Abstract
Tumor angiogenesis plays an essential role in carcinogenesis, cancer progression, and metastasis. Some studies indicate that lipoxins, endogenous anti-inflammatory lipid mediators, might be involved in tumor angiogenesis; however, the governing mechanisms are still unknown. In the present study, we examined the effects of exogenous lipoxin A(4) (LXA(4)) in mouse hepatocarcinoma cell line (H22) and H22-bearing mice model. It was found that in H22 cells, LXA(4) inhibited the production of vascular endothelial growth factor and reduced hypoxia-inducible factor-1 alpha level. In addition, its analogue, BML-111, blocked the expression of vascular endothelial growth factor in serum and tumor sections from H22-bearing mice. H&E staining and immunostaining with antibodies against CD34 revealed that BML-111 suppressed tumor-related angiogenesis in vivo, but LXA(4) could not influence the proliferation of primary cultured human umbilical vein endothelial cells. The tumor growth was also inhibited by BML-111. We also found that BML-111 enhanced the in situ apoptosis while inhibiting macrophage infiltration in tumor tissue. The results provide new evidence that LXA(4) suppresses the growth of transplanted H22 tumor in mice through inhibiting tumor-related angiogenesis.
Highlights
Tumor angiogenesis, the proliferation of blood vessel networks that penetrate into cancerous tissue, plays an essential role in carcinogenesis, cancer progression, and metastasis [1]
As the first family of endogenous “braking signals” in inflammation identified in vivo [5], LXs have been extensively studied preclinically in a growing list of inflammation-related disease models [6,7,8]
Because vascular endothelial growth factor (VEGF) is a well-known potent inducer of angiogenesis [12, 13], in this study, after confirming the expression of lipoxin A4 (LXA4) receptor in H22 cells by Western blotting, we first tested the effect of exogenous LXA4 on VEGF secretion in H22 cells
Summary
The proliferation of blood vessel networks that penetrate into cancerous tissue, plays an essential role in carcinogenesis, cancer progression, and metastasis [1]. The proangiogenic signals within tumors have been a focus of cancer research for several years, and targeting tumor vasculature represents a promising tool for cancer therapy [2]. In 1863, Rudolf Virchow described that cancer and inflammation were connected on the basis that tumors often arose at sites of chronic inflammation and inflammatory cells were present in biopsied samples from tumor [3]. Inflammation is believed to be a key feature of the environment within and around tumors. Note: Supplementary material for this article is available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).
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