lung cancer treated with chemotherapy plus endostatin, a higher peripheral monocyte-to-lymphocyte ratio (MLR) was detected in patients who did not respond to the treatment (progressive disease) compared to the patients with partial regression [224].…”

Hypoxia Alters the Expression of CC Chemokines and CC Chemokine Receptors in a Tumor–A Literature Review

“…Chronic hypoxia has been reported to decrease the expression of this chemokine in glioma cells [154,155], HUVEC [156], monocytes and macrophages [144,157,158], and in uveal melanoma [159]. In contrast, it has also been reported to increase in breast cancer cells [142], cervical squamous carcinoma cells [46], hepatoma cells [160], in another study on HUVEC [161], dermal fibroblasts [162], Lewis lung carcinoma cells [163,164], multiple myeloma [165], primary mouse astrocytes [166], and vascular endothelial cells [167,168]. These discrepancies are associated with the complex regulation of expression of this chemokine in hypoxia.…”